- Departments & Programs
- Medical Library
- Clinical Trials
- Cancer Information
- Medical Education
Genetics of Colorectal Cancer (PDQ®)
- Colon Cancer Genes
- Genetic Polymorphisms and Colorectal Cancer Risk
- Major Genetic Syndromes
- Psychosocial Issues in Hereditary Colon Cancer Syndromes
- Changes to This Summary (02/28/2013)
- About This PDQ Summary
- Get More Information From NCI
Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.
Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women.
Estimated new cases and deaths from CRC in 2013:
- New cases: 142,820.
- Deaths: 50,830.
- Increased incidence of CRC among persons with a family history of CRC.
- Early onset of CRC, which is suggestive, but not always indicative, of heritability.
About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder. The remaining 25% of patients have a family history of CRC that suggests a hereditary contribution, common exposures among family members, or a combination of both. Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer–prone families; these mutations are estimated to account for only 5% to 6% of CRC cases overall. It is likely that other undiscovered genes and background genetic factors contribute to the development of familial CRC in conjunction with nongenetic risk factors.
(Refer to the PDQ summaries on Colorectal Cancer Screening; Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment for more information about sporadic CRC.)
Natural History of CRC
Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas).
Pathologists have classified the lesions into the following three groups:
- Nonneoplastic polyps (hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid polyps), which have not generally been thought of as precursors of cancer.
- Neoplastic polyps (adenomatous polyps, and adenomas).
Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.
Two complementary interpretations of this observation are as follows:
- The adenoma may reflect an innate or acquired tendency of the colon to form tumors.
- Adenomas are the primary precursor lesion of colon cancer.
More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that most CRCs arise from adenomas, adenocarcinomas are generally considered to arise from adenomas, based upon the following important observations:
- Benign and malignant tissue occur within colorectal tumors.
- When patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population.
The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:
- Larger size.
- Villous pathology.
- The degree of dysplasia within the adenoma.
In addition, removal of adenomatous polyps is associated with reduced CRC incidence. While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large, flat, and depressed lesions may be more likely to be severely dysplastic, although this remains to be clearly proven. Specialized techniques may be needed to identify, biopsy, and remove such lesions.
Molecular Events Associated With Colon Carcinogenesis
The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events. This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies. At least five to seven major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least two major pathways by which these molecular events can lead to CRC. While the majority of CRCs are due to events that result in chromosomal instability (CIN), 20% to 30% of CRCs display characteristic patterns of gene hypermethylation, termed CpG island methylator phenotype (CIMP), of which a portion display microsatellite instability (15% of CRCs).
The spectrum of somatic mutations contributing to the pathogenesis of CRC is likely to be far more extensive than previously appreciated. A comprehensive study that sequenced more than 13,000 genes in a series of CRCs found that tumors accumulate an average of approximately 90 mutant genes. Sixty-nine genes were highlighted as relevant to the pathogenesis of CRC, and individual CRCs harbored an average of nine mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature.
Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and frequent detectable losses at the molecular level of portions of chromosome 5q, chromosome 18q, and chromosome 17p; and mutation of the KRAS oncogene. The important genes involved in these chromosome losses are APC (5q), DCC/MADH2/MADH4 (18q), and TP53 (17p), and chromosome losses are associated with instability at the molecular and chromosomal level. Among the earliest events in the colorectal tumor progression pathway is loss of the APC gene, which appears to be consistent with its important role in predisposing persons with germline APC mutations to colorectal tumors. Acquired or inherited mutations of DNA damage-repair genes also play a role in predisposing colorectal epithelial cells to mutations. Furthermore, the specific genes that undergo somatic mutations and the specific type of mutations the tumor acquires may influence the rate of tumor growth or type of pathologic change in the tumors. For example, the rate of adenoma-to-carcinoma progression appears to be faster in microsatellite-unstable tumors compared with microsatellite-stable tumors. Characteristic histologic changes such as increased mucin production can be seen in tumors that demonstrate microsatellite instability (MSI), suggesting that at least some molecular events contribute to the histologic features of the tumors.
The key characteristics of MSI cancers are that they are tumors with a largely intact chromosome complement and that, as a result of defects in the DNA mismatch repair (MMR) system, they more readily acquire mutations in important cancer-associated genes compared with cells that have an effective DNA MMR system. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as DNA microsatellites.
The knowledge derived from the study of inherited CRC syndromes has provided important clues regarding the molecular events that mediate tumor initiation and tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APC gene product, which appears to be consistent with its important role in predisposing persons with germline APC mutations to colorectal tumors.
Family History as a Risk Factor for CRC
Some of the earliest studies of family history of CRC were those of Utah families that reported a higher number of deaths from CRC (3.9%) among the first-degree relatives of patients who had died from CRC than among sex-matched and age-matched controls (1.2%). This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.
Population-based studies have shown a familial association for close relatives of colon cancer patients to develop CRC and other cancers. Using data from a cancer family clinic patient population, the relative and absolute risk of CRC for different family history categories was estimated (Table 1).
A systematic review and meta-analysis of familial CRC risk was reported. Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected first-degree relative. The relative risk (RR) for CRC in the pooled study was 2.25 (95% confidence interval [CI], 2.00–2.53) if there was an affected first-degree family member. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed a RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side).
The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one first-degree relative with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years, for family members of index cases diagnosed at ages 45 to 59 years, and for family members of index cases diagnosed at age 60 years or older, respectively (RR, 3.87; 95% CI, 2.40–6.22 vs. RR, 2.25; 95% CI, 1.85–2.72 vs. RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in a first-degree relative was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had a first-degree relative with an adenoma. This finding has been corroborated. Other studies have reported that age at diagnosis of the adenoma influences the CRC risk, with younger age at adenoma diagnosis associated with higher RR. As with any meta-analysis, there could be potential biases that might affect the results of the analysis, including incomplete and nonrandom ascertainment of studies included; publication bias; and heterogeneity between studies relative to design, target populations, and control selection. This study is reinforcement that there are significant associations between familial CRC risk, age at diagnosis of both CRC and adenomas, and multiplicity of affected family members.Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)Family HistoryRelative Risk of CRC Absolute Risk (%) of CRC by Age 79 yaCI = confidence interval.aData from the Surveillance, Epidemiology, and End Results database.bThe absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRC  and the absolute risk of CRC by age 79 yearsa.No family history14aOne first-degree relative with CRC2.3 (95% CI, 2.0–2.5)9bMore than one first-degree relative with CRC4.3 (95% CI, 3.0–6.1)16bOne affected first-degree relative diagnosed with CRC before age 45 y3.9 (95% CI, 2.4–6.2)15bOne first-degree relative with colorectal adenoma2.0 (95% CI, 1.6–2.6)8b
When the family history includes two or more relatives with CRC, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history to determine the number of relatives affected, their relationship to each other, the age at which the CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Young subjects who report a positive family history of CRC are more likely to represent a high-risk pedigree than older individuals who report a positive family history. Computer models are now available to estimate the probability of developing CRC. These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. At least three validated models are also available for predicting the probability of carrying a mutation in a MMR gene.
Figure 1 shows the types of colon cancer cases that arise in various family risk settings.
Inheritance of CRC Predisposition
Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all gene mutations known to cause a predisposition to CRC are inherited in an autosomal dominant fashion. To date, at least one example of autosomal recessive inheritance, MYH-associated polyposis (MAP), has been identified. (Refer to the MYH-Associated Polyposis (MAP) section of this summary for more information.) Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing mutation. These include the following:
- Vertical transmission of cancer predisposition in autosomal dominant conditions. (Vertical transmission refers to the presence of a genetic predisposition in sequential generations.)
- Inheritance risk of 50% for both males and females. When a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition. The risk is the same for both male and female children.
- Although most cancers occurring in an isolated patient are likely de novo mutations (e.g., adenomatous polyposis coli [APC]), cancers developing within a single generation can suggest autosomal recessive inheritance (as seen in MAP). (Refer to the De novo mutation rate section in the Colon Cancer Genes section of this summary for more information.)
- Other clinical characteristics also suggest inherited risk:Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic (nongenetic) cases. A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary. In addition, two or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., two separate primary CRCs) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual). The presence of non-neoplastic extracolonic features may suggest a hereditary colon cancer predisposition syndrome (e.g., congenital hypertrophy of the retinal pigment epithelium and desmoids in familial adenomatous polyposis [FAP]).An uncommon tumor (e.g., adrenocortical, sebaceous carcinoma, ampullary, and small bowel) may serve as a clue to the presence of a hereditary cancer syndrome, such as Li-Fraumeni or FAP.
Hereditary CRC has two well-described forms: FAP (including an attenuated form of polyposis [AFAP]), due to germline mutations in the APC gene, and Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline mutations in DNA MMR genes. Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC.
Difficulties in Identifying a Family History of CRC Risk
The accuracy and completeness of family history data must be taken into account in using family history to assess individual risk in clinical practice, and in identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer. In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, due to incomplete penetrance, some persons may carry a genetic predisposition to CRC but do not develop cancer, giving the impression of skipped generations in a family tree.
Accuracy of patient-reported family history of colon cancer has been shown to be good, but it is not optimal. Patient report should be verified by obtaining medical records whenever possible, especially for reproductive tract cancers that may be relevant in identifying risk of LS. (Refer to the Accuracy of the Family History section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Other Risk Factors for CRC
Other risk factors that may influence the development of adenomatous polyps and CRC risk include diet, use of nonsteroidal anti-inflammatory drugs (NSAIDs), postmenopausal hormone use, cigarette smoking, colonoscopy with removal of adenomatous polyps, and physical activity. Even in LS, a hereditary form of colon cancer, cigarette smoking has been identified as a risk factor for the development of colorectal adenomas. (Refer to the Lynch Syndrome (LS) section of this summary for more information).
(Refer to the PDQ Summary on Prevention of Colorectal Cancer for more information.)
In practical terms, knowing that a person is at an increased risk of CRC because of a germline abnormality is most useful if the knowledge can be used to prevent the development of cancer or cancer-related morbidity and mortality once it has developed. While one can also use the information for family planning, decisions about work and retirement, and other important life decisions, prevention is usually the central concern.
This section covers screening: testing in the absence of symptoms for CRC and its precursors (i.e., adenomatous polyps) to identify people with an increased probability of developing CRC. Those with abnormalities should undergo diagnostic testing to see whether they have an occult cancer, followed by treatment if cancer or a precursor is found. Taken together, this set of activities is aimed at either preventing the development of CRC by finding and removing its precursor, the adenomatous polyp, or increasing the likelihood of cure by early detection and treatment.
In the context of high-risk syndromes such as LS or FAP, surveillance implies examining patients in whom adenoma or cancer occurrence is highly probable, and the examination is done for early detection. It is not screening in the traditional sense. The meaning of the terms screening versus surveillance has evolved over time and their usage in this summary may not be consistent with other oncologic and epidemiologic contexts.
Primary prevention (eliminating the causes of CRC in people with genetically increased risk) is addressed later in this section.
State of the evidence base
Currently, there are no published randomized controlled trials of surveillance in people with a genetically increased risk of CRC and few controlled comparisons. While a randomized trial with a no-surveillance arm is not feasible, there is a need for well-designed studies comparing various surveillance methods or differing periods of time between procedures. An observational study that compared surveilled subjects with unsurveilled (by choice) controls evaluated a 15-year experience with 252 relatives at risk of LS, 119 of whom declined surveillance. Eight of 133 (6%) in the surveilled group developed CRC, compared with 19 in the unsurveilled group (16%, P = .014). In general, however, people with genetic risk have been excluded from the trials of CRC screening that have been published thus far, so it is not possible to estimate effectiveness by subgroup analyses. Therefore, prevention in these patients cannot be based on strong evidence of effectiveness, as is ordinarily relied on by expert groups when suggesting screening or surveillance guidelines.
Given these considerations, clinical decisions are based on clinical judgment. These decisions take into account the biologic and clinical behavior of each kind of genetic condition, and possible parallels with patients at average risk, for whom screening is known to be effective.
The evidence base for the effectiveness of screening in average-risk people (those without apparent genetic risk) is the benchmark for considering an approach to people at increased risk. (Refer to the PDQ summary on Screening for Colorectal Cancer for more information.)
The fact that screening of average-risk persons reduces the risk of dying from CRC forms the basis for recommending surveillance in persons at a higher genetic risk of CRC. As logical as this approach seems, it is important to note that randomized trials of surveillance have not been performed in this special population, though observational studies performed on families with LS  and FAP  support the value of surveillance. These studies demonstrate a shift towards earlier stage at diagnosis and a corresponding reduction in CRC mortality among colonoscopy-detected cancers.
(Refer to the Major Genetic Syndromes section of this summary for more information about surveillance in high-risk populations.)
Rationale for screening
Widely accepted criteria (1–3 below) for appropriate screening apply as much to diseases with a strong genetic component (more than one affected first-degree relative or one first-degree relative diagnosed at younger than 60 years) as they do to other diseases. Additional criteria (4 and 5) were added below.
- A high burden of suffering, in terms of morbidity, mortality, and loss of function.
- A screening test that is sufficiently sensitive, specific, safe, convenient, and inexpensive.
- Evidence that treating the condition when it is detected early, by screening, results in a better prognosis than treatment after it is detected because of symptoms.
- Evidence on the extent to which the screening test and treatment do harm.
- The value judgment that the screening test does more good than harm.
Of these criteria, the first and second are satisfied in genetically determined CRC. The harms of screening (criterion 4), especially major complications of diagnostic colonoscopy (perforation and major bleeding), are also known. Evidence that early intervention results in better outcomes (criterion 3) is limited but suggests benefit. One study in the setting of LS found earlier stage/local tumors in the screened individuals.
Identification of persons at high genetic risk of CRC
Clinical criteria may be used to identify persons who are candidates for genetic testing to determine whether an inherited susceptibility to CRC is present. These criteria include the following:
- A strong family history of CRC and/or polyps.
- Multiple primary cancers in a patient with CRC.
- Existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of CRC, such as endometrial cancer.
- Early age at diagnosis of CRC.
When such persons are identified, options tailored to the patient situation are considered. (Refer to the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)
At this time, the use of mutation testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of mutations in the APC tumor suppressor gene and LS-associated MMR genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost effective.
Rather detailed recommendations for surveillance in FAP and LS have been provided by several organizations representing various medical specialties and societies. The following guidelines are readily available through the National Guideline Clearinghouse:
- American Cancer Society.
- United States Multisociety (American Gastroenterological Association and American Society for Gastrointestinal Endoscopy) Task Force on Colorectal Cancer.
- American Society of Colon and Rectal Surgeons.
- National Comprehensive Cancer Network.
- Gene Reviews.
The evidence bases for recommendations are generally included within the statements or guidelines. In many instances, these guidelines reflect expert opinion resting on studies that are rarely randomized prospective trials.
Primary Prevention of Familial CRC
Observational studies of average-risk people have suggested that the use of some drugs and supplements (NSAIDs, estrogens, folic acid, and calcium) might prevent the development of CRC. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) None of the evidence is convincing enough to lead expert groups to recommend these drugs and supplements specifically to prevent CRC, and few studies specifically enrolled people with an inherited predisposition for CRC. Although antioxidants are hypothesized to prevent cancer, a randomized controlled trial of antioxidant vitamins (beta carotene, vitamin C, and vitamin E) has shown no effect on CRC incidence.
(Refer to the Interventions/FAP section and the Chemoprevention in LS section in the Major Genetic Syndromes section of this summary for more information about chemoprevention.)
Modifying behavioral risk factors
Several components of diet and behavior have been suggested, with various levels of consistency, to be risk factors for CRC. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) These lifestyle factors may represent potential means of prevention. Expert groups differ on the interpretation of the evidence for some of these components.
Little is known about whether these same factors are protective in people with a genetically increased risk of CRC. In one case-control study, low levels of physical activity, high caloric intake, and low vegetable intake were significantly related to cancer risk in people with no family history of CRC but showed no relationship in people with a family history, despite adequate statistical power to do so.1American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online. Last accessed May 2, 2013.2Burt RW, Petersen GM: Familial colorectal cancer: diagnosis and management. In: Young GP, Rozen P, Levin B, eds.: Prevention and Early Detection of Colorectal Cancer. London, England: WB Saunders, 1996, pp 171-194.3Lynch HT, Smyrk T: Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78 (6): 1149-67, 1996.4Utsunomiya J, Lynch HT, eds.: Hereditary Colorectal Cancer: Proceedings of the Fourth International Symposium on Colorectal Cancer (ISCC-4) November 9-11, 1989, Kobe, Japan. Tokyo, Japan: Springer-Verlag, 1990.5Herrera L, ed.: Familial Adenomatous Polyposis. New York, NY: Alan R. Liss Inc, 1990.6Schoen RE: Families at risk for colorectal cancer: risk assessment and genetic testing. J Clin Gastroenterol 31 (2): 114-20, 2000.7Howe JR, Mitros FA, Summers RW: The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 5 (8): 751-6, 1998.8Jeevaratnam P, Cottier DS, Browett PJ, et al.: Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol 179 (1): 20-5, 1996.9Rashid A, Houlihan PS, Booker S, et al.: Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119 (2): 323-32, 2000.10Neugut AI, Jacobson JS, DeVivo I: Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 2 (2): 159-76, 1993 Mar-Apr.11Shinya H, Wolff WI: Morphology, anatomic distribution and cancer potential of colonic polyps. Ann Surg 190 (6): 679-83, 1979.12Fenoglio CM, Lane N: The anatomical precursor of colorectal carcinoma. Cancer 34 (3): suppl:819-23, 1974.13Morson B: President's address. The polyp-cancer sequence in the large bowel. Proc R Soc Med 67 (6): 451-7, 1974.14Muto T, Bussey HJ, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36 (6): 2251-70, 1975.15Stryker SJ, Wolff BG, Culp CE, et al.: Natural history of untreated colonic polyps. Gastroenterology 93 (5): 1009-13, 1987.16O'Brien MJ, Winawer SJ, Zauber AG, et al.: The National Polyp Study. Patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology 98 (2): 371-9, 1990.17Winawer SJ, Stewart ET, Zauber AG, et al.: A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group. N Engl J Med 342 (24): 1766-72, 2000.18Winawer SJ, Zauber AG, Ho MN, et al.: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329 (27): 1977-81, 1993.19Müller AD, Sonnenberg A: Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern Med 123 (12): 904-10, 1995.20O'brien MJ, Winawer SJ, Zauber AG, et al.: Flat adenomas in the National Polyp Study: is there increased risk for high-grade dysplasia initially or during surveillance? Clin Gastroenterol Hepatol 2 (10): 905-11, 2004.21Zauber AG, O'Brien MJ, Winawer SJ: On finding flat adenomas: is the search worth the gain? Gastroenterology 122 (3): 839-40, 2002.22Rembacken BJ, Fujii T, Cairns A, et al.: Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 355 (9211): 1211-4, 2000.23Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990.24Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet 9 (4): 138-41, 1993.25Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature 396 (6712): 643-9, 1998.26Vogelstein B, Fearon ER, Hamilton SR, et al.: Genetic alterations during colorectal-tumor development. N Engl J Med 319 (9): 525-32, 1988.27Vogelstein B, Fearon ER, Kern SE, et al.: Allelotype of colorectal carcinomas. Science 244 (4901): 207-11, 1989.28Kinzler KW, Vogelstein B: Landscaping the cancer terrain. Science 280 (5366): 1036-7, 1998.29Lindblom A: Different mechanisms in the tumorigenesis of proximal and distal colon cancers. Curr Opin Oncol 13 (1): 63-9, 2001.30Leggett B, Whitehall V: Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138 (6): 2088-100, 2010.31Boland CR, Shin SK, Goel A: Promoter methylation in the genesis of gastrointestinal cancer. Yonsei Med J 50 (3): 309-21, 2009.32Weisenberger DJ, Siegmund KD, Campan M, et al.: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38 (7): 787-93, 2006.33Sjöblom T, Jones S, Wood LD, et al.: The consensus coding sequences of human breast and colorectal cancers. Science 314 (5797): 268-74, 2006.34Kinzler KW, Vogelstein B: Colorectal tumors. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill, 2002, pp 583-612.35Woolf CM: A genetic study of carcinoma of the large intestine. Am J Hum Genet 10 (1): 42-7, 1958.36Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994.37Slattery ML, Kerber RA: Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 86 (21): 1618-26, 1994.38Negri E, Braga C, La Vecchia C, et al.: Family history of cancer and risk of colorectal cancer in Italy. Br J Cancer 77 (1): 174-9, 1998.39St John DJ, McDermott FT, Hopper JL, et al.: Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 118 (10): 785-90, 1993.40Duncan JL, Kyle J: Family incidence of carcinoma of the colon and rectum in north-east Scotland. Gut 23 (2): 169-71, 1982.41Rozen P, Fireman Z, Figer A, et al.: Family history of colorectal cancer as a marker of potential malignancy within a screening program. Cancer 60 (2): 248-54, 1987.42Hemminki K, Chen B: Familial association of colorectal adenocarcinoma with cancers at other sites. Eur J Cancer 40 (16): 2480-7, 2004.43Houlston RS, Murday V, Harocopos C, et al.: Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic. BMJ 301 (6748): 366-8, 1990 Aug 18-25.44Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.45Cottet V, Pariente A, Nalet B, et al.: Colonoscopic screening of first-degree relatives of patients with large adenomas: increased risk of colorectal tumors. Gastroenterology 133 (4): 1086-92, 2007.46Winawer SJ, Zauber AG, Gerdes H, et al.: Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 334 (2): 82-7, 1996.47Ahsan H, Neugut AI, Garbowski GC, et al.: Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Ann Intern Med 128 (11): 900-5, 1998.48Murff HJ, Peterson NB, Greevy R, et al.: Impact of patient age on family cancer history. Genet Med 8 (7): 438-42, 2006.49Chen S, Wang W, Lee S, et al.: Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296 (12): 1479-87, 2006.50Balmaña J, Stockwell DH, Steyerberg EW, et al.: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296 (12): 1469-78, 2006.51Barnetson RA, Tenesa A, Farrington SM, et al.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354 (26): 2751-63, 2006.52Burt RW: Colon cancer screening. Gastroenterology 119 (3): 837-53, 2000.53Kinzler KW, Nilbert MC, Su LK, et al.: Identification of FAP locus genes from chromosome 5q21. Science 253 (5020): 661-5, 1991.54Groden J, Thliveris A, Samowitz W, et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66 (3): 589-600, 1991.55Leppert M, Burt R, Hughes JP, et al.: Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 322 (13): 904-8, 1990.56Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75 (5): 951-7, 1993.57Brensinger JD, Laken SJ, Luce MC, et al.: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 43 (4): 548-52, 1998.58Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62 (6): 1290-301, 1998.59Pedemonte S, Sciallero S, Gismondi V, et al.: Novel germline APC variants in patients with multiple adenomas. Genes Chromosomes Cancer 22 (4): 257-67, 1998.60Sieber OM, Lamlum H, Crabtree MD, et al.: Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. Proc Natl Acad Sci U S A 99 (5): 2954-8, 2002.61Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75 (6): 1215-25, 1993.62Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994.63Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994.64Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997.65Glanz K, Grove J, Le Marchand L, et al.: Underreporting of family history of colon cancer: correlates and implications. Cancer Epidemiol Biomarkers Prev 8 (7): 635-9, 1999.66Winkels RM, Botma A, Van Duijnhoven FJ, et al.: Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome. Gastroenterology 142 (2): 241-7, 2012.67Järvinen HJ, Aarnio M, Mustonen H, et al.: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118 (5): 829-34, 2000.68Vasen HF, den Hartog Jager FC, Menko FH, et al.: Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands. Am J Med 86 (3): 278-81, 1989.69Järvinen HJ, Mecklin JP, Sistonen P: Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 108 (5): 1405-11, 1995.70Bülow S, Bülow C, Nielsen TF, et al.: Centralized registration, prophylactic examination, and treatment results in improved prognosis in familial adenomatous polyposis. Results from the Danish Polyposis Register. Scand J Gastroenterol 30 (10): 989-93, 1995.71U.S. Preventive Services Task Force.: Guide to Clinical Preventive Services: Report of the U.S. Preventive Services Task Force. 2nd ed. Baltimore, Md: Williams & Wilkins, 1996.72The periodic health examination. Canadian Task Force on the Periodic Health Examination. Can Med Assoc J 121 (9): 1193-254, 1979.73Woolf SH: Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 333 (21): 1401-5, 1995.74Smith RA, Cokkinides V, Eyre HJ: American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 56 (1): 11-25; quiz 49-50, 2006 Jan-Feb.75Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003.76Church J, Simmang C; Standards Task Force., American Society of Colon and Rectal Surgeons.Collaborative Group of the Americas on Inherited Colorectal Cancer and the Standards Committee of The American Society of Colon and Rectal Surgeons., et al.: Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum 46 (8): 1001-12, 2003.77National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 2.2012. Rockledge, PA: National Comprehensive Cancer Network, 2012. Available online with free registration. Last accessed February 04, 2013.78Tomeo CA, Colditz GA, Willett WC, et al.: Harvard Report on Cancer Prevention. Volume 3: prevention of colon cancer in the United States. Cancer Causes Control 10 (3): 167-80, 1999.79Greenberg ER, Baron JA, Tosteson TD, et al.: A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. N Engl J Med 331 (3): 141-7, 1994.80Potter JD: Colorectal cancer: molecules and populations. J Natl Cancer Inst 91 (11): 916-32, 1999.81Cummings JH, Bingham SA: Diet and the prevention of cancer. BMJ 317 (7173): 1636-40, 1998.82La Vecchia C, Gallus S, Talamini R, et al.: Interaction between selected environmental factors and familial propensity for colon cancer. Eur J Cancer Prev 8 (2): 147-50, 1999.
Colon Cancer Genes
Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic mutations in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize. Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.
The functions of the major colon cancer genes have been reasonably well characterized over the past decade. Three proposed classes of colon cancer genes are tumor suppressor genes, oncogenes, and DNA repair genes. Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for both familial adenomatous polyposis (FAP) and juvenile polyposis, among others. Germline mutations of oncogenes are not an important cause of inherited susceptibility to colorectal cancer (CRC), even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch syndrome (LS) section in the Major Genetic Syndromes section of this summary for more information). MYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.Table 2. Major Genes Associated with Risk of Colorectal CancerGeneSyndromeHereditary PatternPredominant CancerFAP = familial adenomatous polyposis; GI = gastrointestinal; OMIM = Online Mendelian Inheritance in Man database.Adapted from Vogelstein et al.Tumor suppressor genesAPC (OMIM)FAP (OMIM)DominantColon, intestine, etc.AXIN2 (OMIM)Attenuated polyposis (OMIM)DominantColonTP53 (p53) (OMIM)Li-Fraumeni (OMIM)DominantMultiple (including colon) STK11 (OMIM)Peutz-Jeghers (OMIM)DominantMultiple (including intestine)PTEN (OMIM)Cowden (OMIM)DominantMultiple (including intestine)BMPR1A (OMIM)Juvenile polyposis (OMIM)DominantGastrointestinalSMAD4 (DPC4) (OMIM)Juvenile polyposis (OMIM)DominantGastrointestinalRepair/stability genesMLH1 (OMIM), MSH2 (OMIM), MSH6 (OMIM), PMS2 (OMIM)Lynch (OMIM)DominantMultiple (including colon, uterus, and others)EPCAM (TACSTD1) (OMIM)Lynch (OMIM)DominantMultiple (including colon, uterus, and others)MYH (MUTYH) (OMIM)Attenuated polyposis (OMIM)RecessiveColonBLM (OMIM)Bloom (OMIM)RecessiveMultiple (including colon)OncogenesKIT (OMIM)Familial GI stromal tumor (OMIM)GI stromal tumorsPDGFRA (OMIM)Familial GI stromal tumor (OMIM)GI stromal tumors
Adenomatous Polyposis Coli (APC)
The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with FAP and attenuated FAP (AFAP). Both conditions can be diagnosed genetically by testing for germline mutations in the APC gene in DNA from peripheral blood leukocytes. Most FAP pedigrees have APC alterations that produce truncating mutations, primarily in the first half of the gene. AFAP is associated with truncating mutations primarily in the 5’ and 3’ ends of the gene and possibly missense mutations elsewhere.
More than 300 different disease-associated mutations of the APC gene have been reported. The vast majority of these changes are insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC mutation (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other mutations appear to predominate. Mutations that reduce rather than eliminate production of the APC protein may also lead to FAP.
Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype. There has been much interest in correlating the location of the mutation within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with mutations that occur in or before exon 4 and in the latter two-thirds of exon 15, and that retinal lesions are rarely associated with mutations that occur before exon 9. Exon 9 mutations have also been associated with attenuated polyposis. Additionally, individuals with exon 9 mutations tend not to have duodenal adenomas.
Mut Y Homolog
The Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1. The protein encoded by MYH is a base excision repair glycosylase. It repairs one of the most common forms of oxidative damage. Over 100 unique sequence variants of MYH have been reported (Leiden Open Variation Database). A founder mutation with ethnic differentiation is assumed for MYH mutations. In Caucasian populations, two major variants (Y165C and/or G382D) account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations. Biallelic MYH mutations are associated with a 93-fold excess risk of CRC with near complete penetrance by age 60 years.
DNA MMR Genes
LS is caused by mutation of one of several DNA MMR genes. The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in LS include MSH2 (mutS homolog 2) on chromosome 2p22-21; MLH1 (mutL homolog 1) on chromosome 3p21; PMS2 (postmeiotic segregation 2) on chromosome 7p22; and MSH6 on chromosome 2p16. The genes MSH2 and MLH1 are thought to account for most mutations of the MMR genes found in LS families.
A variety of LS-associated mutations in MSH2 and MLH1 have been identified. These include founder mutations in the Ashkenazi Jewish, Finnish, Portuguese, and German American populations. The wide distribution of the mutations in the two genes preclude simple gene testing assays (i.e., assays that would identify only a few mutations). Commercial testing is available to search for mutations in MSH2, MLH1, MSH6, and most recently for PMS2. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for MSH2 and MLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in LS, methods such as Southern blot or multiplex ligation-dependent probe amplification (MLPA), for detection of large deletions, are being used. (Refer to the Genetic/Molecular testing for LS section of this summary for more information about issues to be considered in testing for these mutations.)
Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal polyposis and is caused by mutations in the STK11 (also named LKB1) tumor suppressor gene located on chromosome 19p13. Unlike the adenomas seen in FAP, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (loss of heterozygosity [LOH]) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene. However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS. Subsequently, the cancers that develop in STK11 +/- mice do show LOH; indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.
Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, and splice-site variants and large deletions. Approximately 85% of mutations are localized to regions of the kinase domain of the expressed protein, and no germline mutations have been reported in exon 9. No strong genotype-phenotype correlations have been identified.
One gene (STK11) has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% mutation detection rate in STK11, studies adding techniques to detect large deletions have found mutations in up to 94% of individuals meeting clinical criteria for PJS. Given the results of these studies, it is unlikely that other major genes cause PJS.
(Refer to the Peutz-Jeghers syndrome (PJS) section in the Rare Colon Cancer Syndromes section of this summary for more information.)
Juvenile Polyposis Gene(s)
Juvenile polyposis is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, usually in the setting of a family history. The diagnosis of a juvenile polyp is based on its histologic appearance rather than age of onset, and the familial form is caused by mutations in the BMPR1A gene in 20% of cases and by mutations in the SMAD4 gene in another 20%.
SMAD4 encodes a protein that is a mediator of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline mutations in SMAD4 predispose individuals to forming juvenile polyps and cancer, and germline mutations have been found in 6 of 11 exons. Most mutations are unique, but several recurrent mutations have been identified in multiple independent families.
BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with juvenile polyposis who did not have identifiable mutations in SMAD4. Mutations in BMPR1A include nonsense, frameshift, missense, and splice-site mutations. Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with juvenile polyposis syndrome. It was reported that two individuals with mutations in both PTEN and BMPR1A also had phenotypic features of juvenile polyposis syndrome (JPS) and Cowden syndrome (see below). Rare JPS families have demonstrated mutations in the ENG and PTEN genes but these have not been confirmed in other studies.
JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN.
Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome and approximately 60% of patients with BRRS have an identifiable mutation of PTEN.
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine and serine and threonine. Mutations of PTEN are diverse, including nonsense, missense, frameshift, and splice-variant mutations. Approximately 40% of mutations are found in exon 5, which represents the phosphate core motif, and several recurrent mutations have been observed. Individuals with mutations in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.
(Refer to the Cowden Syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)
De novo mutation rate
Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous mutation rate (de novo mutation rate) in these populations. Interestingly, FAP, JPS, PJS, Cowden syndrome, and BRRS are all thought to have high rates of spontaneous mutations, in the 25% to 30% range, while estimates of de novo mutations in the MMR genes associated with LS are thought to be low, in the 0.9% to 5% range. These estimates of spontaneous mutation rates in LS seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%), making the de novo mutation rate for LS seem quite low in contrast to the relatively high rates in the other polyposis syndromes.1Caporaso N, Goldstein A: Cancer genes: single and susceptibility: exposing the difference. Pharmacogenetics 5 (2): 59-63, 1995.2Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 10 (8): 789-99, 2004.3Grady WM, Markowitz SD: Hereditary colon cancer genes. Methods Mol Biol 222: 59-83, 2003.4Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348 (10): 919-32, 2003.5Grady WM: Genetic testing for high-risk colon cancer patients. Gastroenterology 124 (6): 1574-94, 2003.6Miyoshi Y, Ando H, Nagase H, et al.: Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A 89 (10): 4452-6, 1992.7Laurent-Puig P, Béroud C, Soussi T: APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res 26 (1): 269-70, 1998.8Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75 (5): 951-7, 1993.9Brensinger JD, Laken SJ, Luce MC, et al.: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 43 (4): 548-52, 1998.10Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62 (6): 1290-301, 1998.11Pedemonte S, Sciallero S, Gismondi V, et al.: Novel germline APC variants in patients with multiple adenomas. Genes Chromosomes Cancer 22 (4): 257-67, 1998.12Yan H, Dobbie Z, Gruber SB, et al.: Small changes in expression affect predisposition to tumorigenesis. Nat Genet 30 (1): 25-6, 2002.13Bertario L, Russo A, Sala P, et al.: Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 21 (9): 1698-707, 2003.14Rozen P, Samuel Z, Shomrat R, et al.: Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9. Gut 45 (6): 829-33, 1999.15Nielsen M, Morreau H, Vasen HF, et al.: MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 79 (1): 1-16, 2011.16Nielsen M, Joerink-van de Beld MC, Jones N, et al.: Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology 136 (2): 471-6, 2009.17Balaguer F, Castellví-Bel S, Castells A, et al.: Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol 5 (3): 379-87, 2007.18Peltomäki P, Aaltonen LA, Sistonen P, et al.: Genetic mapping of a locus predisposing to human colorectal cancer. Science 260 (5109): 810-2, 1993.19Lindblom A, Tannergård P, Werelius B, et al.: Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nat Genet 5 (3): 279-82, 1993.20Bronner CE, Baker SM, Morrison PT, et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368 (6468): 258-61, 1994.21Fishel R, Lescoe MK, Rao MR, et al.: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75 (5): 1027-38, 1993.22Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75 (6): 1215-25, 1993.23Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994.24Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994.25Worthley DL, Walsh MD, Barker M, et al.: Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128 (5): 1431-6, 2005.26Marra G, Boland CR: Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87 (15): 1114-25, 1995.27Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 (4): 1146-58, 1997.28Mitchell RJ, Farrington SM, Dunlop MG, et al.: Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. Am J Epidemiol 156 (10): 885-902, 2002.29Foulkes WD, Thiffault I, Gruber SB, et al.: The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am J Hum Genet 71 (6): 1395-412, 2002.30Wagner A, Barrows A, Wijnen JT, et al.: Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 72 (5): 1088-100, 2003.31Pinheiro M, Pinto C, Peixoto A, et al.: A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families. Genet Med 13 (10): 895-902, 2011.32Tomsic J, Liyanarachchi S, Hampel H, et al.: An American founder mutation in MLH1. Int J Cancer 130 (9): 2088-95, 2012.33Ainsworth PJ, Koscinski D, Fraser BP, et al.: Family cancer histories predictive of a high risk of hereditary non-polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1. Clin Genet 66 (3): 183-8, 2004.34Gruber SB: New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 130 (2): 577-87, 2006.35Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.36Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998.37Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998.38Wang ZJ, Ellis I, Zauber P, et al.: Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. J Pathol 188 (1): 9-13, 1999.39Miyoshi H, Nakau M, Ishikawa TO, et al.: Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 62 (8): 2261-6, 2002.40Nakau M, Miyoshi H, Seldin MF, et al.: Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res 62 (16): 4549-53, 2002.41Takeda H, Miyoshi H, Kojima Y, et al.: Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice. Oncogene 25 (12): 1816-20, 2006.42Hearle N, Schumacher V, Menko FH, et al.: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12 (10): 3209-15, 2006.43Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26 (6): 513-9, 2005.44Amos CI, Keitheri-Cheteri MB, Sabripour M, et al.: Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 41 (5): 327-33, 2004.45van Lier MG, Wagner A, Mathus-Vliegen EM, et al.: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105 (6): 1258-64; author reply 1265, 2010.46Sayed MG, Ahmed AF, Ringold JR, et al.: Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 9 (9): 901-6, 2002.47Howe JR, Sayed MG, Ahmed AF, et al.: The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 41 (7): 484-91, 2004.48Howe JR, Roth S, Ringold JC, et al.: Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280 (5366): 1086-8, 1998.49Howe JR, Bair JL, Sayed MG, et al.: Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28 (2): 184-7, 2001.50Calva-Cerqueira D, Chinnathambi S, Pechman B, et al.: The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet 75 (1): 79-85, 2009.51Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 44 (11): 702-9, 2007.52van Hattem WA, Brosens LA, de Leng WW, et al.: Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut 57 (5): 623-7, 2008.53Sweet K, Willis J, Zhou XP, et al.: Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294 (19): 2465-73, 2005.54Dahdaleh FS, Carr JC, Calva D, et al.: Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet 81 (2): 110-6, 2012.55Zhou XP, Waite KA, Pilarski R, et al.: Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73 (2): 404-11, 2003.56Eng C: PTEN: one gene, many syndromes. Hum Mutat 22 (3): 183-98, 2003.57Marsh DJ, Kum JB, Lunetta KL, et al.: PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8 (8): 1461-72, 1999.58Aretz S, Uhlhaas S, Caspari R, et al.: Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur J Hum Genet 12 (1): 52-8, 2004.59Westerman AM, Entius MM, Boor PP, et al.: Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13 (6): 476-81, 1999.60Schreibman IR, Baker M, Amos C, et al.: The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 100 (2): 476-90, 2005.61Morak M, Laner A, Scholz M, et al.: Report on de-novo mutation in the MSH2 gene as a rare event in hereditary nonpolyposis colorectal cancer. Eur J Gastroenterol Hepatol 20 (11): 1101-5, 2008.62Plasilova M, Zhang J, Okhowat R, et al.: A de novo MLH1 germ line mutation in a 31-year-old colorectal cancer patient. Genes Chromosomes Cancer 45 (12): 1106-10, 2006.63Win AK, Jenkins MA, Buchanan DD, et al.: Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet 48 (8): 530-4, 2011.64Anderson KG: How well does paternity confidence match actual paternity? Evidence from worldwide nonpaternity rates. Curr Anthropol 47 (3): 513-20, 2006. Also available online. Last accessed May 06, 2013.65Sasse G, Müller H, Chakraborty R, et al.: Estimating the frequency of nonpaternity in Switzerland. Hum Hered 44 (6): 337-43, 1994 Nov-Dec.66Voracek M, Haubner T, Fisher ML: Recent decline in nonpaternity rates: a cross-temporal meta-analysis. Psychol Rep 103 (3): 799-811, 2008.
Genetic Polymorphisms and Colorectal Cancer Risk
It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes. Based on epidemiological studies, the risk of colon cancer in a first-degree relative of an affected individual can increase an individual’s lifetime risk of colon cancer 2-fold to 4.3-fold. The relative risk (RR) and absolute risk of colorectal cancer (CRC) for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in first-degree relatives of individuals with colon adenomas. The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by low-penetrance genes or gene combinations. Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.
Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome (LS) or familial adenomatous polyposis (FAP). However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide polymorphisms (SNPs).
Polymorphisms underlying polygenic susceptibility to CRC are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example those APC or mismatch repair (MMR) gene mutations leading to an autosomal dominant inheritance pattern in a family. The definition of a moderate risk of cancer is arbitrary, but it is usually considered to be in the range of an RR of 1.5 to 2.0. Because these types of sequence variants are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from the relatively rare syndromes such as FAP or LS. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (for example average age of CRC) in individuals with LS.
In general, low-penetrance variants have been identified in one of two manners. Earlier studies focused on candidates genes chosen because of biologic relevance to colon cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the Genome-wide searches section of this summary for more information.)
Polymorphism-Modifying Risk in Average-Risk Populations
Low-penetrance candidate genes
Several candidate genes have been identified and their potential use for clinical genetic testing is being determined. Candidate alleles that have been shown to associate with modest increased frequencies of colon cancer include heterozygous BLMAsh (the allele that is a founder mutation in Ashkenazi Jewish individuals with Bloom syndrome), the GH1 1663 T→A polymorphism (a polymorphism of the growth hormone gene associated with low levels of growth hormone and IGF-1), and the APC I1307K polymorphism.
Of these, the variant that has been most extensively studied is APC I1307K. Yet, neither it nor any of the other variants mentioned above are routinely used in clinical practice. (Refer to the APC I1307K section of this summary for more information.)
Although the major genes for polyposis and nonpolyposis inherited CRC syndromes have been identified, between 20% and 50% of cases from any given series of suspected FAP or LS cases fail to have a mutation detected by currently available technologies. It is estimated that heredity is responsible for approximately one-third of our susceptibility to CRC, and causative germline mutations account for less than 6% of all CRC cases. This has led to suspicions that there may be other major genes that, when mutated, predispose to CRC with or without polyposis. A few such genes have been detected (e.g., MYH, EPCAM) but the probability for discovery of other such genes is fairly low. More recent measures for new gene discovery have taken a genome-wide approach. Several GWAS have been conducted with relatively large, unselected series of CRC patients that have been evaluated for patterns of polymorphisms in candidate and anonymous genes spread throughout the genome. These SNPs are chosen to capture a large portion of common variation within the genome, based on the International HapMap Project. The goal is to identify alleles that, while not pathologically mutated, may confer an increase (or potential decrease) in CRC risk. Identification of yet unknown aberrant CRC alleles would permit further stratification of at-risk individuals on a genetic basis. Such risk stratification would potentially enhance CRC screening. The use of genome-wide scans has led to the discovery of multiple common low-risk CRC susceptibility alleles. Refer to Table 3 for more information.
A large GWAS was performed using tagSNPs in a total of 10,731 CRC cases and 10,961 controls from eight centers to identify and enrich for CRC susceptibility alleles. In addition to the previously reported 8q24, 15q13, and 18q21 CRC risk loci, two previously unreported associations at 10p14 (P = 2.5 × 10-13) and 8q23.3 (P = 3.3 × 10-8) were identified. The 8q23.3 locus tags a plausible causative gene, EIF3H (OMIM). The authors of this study estimated that the loci identified account for approximately 3% to 4% of the excess familial CRC risk, but that a high proportion of the population would be carriers of at-risk genotypes. They estimated that 3% of individuals may carry seven or more deleterious alleles. The authors concluded that their data are compatible with a polygenic model in which individual alleles, each exerting a small effect, combine either additively or multiplicatively to produce much larger risks in carriers of multiple risk alleles.
A GWAS using 555,510 SNPs in 14,500 cases of CRC and 13,294 controls from seven different centers revealed a previously unreported association on 11q23 (odds ratio [OR], 1.1; P = 5.8 × 10-10) and replicated susceptibility loci at 8q24 (OR, 1.19; P = 8.6 × 10-26) and 18q21 (OR, 1.2; P = 7.8 × 10-28). Furthermore, the authors were unable to identify causative coding sequence variants in any of the candidate genes at 8q24 (POU5F1P1, HsG57825, and DQ515897) or 18q21 (SMAD7). The variants identified are common in the general population, with risk-allele frequencies in populations of European ancestry of 0.29, 0.37, and 0.52, respectively. It was estimated that carrying all six possible risk alleles yielded an OR of 2.6 (95% confidence interval [CI], 1.75–3.89) for CRC.
A meta-analysis of GWAS data obtained from the two studies above (the combined dataset analyzed contained 38,710 polymorphic SNPs in 2,024 cases and 2,092 controls) revealed four additional susceptibility loci. In addition to six loci identified in previous GWAS (8q23, 8q24, 10p14, 11q23, 15q13, and18q21), the following four new loci were identified:
- Two SNPs linked to a 38 kilobase (kb) region on 20p12.3 [two SNPs: (i) combined OR, 1.12; 95% CI, 1.08–1.16; P = 2.0 × 10-10 and (ii) combined OR, 1.12; 95% CI, 1.08–1.17; P = 2.1 × 10-10] lacking genes or predicted protein-encoding transcripts;
- 14q22.2 (combined OR, 1.11; 95% CI, 1.08–1.15; P = 8.1 × 10-10) in a region 9.4kb from the transcription start site of the BMP4 gene;
- 19q13.1 [two SNPs: (i) combined OR, 0.87; 95% CI, 0.83–0.91; P = 4.6 × 10-9 and (ii) combined OR, 0.89; 95% CI, 0.85–0.93; P = 2.2 , 10-7], which lies within the Rho GTPase binding protein 2 (RHPN2) gene; and
- 16q22.1 (combined OR, 0.91; 95% CI, 0.89–0.94; P = 1.2 × 10-8), which lies within intron 1 of the E-cadherin (CDH1) gene.
No interactions between the loci were associated with an increased risk of CRC and the loci identified were estimated to collectively account for approximately 6% of the excess familial risk of CRC. The data analyses led the authors to conclude the following:
- The loci readily detectable through current GWAS are associated with modest effects (genotypic risks of approximately 1.2).
- The number of common variants explaining more than 1% of inherited risk is very low.
- Only a small proportion of heritability of any cancer can be explained by the currently identified loci.
- Of the common risk loci identified thus far, no significant epistatic effects were observed.
Because few of the observed associations seem to be due to correlation with common coding variants and many of the loci map to regions lacking genes of protein-coding transcripts, it seems likely that much of the common variation in cancer risk is mediated through sequence changes influencing gene expression.
A genome-wide linkage analysis was performed in 30 Swedish non-FAP/non-LS families with a strong family history of CRC. Several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected by parametric and nonparametric analysis.
A GWAS of affected, unaffected, and discordant sibling pairs in 194 kindreds utilized clinical information (histopathology, size and number of polyps, and other primary cancers) in conjunction with age at onset and family history to define five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancer) prior to analysis. 1p31.1 strongly linked to the multiple-cancer subgroup (P < .00007). 15q14-q22 linked to the full-sample (P < .018), oligopolyposis (P < .003), and young (P < .0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome (HMPS) in families of Ashkenazi descent. BRCA2 linked with the colon/breast phenotypic subgroup. Linkage to 17p13.3 in the breast/colon subgroup identified HIC1 (hypermethylated in colon cancer 1) as a candidate gene.
Nonparametric analysis revealed three loci at 3q29 (logarithm of the odds [LOD] score = 2.61; P = .0003), 4q31.3 (LOD = 2.13; P = .0009), and 7q31.31 (LOD = 3.08; P = .00008) in a GWAS performed in 70 kindreds with at least two siblings affected with colorectal adenocarcinoma or colorectal polyps with high-grade dysplasia. Linkage to 8q24, 9q22, and 11q23 was not obtained in these kindreds. Minor linkage to 3q21-q24 was present in this study population.Table 3. Colorectal Cancer Susceptibility Loci Identified Through Genome-Wide Association StudiesChromosomeLogarithm of the Odds (LOD) Score/Odds Ratio (OR) P ValueSingle Nucleotide Polymorphism (SNP)MarkerORhet = odds ratio among heterozygotes; ORhom = odds ratio among homozygotes. aIdentified in a breast/colon cohort.3q29LOD = 2.61  .0003 D3S240 4q31.3LOD = 2.13 .0009D4S29997q31.31LOD = 3.08 .00008D7S6438q23.3 Combined OR = 1.29 1.1 × 10-10rs119860638q23.3ORallelic = 1.25, ORhet = 1.27, ORhom = 1.43  3.3 × 10-18rs16892766Combined OR = 1.32 1.1 × 10-108q24ORallelic = 1.24, ORhet = 1.35, ORhom = 1.57  7.0 × 10-11rs6983267Combined OR = 0.83 2.1 × 10-148q24OR = 1.19  8.6 × 10-26 rs7014346 Combined OR = 1.21 3.0 × 10-138q24Combined OR = 1.17 1.2 × 10-10 rs7837328 8q24Combined OR = 1.14  1.5 × 10-7 rs1080855510p14ORallelic = 0.89, ORhet = 0.87, ORhom = 0.80  2.5 × 10-13 rs10795668 Combined OR = 0.91 3.1 × 10-411q23OR = 1.11  5.8 × 10-10 rs3802842Combined OR = 1.21 5.2 × 10-1314q22.2Combined OR = 1.11 8.1 × 10-10rs444423515q13ORallelic = 1.23, ORhet = 1.17, ORhom = 1.70  4.7 × 10-7rs4779584 Combined OR = 1.19 1.7 × 10-816q22.1Combined OR = 0.91  1.2 × 10-8 rs9929218 17p13.3aNot available .0364D17S1308 18q21ORallelic = 0.85, ORhet = 0.84, ORhom = 0.73  1.7 × 10-6rs4939827 OR = 1.20  7.8 × 10-28 Combined OR = 0.85 2.2 × 10-1119q13.1Combined OR = 0.89 2.2 × 10-7 rs7259371 19q13.1 Combined OR = 0.87 4.6 × 10-9rs1041121020p12.3Combined OR = 1.12 2.0 × 10-10 rs355527 20p12.3 Combined OR = 1.12 2.1 10-10rs961253
It is important to note the limitations of the tagged SNP approach in GWAS in identifying SNPs with minor allele frequencies of 5% to 10%, low-frequency variants with potentially stronger effects, and copy number variants. It is yet unclear how the identification of these new susceptibility alleles in individuals will apply to CRC screening and how comprehensive panels of low-penetrance cancer associated alleles may be applied in the clinical setting.
Genetic Variation in 8q24 and SMAD7
Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with RR ranging from 1.17 to 1.27.  Although the RR is modest for the risk alleles in 8q24, the prevalence (and population-attributable fraction) of these risk alleles is high. The genes responsible for this association have not yet been identified. In addition, common alleles of SMAD7 have also been shown to be associated with an approximately 35% increase in risk of colon cancer.
Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele. None of these alleles has been characterized enough to currently support its routine use in a clinical setting. Family history remains the most valuable tool for establishing risk of colon cancer in these families. Similar to what has been reported in prostate cancer, a combination of susceptibility loci may yet hold promise in profiling individual risk.
Variants of Uncertain Significance in Major Cancer Susceptibility Genes
Polymorphisms in APC are the most extensively studied polymorphisms with regard to cancer association. The APC I1307K polymorphism is associated with an increased risk of colon cancer but does not cause colonic polyposis. The I1307K polymorphism occurs almost exclusively in people of Ashkenazi Jewish descent and results in a twofold increased risk of colonic adenomas and adenocarcinomas compared with the general population. The I1307K polymorphism results from a transition from T→A at nucleotide 3920 in the APC gene and appears to create a region of hypermutability. Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated colon cancer risk is not high enough to support routine use. On the basis of currently available data, it is not yet known whether the I1307K carrier state should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.
Clinical implications of low-penetrance alleles
Although the statistical evidence for an association between genetic variation at these loci and CRC risk is convincing, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with ORs for developing CRC in heterozygous carriers usually from 1.1 to 1.3. More risk variants will likely be identified. Risks in this range do not appear to confer enough increase in age-specific risk as to warrant modification of otherwise clinically prudent screening. Until their collective influence is prospectively evaluated, their use cannot be recommended in clinical practice.
Polymorphisms in Unrelated Genes Affecting Expression in LS
Polymorphisms potentially affecting expression in MMR genes fall into two categories: those whose mechanisms are already suspected to have an effect on cancer-related pathways, and those that are truly anonymous. Several candidate genes have been studied. Anonymous genes have also been evaluated.
Studies have demonstrated that a polymorphism in the promoter region of the insulin-like growth factor 1 (IGF1) gene modifies age of onset of CRC in LS.. The polymorphism is a variable number of CA-dinucleotide repeats approximately 1 kb upstream of the transcription start site of IGF1. There is significant variability between individuals and populations with respect to repeat length. Carriers of shorter repeat lengths (shortest allele ≤17 repeats) develop CRC on average 12 years earlier than those with longer repeat lengths. It is unclear what influence this polymorphism may have on extracolonic malignancies. Additionally, the cyclin D1 polymorphism G870A may be associated with earlier age of onset of CRC in LS, although the association appears to be more reproducible in MSH2 mutation carriers than in MLH1 mutation carriers.
Two SNPs identified in GWAS have been reported to increase CRC risk in MMR gene mutation carriers. (Refer to the Genome-wide searches section of this summary for more information.) Having the C-allele of either SNP increased the risk of CRC in a dose-dependent fashion (with homozygotes at a higher risk than heterozygotes). The first SNP in 8q23.3 increased CRC risk 2.16-fold for homozygote carriers of the SNP. The second SNP, located in 11q23.1, increased CRC risk only in female SNP carriers by 3.08 for homozygotes and 1.49 for heterozygote SNP carriers.
In a study of 684 mutation carriers from 298 Australian and Polish families, nine SNPs within six previous CRC susceptibility loci were genotyped to investigate their potential as modifiers of disease risk in LS. Two SNPs, rs3802842 (11q23.1) and rs16892766 (8q23.3), were associated with CRC susceptibility in MLH1 mutation–positive LS patients. However, a subsequent study of 748 French MMR mutation carriers did not replicate the association between the IGF1 CA repeat and age of CRC onset or the association between SNPs in 8q23.3 and 11q23.1 and CRC risk.
Given the inconsistent results of these studies, genetic testing for these polymorphisms has no clinical utility at present.1Burt RW, Bishop DT, Lynch HT, et al.: Risk and surveillance of individuals with heritable factors for colorectal cancer. WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68 (5): 655-65, 1990.2Butterworth AS, Higgins JP, Pharoah P: Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 42 (2): 216-27, 2006.3Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.4Gruber SB, Ellis NA, Scott KK, et al.: BLM heterozygosity and the risk of colorectal cancer. Science 297 (5589): 2013, 2002.5Le Marchand L, Donlon T, Seifried A, et al.: Association of a common polymorphism in the human GH1 gene with colorectal neoplasia. J Natl Cancer Inst 94 (6): 454-60, 2002.6Laken SJ, Petersen GM, Gruber SB, et al.: Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 17 (1): 79-83, 1997.7Lichtenstein P, Holm NV, Verkasalo PK, et al.: Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343 (2): 78-85, 2000.8Aaltonen L, Johns L, Järvinen H, et al.: Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res 13 (1): 356-61, 2007.9The International HapMap Consortium.: The International HapMap Project. Nature 426 (6968): 789-96, 2003.10Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.11Tomlinson IP, Webb E, Carvajal-Carmona L, et al.: A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet 40 (5): 623-30, 2008.12Tenesa A, Farrington SM, Prendergast JG, et al.: Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40 (5): 631-7, 2008.13Houlston RS, Webb E, Broderick P, et al.: Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40 (12): 1426-35, 2008.14Picelli S, Vandrovcova J, Jones S, et al.: Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q. BMC Cancer 8: 87, 2008.15Daley D, Lewis S, Platzer P, et al.: Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study. Am J Hum Genet 82 (3): 723-36, 2008.16Neklason DW, Kerber RA, Nilson DB, et al.: Common familial colorectal cancer linked to chromosome 7q31: a genome-wide analysis. Cancer Res 68 (21): 8993-7, 2008.17Zanke BW, Greenwood CM, Rangrej J, et al.: Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39 (8): 989-94, 2007.18Tomlinson I, Webb E, Carvajal-Carmona L, et al.: A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39 (8): 984-8, 2007.19Gruber SB, Moreno V, Rozek LS, et al.: Genetic variation in 8q24 associated with risk of colorectal cancer. Cancer Biol Ther 6 (7): 1143-7, 2007.20Broderick P, Carvajal-Carmona L, Pittman AM, et al.: A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39 (11): 1315-7, 2007.21Hirschhorn JN, Lohmueller K, Byrne E, et al.: A comprehensive review of genetic association studies. Genet Med 4 (2): 45-61, 2002 Mar-Apr.22Zheng SL, Sun J, Wiklund F, et al.: Cumulative association of five genetic variants with prostate cancer. N Engl J Med 358 (9): 910-9, 2008.23Slattery ML, Herrick J, Curtin K, et al.: Increased risk of colon cancer associated with a genetic polymorphism of SMAD7. Cancer Res 70 (4): 1479-85, 2010.24Lothe RA, Hektoen M, Johnsen H, et al.: The APC gene I1307K variant is rare in Norwegian patients with familial and sporadic colorectal or breast cancer. Cancer Res 58 (14): 2923-4, 1998.25Reeves SG, Rich D, Meldrum CJ, et al.: IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer. Int J Cancer 123 (6): 1339-43, 2008.26Zecevic M, Amos CI, Gu X, et al.: IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst 98 (2): 139-43, 2006.27Kong S, Amos CI, Luthra R, et al.: Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res 60 (2): 249-52, 2000.28Talseth BA, Ashton KA, Meldrum C, et al.: Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer 122 (6): 1273-7, 2008.29Bala S, Peltomäki P: CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. Cancer Res 61 (16): 6042-5, 2001.30Wijnen JT, Brohet RM, van Eijk R, et al.: Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology 136 (1): 131-7, 2009.31Talseth-Palmer BA, Brenne IS, Ashton KA, et al.: Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in Lynch syndrome. J Med Genet 48 (4): 279-84, 2011.32Houlle S, Charbonnier F, Houivet E, et al.: Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers. Eur J Hum Genet 19 (8): 887-92, 2011.
Major Genetic Syndromes
Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient/family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch I and II syndromes, Peutz-Jeghers syndrome (PJS), Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first five, while hamartomas were found to be characteristic in the last three.
With the development of the Human Genome Project and the identification in 1990 of the Adenomatous Polyposis Coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by mutations in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations as having FAP mutation on the 3’ and 5’ ends of the gene. Turcot syndrome families were shown to be genetically part of FAP with medulloblastomas and Lynch syndrome (LS) with glioblastomas. Muir-Torre and LS were shown to have genetic similarities. MYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the mutations were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for mutation carriers (Table 4).Table 4. Absolute Risks of Colorectal Cancer for Mutation Carriers in Hereditary Colorectal Cancer SyndromesSyndromeAbsolute Risk in Mutation CarriersFAP = familial adenomatous polyposis. aRefer to the Lynch syndrome (LS) section of this summary for a full discussion of risk.FAP90% by age 45 y Attenuated FAP69% by age 80 y  Lynch 40% to 80% by age 75 ya MYH-associated polyposis35% to 53% Peutz-Jeghers 39% by age 70 y Juvenile polyposis 17% to 68% by age 60 y 
With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for mutations in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron-exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic mutations from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance that cannot be used for predictive purposes.
Familial Adenomatous Polyposis (FAP)
FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes. It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births, with the syndrome being more common in Western countries. Autosomal dominant inheritance means that affected persons are genetically heterozygous, such that each offspring of a patient with FAP has a 50% chance of inheriting the disease gene. Males and females are equally likely to be affected.
Classically, FAP is characterized by multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. Variant features in addition to the colonic polyps may include polyps in the upper gastrointestinal tract, extraintestinal manifestations such as congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignant changes such as thyroid tumors, small bowel cancer, hepatoblastoma, and brain tumors, particularly medulloblastoma. Refer to Table 5 for more information.Table 5. Extracolonic Tumor Risks in Familial Adenomatous PolyposisMalignancyRelative RiskAbsolute Lifetime Risk (%)Adapted from Giardiello et al., Jagelman et al., Sturt et al., Lynch et al., Bülow et al., Burt et al., and Galiatsatos et al.aThe Leeds Castle Polyposis Group.Desmoid852.015.0Duodenum330.85.0–12.0Thyroid7.62.0Brain7.02.0Ampullary123.71.7Pancreas4.51.7Hepatoblastoma847.01.6Gastric—0.6a
FAP is also known as familial polyposis coli, adenomatous polyposis coli (APC), or Gardner syndrome (colorectal polyposis, osteomas, and soft tissue tumors). Gardner syndrome has sometimes been used to designate FAP patients who manifest these extracolonic features. However, Gardner syndrome has been shown molecularly to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.
Most cases of FAP are due to mutations of the APC gene on chromosome 5q21. Individuals who inherit a mutant APC gene have a very high likelihood of developing colonic adenomas; the risk has been estimated to be more than 90%. The age at onset of adenomas in the colon is variable: By age 10 years, only 15% of FAP gene carriers manifest adenomas; by age 20 years, the probability rises to 75%; and by age 30 years, 90% will have presented with FAP. Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life. Thus, surveillance and intervention for APC gene mutation carriers and at-risk persons have conventionally consisted of annual sigmoidoscopy beginning around puberty. The objective of this regimen is early detection of colonic polyps in those who have FAP, leading to preventive colectomy.
The early appearance of clinical features of FAP and the subsequent recommendations for surveillance beginning at puberty raise special considerations relating to the genetic testing of children for susceptibility genes. Some proponents feel that the genetic testing of children for FAP presents an example in which possible medical benefit justifies genetic testing of minors, especially for the anticipated 50% of children who will be found not to be mutation carriers and who can thus be spared the necessity of unpleasant and costly annual sigmoidoscopy. The psychological impact of such testing is currently under investigation and is addressed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary.
A number of different APC mutations have been described in a series of FAP patients. (Refer to the Colon Cancer Genes section of this summary for more information.) The clinical features of FAP appear to be generally associated with the location of the mutation in the APC gene and the type of mutation (i.e., frameshift mutation vs. missense mutation). Two features of particular clinical interest that are apparently associated with APC mutations are (1) the density of colonic polyposis and (2) the development of extracolonic tumors.
Density of colonic polyposis
Researchers have found that dense carpeting of colonic polyps, a feature of classic FAP, is seen in most patients with APC mutations, particularly those mutations that occur between codons 169 and 1393. At the other end of the spectrum, sparse polyps are features of patients with mutations occurring at the extreme ends of the APC gene or in exon 9. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section of this summary for more information.)
Desmoid tumors are proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening. Desmoids may occur sporadically, as part of classical FAP, or in a hereditary manner without the colon findings of FAP. Desmoids have been associated with hereditary APC gene mutations even when not associated with typical adenomatous polyposis of the colon.
Most studies have found that 10% of FAP patients develop desmoids, with reported ranges of 8% to 38%. The incidence varies with the means of ascertainment and the location of the mutation in the APC gene. APC mutations occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients. Desmoid tumors with a late onset and a milder intestinal polyposis phenotype (hereditary desmoid disease) have been described in patients with mutations at codon 1924.
A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors. The desmoid risk factor scale was based on gender, presence or absence of extracolonic manifestations, family history of desmoids, and genotype, if available. By utilizing this scale, it was possible to stratify FAP patients into low-, medium-, and high-risk groups for developing desmoid tumors. It was concluded that the desmoid risk factor scale could be used for surgical planning. Validation of the risk factors comprising this scale were recently supported by a large, multiregistry, retrospective study from Europe.
The natural history of desmoids is variable. Some authors have proposed a model for desmoid tumor formation whereby abnormal fibroblast function leads to mesenteric plaque-like desmoid precursor lesions, which in some cases occur prior to surgery and progress to mesenteric fibromatosis after surgical trauma, ultimately giving rise to desmoid tumors. It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly. Desmoids often occur after surgical or physiological trauma, and both endocrine and genetic factors have been implicated. Approximately 80% of intra-abdominal desmoids in FAP occur after surgical trauma.
The desmoids in FAP are often intra-abdominal, may present early, and can lead to intestinal obstruction or infarction and/or obstruction of the ureters. In some series, desmoids are the second most common cause of death after CRC in FAP patients. A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity. The proposed staging system for intra-abdominal desmoids is as follows: stage I for asymptomatic, nongrowing desmoids; stage II for symptomatic, nongrowing desmoids of 10 cm or less in maximum diameter; stage III for symptomatic desmoids of 11 to 20 cm or for asymptomatic, slow-growing desmoids; and stage IV for desmoids larger than 20 cm, or rapidly growing, or with life-threatening complications.
These data suggest that genetic testing could be of value in the medical management of patients with FAP and/or multiple desmoid tumors. Those with APC genotypes, especially those predisposing to desmoid formation (e.g., at the 3’ end of APC codon 1445), appear to be at high risk of developing desmoids following any surgery, including risk-reducing colectomy and surgical surveillance procedures such as laparoscopy.
The management of desmoids in FAP can be challenging and can complicate prevention efforts. Currently, there is no accepted standard treatment for desmoid tumors. Multiple medical treatments have generally been unsuccessful in the management of desmoids. Treatments have included antiestrogens, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy, and radiation therapy, among others. Studies have evaluated the use of raloxifene alone, tamoxifen or raloxifene combined with sulindac, and pirfenidone alone. There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed. Significant desmoid tumor regression was reported in seven patients who had symptomatic, unresectable, intra-abdominal desmoid tumors and failed hormonal therapy when treated with chemotherapy (doxorubicin and dacarbazine) followed by meloxicam.
Thirteen patients with intra-abdominal desmoids and/or unfavorable response to other medical treatments, who had expression of estrogen alpha receptors in their desmoid tissues, were included in a prospective study of raloxifene, given in doses of 120 mg daily. Six of the patients had been on tamoxifen or sulindac before treatment with raloxifene, and seven patients were previously untreated. All 13 patients with intra-abdominal desmoid disease had either a partial or a complete response 7 months to 35 months after starting treatment, and most desmoids decreased in size at 4.7 ± 1.8 months after treatment. Response occurred in patients with desmoid plaques and with distinct lesions. Study limitations include small sample size, and the clinical evaluation of response was not consistent in all patients. Several questions remain concerning patients with desmoid tumors not expressing estrogen alpha receptors who have received raloxifene and their outcome and which patients may benefit from this potential treatment.
A second study of 13 patients with FAP-associated desmoids, who were treated with tamoxifen 120 mg/day or raloxifene 120 mg/day in combination with sulindac 300 mg/day, reported that ten patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that three patients had stable disease for more than 30 months. These results suggest that the combination of these agents may be effective in at least slowing the growth of desmoid tumors. However, the natural history of desmoids is variable, with both spontaneous regression and variable growth rates.
A third study reported mixed results in 14 patients with FAP-associated desmoid tumors treated with pirfenidone for 2 years. In this study, some patients had regression, some patients had progression, and some patients had stable disease.
These three studies illustrate some of the problems encountered in the study of desmoid disease in FAP patients:
- The definition of desmoid disease has been used inconsistently.
- In some patients, desmoid tumors do not progress or are very slow growing and may not need therapy.
- There is no consistent, systematic way to evaluate the response to therapy.
- There is no single institution that will enroll enough patients to perform a randomized trial.
No randomized clinical trials using these agents have been performed and their use in clinical practice is based on anecdotal experience only.
Level of evidence: 4
Because of the high rates of morbidity and recurrence, in general, surgical resection is not recommended in the treatment of intra-abdominal desmoid tumors. However, some have advocated a role for surgery given the ineffectiveness of medical therapy, even when the potential hazards of surgery are considered, and recognizing that not all desmoids are resectable. A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed. Issues of subject selection are critical in evaluating surgical outcome data. Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.
The most common FAP-related gastric polyps are fundic gland polyps (FGPs). FGPs are often diffuse and not amenable to endoscopic removal. The incidence of FGPs has been estimated to be as high as 60% in patients with FAP, compared with 0.8% to 1.9% in the general population. These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.
The hyperplastic surface epithelium is, by definition, nonneoplastic. Accordingly, FGPs have not been considered precancerous; in Western FAP patients the risk of stomach cancer is minimally increased, if at all. However, case reports of stomach cancer appearing to arise from FGPs have led to a reexamination of this issue. In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs. In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, FGPs were detected in 88% of the patients. Low-grade dysplasia was detected in 38% of these patients, whereas high-grade dysplasia was detected in 3% of these patients. In the author's view, if a polyp with high-grade dysplasia is identified, polypectomy can be considered with repeat endoscopic surveillance in 3 to 6 months. Consideration for treatment with daily proton-pump inhibitors also may be given.
Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs). FGPs in this setting commonly show a “PPI effect” consisting of congestion of secretory granules in parietal cells, leading to irregular bulging of individual cells into the lumen of glands. To the trained eye, the presence of dysplasia and the concomitant absence of a characteristic PPI effect can be considered highly suggestive of the presence of underlying FAP. The number of FGPs tends to be greater in FAP than that seen in patients consuming PPIs, although there is some overlap.
Gastric adenomas also occur in FAP patients. The incidence of gastric adenomas in Western patients has been reported to be between 2% and 12%, whereas in Japan, it has been reported to be between 39% and 50%. These adenomas can progress to carcinoma. FAP patients in Korea and Japan are reported to have a threefold to fourfold increased gastric cancer risk compared with their general population, a finding not observed in Western populations. The recommended management for gastric adenomas is endoscopic polypectomy. The management of adenomas in the stomach is usually individualized based on the size of the adenoma and the degree of dysplasia.
Level of evidence: None assigned
Duodenum/small bowel tumors
Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper gastrointestinal (GI) endoscopy, duodenal adenomas are found in 80% to 100% of FAP patients. The vast majority are located in the first and second portions of the duodenum, especially in the periampullary region. There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.  In a prospective multicenter surveillance study of duodenal adenomas in 368 northern Europeans with FAP, 65% had adenomas at baseline evaluation (mean age, 38 years), with cumulative prevalence reaching 90% by age 70 years. In contrast to earlier beliefs regarding an indolent clinical course, the adenomas increased in size and degree of dysplasia during the 8 years of average surveillance, though only 4.5% developed cancer while under prospective surveillance. While this study is the largest to date, it is limited by the use of forward-viewing rather than side-viewing endoscopy and the large number of investigators involved in the study. Another modality through which intestinal polyps can be assessed in FAP patients is capsule endoscopy. One study of computed tomography (CT) duodenography found that larger adenoma size could be accurately measured but smaller, flatter adenomas could not be accurately counted.
A retrospective review of FAP patients suggested that the adenoma-carcinoma sequence occurred in a temporal fashion for periampullary adenocarcinomas with a diagnosis of adenoma at a mean age of 39 years, high-grade dysplasia at a mean age of 47 years, and adenocarcinoma at a mean age of 54 years. A decision analysis of 601 FAP patients suggested that the benefit of periodic surveillance starting at age 30 years led to an increased life expectancy of 7 months. Although polyps in the duodenum can be difficult to treat, small series suggest that they can be managed successfully with endoscopy but with potential morbidity—primarily from pancreatitis, bleeding, and duodenal perforation.
FAP patients with particularly severe duodenal polyposis, sometimes called dense polyposis, or with histologically advanced duodenal adenomas appear to be at the highest risk of developing duodenal adenocarcinoma. Because the risk of duodenal adenocarcinoma is correlated with the number and size of polyps, and the severity of dysplasia of the polyps, a stratification system based on these features was developed in order to attempt to identify those individuals with FAP at highest risk of developing duodenal adenocarcinoma. According to this system, known as the Spigelman Classification (see Table 6), 36% of patients with the most advanced stage will develop carcinoma.Table 6. Spigelman ClassificationPointsPolyp NumberPolyp Size (mm)HistologyDysplasiaStage I, 1–4 points; Stage II, 5–6 points; Stage III, 7–8 points; Stage IV, 9–12 points11–41–4TubularMild25–204–10TubulovillousModerate3>20>10VillousSevere
A baseline upper endoscopy, including side-viewing duodenoscopy, should be performed between ages 25 and 30 years in FAP patients. The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy, often, based on Spigelman stage. Recommended intervals are based on expert opinion although the relatively liberal intervals for stage 0-II disease are based in part on the natural history data generated by the Dutch/Scandinavian duodenal surveillance trial. Refer to Table 7 for more information.
The main advantages of the Spigelman Classification are its long-standing familiarity to and usage by those in the field, which allows reasonable standardization of outcome comparisons across studies. However, there are several limitations on attempted application of the Spigelman Classification:
- Most pathologists do not currently employ the term moderate dysplasia, preferring a simpler low- versus high-grade dysplasia system.
- Because of the villous nature of normal duodenal epithelium, pathologists commonly disagree over the classification of “tubular,” “tubulovillous,” and “villous.”
- Spigelman staging requires biopsy, which is not always essential when only a few small plaques are present; conversely, for larger adenomas, sampling variation leads to understaging.
Many factors, including severity of polyposis, comorbidities of the patient, patient preferences, and availability of adequately trained physicians, determine whether surgical or endoscopic therapy is selected for polyp management. Endoscopic resection or ablation of large or histologically advanced adenomas appears to be safe and effective in reducing the short-term risk of developing duodenal adenocarcinoma; however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum. The most definitive procedure for reducing the risk of adenocarcinoma is surgical resection of the ampulla and duodenum, though these procedures also have higher morbidity and mortality associated with them than do endoscopic treatments. Duodenotomy and local resection of duodenal polyps or mucosectomy have been reported, but invariably, the polyps recur after these procedures. In a series of 47 patients with FAP and Spigelman stage III or stage IV disease who underwent definitive radical surgery, the local recurrence rate was reported to be 9% at a mean follow-up of 44 months. This local recurrence rate is dramatically lower than any local endoscopic or surgical approach from the same study. Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma. If such surgical options are considered, preservation of the pylorus is of particular benefit in this group of patients because most will have undergone a subtotal colectomy with ileorectal anastomosis or total colectomy with ileal pouch anal anastomosis. As noted in a Northern European study, and others, the vast majority of patients with duodenal adenomas will not develop cancer and can be followed with endoscopy. However, individuals with advanced adenomas (Spigelman stage III or stage IV disease) generally require endoscopic or surgical treatment of the polyps. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.
The endoscopic approach to larger and/or flatter adenomas of the duodenum depends on whether the ampulla is involved. Endoscopic mucosal resection (EMR) following submucosal injection of saline, with or without epinephrine and/or dye, such as indigo carmine, can be employed for nonampullary lesions. Ampullary lesions require even greater care including endoscopic ultrasound evaluation for evidence of bile or pancreatic duct involvement. Stenting of the pancreatic duct is commonly performed to prevent stricturing and pancreatitis. The stents require endoscopic removal at an interval of 1 to 4 weeks. Because the ampulla is tethered at the ductal orifices, it typically does not uniformly “lift” with injection, so injection is commonly not used. Any consideration of EMR or ampullectomy requires great experience and judgment, with careful consideration of the natural history of untreated lesions and an appreciation of the high rate of adenoma recurrence despite aggressive endoscopic intervention. The literature uniformly supports duodenectomy for Spigelman stage IV disease. For Spigelman stage II and III disease, there is a role for endoscopic treatment invariably focusing on the one or two worst lesions that are present.
Reluctance to consider surgical resection has to do with short-term morbidity and mortality and long-term complications related to surgery. Although these concerns are likely overstated, fear of surgical intervention can lead to aggressive and somewhat ill-advised endoscopic interventions. In some circumstances, endoscopic resection of ampullary and/or other duodenal adenomas cannot be accomplished completely or safely by endoscopic means, and duodenectomy cannot be accomplished without risking a short-gut syndrome or cannot be done at all because of mesenteric fibrosis. In such cases, surgical transduodenal ampullectomy/polypectomy can be performed. This is, however, associated with a high risk of local recurrence similar to that of endoscopic treatment.
Level of evidence: 3diii
The spectrum of tumors arising in FAP is summarized in Table 5.
Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP. However, a recent study  of papillary thyroid cancers in six females with FAP failed to demonstrate loss of heterozygosity (LOH) or mutations of the wild-type allele in codons 545 and 1061 to 1678 of the six tumors. In addition, four out of five of these patients had detectable somatic RET/PTC chimeric genes. This mutation is generally restricted to sporadic papillary thyroid carcinomas, suggesting the involvement of genetic factors other than APC mutations. Further studies are needed to show whether other genetic factors such as the RET/PTC chimeric gene are independently responsible for or cooperative with APC mutations in causing papillary thyroid cancers in FAP patients. Although level 1 evidence is lacking, a consensus opinion recommends annual thyroid examinations beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP. The same panel suggests clinicians could consider the addition of annual thyroid ultrasounds to this screening routine.
Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma in an FAP patient. In a study of 162 FAP patients who underwent abdominal CT for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors. Of these, two had symptoms attributable to cortisol hypersecretion. Three of these patients underwent subsequent surgery and were found to have adrenocortical carcinoma, bilateral nodular hyperplasia, or adrenocortical adenoma. The prevalence of an unexpected adrenal neoplasia in this cohort was 7.4%, which compares with a prevalence of 0.6% to 3.4% (P < .001) in non-FAP patients. No molecular genetic analyses were provided for the tumors resected in this series.
Hepatoblastoma is a rare, rapidly progressive, and usually fatal childhood malignancy that, if confined to the liver, can be cured by radical surgical resection. Multiple cases of hepatoblastoma have been described in children with an APC mutation. Some series have also demonstrated LOH of APC in these tumors. No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma. Although lacking level 1 evidence, a consensus panel has recommended abdominal examination, abdominal ultrasound, and measurement of serum alpha fetoprotein every 3 to 6 months for the first 5 years of life in children with a predisposition to FAP.
The constellation of CRC and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with mutations in APC, while colon cancer and glioblastoma are associated with mutations in mismatch repair (MMR) genes.
There are several reports of other extracolonic tumors associated with FAP, but whether these are simply coincidence or actually share a common molecular genetic origin with the colonic tumors is not always evident. Some of these reports have demonstrated LOH or a mutation of the wild-type APC allele in extracolonic tumors in FAP patients, which strengthens the argument for their inclusion in the FAP syndrome.
Genetic testing for FAP
APC gene testing is now commercially available and has led to changes in management guidelines, particularly for those whose tests indicate they are not mutation carriers. Presymptomatic genetic diagnosis of FAP in at-risk individuals has been feasible with linkage  and direct detection  of APC mutations. These tests require a small sample (<10 cc) of blood in which the lymphocyte DNA is tested. If one were to use linkage analysis to identify gene carriers, ancillary family members, including more than one affected individual, would need to be studied. With direct detection, fewer family members’ blood samples are required than for linkage analysis, but the specific mutation must be identified in at least one affected person by DNA mutation analysis or sequencing. The detection rate is approximately 80% using sequencing alone.
Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing. For this reason, deletion testing has been added as an optional adjunct to sequencing of APC. Furthermore, mutation detection assays that use MLPA are being developed and appear to be accurate for detecting intragenic deletions. MYH gene testing may be considered in APC mutation–negative affected individuals. (Refer to the Colon Cancer Genes section of this summary for more information.)
Patients who develop fewer than 100 colorectal adenomatous polyps are a diagnostic challenge. The differential diagnosis should include AFAP and MYH-associated colorectal neoplasia (also reported as MYH-associated polyposis or MAP). AFAP can be diagnosed by testing for germline APC gene mutations. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section in the Major Genetic Syndromes section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.
Presymptomatic genetic testing removes the necessity of annual screening of those at-risk individuals who do not have the gene mutation. For at-risk individuals who have been found to be definitively mutation-negative by genetic testing, there is no clear consensus on the need for or frequency of colon screening, though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 years). Colon adenomas will develop in nearly 100% of persons who are APC gene mutation positive; risk-reducing surgery comprises the standard of care to prevent colon cancer after polyps have appeared.
Individuals at risk of FAP, because of a known APC mutation in either the family or themselves, are evaluated for onset of polyposis by flexible sigmoidoscopy or colonoscopy. Once an FAP family member is found to manifest polyps, the only effective management to prevent CRC is eventual colectomy. In patients with classic FAP identified very early in their course, the surgeon, endoscopist, and family may choose to delay surgery for several years in the interest of achieving social milestones. In addition, in carefully selected patients with AFAP (those with minimal polyp burden and advanced age), deferring a decision about colectomy may be reasonable with surgery performed only in the face of advancing polyp burden or dysplasia.
The recommended age at which surveillance for polyposis should begin involves a trade-off. On the one hand, someone who waits until the late teens to begin surveillance faces a remote possibility that a cancer will have developed at an earlier age. Although it is rare, CRC can develop in a teenager who carries an APC mutation. On the other hand, it is preferable to allow people at risk to develop emotionally before they are faced with a major surgical decision regarding the timing of colectomy. Therefore, surveillance is usually begun in the early teenage years (age 10–15 years). Surveillance has consisted of either flexible sigmoidoscopy or colonoscopy every year. If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Historically, sigmoidoscopy may have been a reasonable approach at the time in identifying early adenomas in a majority of the patients. However, colonoscopy must be considered the tool of choice in light of (a) improved instrumentation for full colonoscopy, (b) safer and deeper sedation (Propofol), (c) recognition of AFAP, in which the disease is typically most manifest in the right colon, and (d) the growing tendency to defer surgery for a number of years. Individuals who have tested negative for an otherwise known family mutation do not need FAP-oriented surveillance at all. They are recommended to undergo average-risk population screening. In the case of families in which no family mutation has been identified in an affected person, then clinical surveillance is warranted. Colon surveillance should not be stopped in persons who are known to carry an APC mutation but who do not yet manifest polyps, since adenomas occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section of this summary for more information.) (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)
In some circumstances, full colonoscopy may be preferred over the more limited sigmoidoscopy. Among pediatric gastroenterologists, tolerability of endoscopic procedures in general has been regarded as improved with the use of deeper intravenous sedation.
Table 8 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) OrganizationAPC Gene Test Recommended Age Screening Initiated FrequencyMethodCommentC = colonoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; NA = not addressed; NCCN = National Comprehensive Cancer Network.aGI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.American Cancer Society NAPubertyNAEndoscopyReferral to a center specializing in FAP screening suggested.American Society of Colon and Rectal Surgeons YesNANANAGI Societiesa Yes 10–12 y Annual FS NCCN Yes 10–15 y AnnualFS or CConsider MYH mutation testing if APC testing is negative and family history is compatible with recessive inheritance; in families in which no mutation is found, offspring of those affected are screened as if they were carriers.
Once an FAP family member is found to manifest polyposis, the only effective management is colectomy. Patient and doctor should enter into an individualized discussion to decide when surgery should be done. It is useful to incorporate into the discussion the risk of developing desmoid tumors following surgery. Timing of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology. Once numerous polyps have developed, surveillance colonoscopy is no longer useful in timing the colectomy because polyps are so numerous that it is not possible to biopsy or remove all of them. At this time, it is appropriate for patients to consult with a surgeon who is experienced with available options, including total colectomy and postcolectomy reconstruction techniques. Rectum-sparing surgery, with sigmoidoscopic surveillance of the remaining rectum, is a reasonable alternative to total colectomy in those compliant individuals who understand the consequences and make an informed decision to accept the residual risk of rectal cancer occurring despite periodic surveillance.
Surgical options include restorative proctocolectomy with ileal pouch anal anastomosis (IPAA), subtotal colectomy with ileorectal anastomosis (IRA), or total proctocolectomy with ileostomy (TPC). TPC is reserved for patients with low rectal cancer in which the sphincter cannot be spared or for patients on whom an IPAA cannot be performed because of technical problems. Following TPC, there is no risk of developing rectal cancer because the whole mucosa at risk has been removed. Whether a colectomy and an IRA or a restorative proctocolectomy is performed, most experts suggest that periodic and lifelong surveillance of the rectum or the ileal pouch be performed to remove or ablate any polyps. This is necessitated by case series of rectal cancers arising in the rectum of FAP patients who had subtotal colectomies with an IRA in which there was an approximately 25% cumulative risk of rectal adenocarcinoma 20 years after IRA and by case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy. The cumulative risk of rectal cancer after IRA may be lower than that reported in the literature, in part because of better selection of patients for this procedure, such as those with minimal polyp burden in the rectum. Other factors that have been reported to increase the rectal cancer risk after IRA include the presence of colon cancer at the time of IRA, the length of the rectal stump, and the duration of follow-up after IRA.  
In most cases, the clinical polyp burden in the rectum at the time of surgery dictates the type of surgical intervention, namely restorative proctocolectomy with IPAA versus IRA. Patients with a mild phenotype (<1,000 colonic adenomas) and fewer than 20 rectal polyps may be candidates for IRA at the time of prophylactic surgery. In some cases, however, the polyp burden is equivocal, and in such cases, investigators have considered the role of genotype in predicting subsequent outcomes with respect to the rectum. Mutations reported to increase the rectal cancer risk and eventual completion proctectomy after IRA include mutations in exon 15 codon 1250, exon 15 codons 1309 and 1328, and exon 15 mutations between codons 1250 and 1464.  In patients who have undergone IPAA, it is important to continue annual surveillance of the ileal pouch because the cumulative risk of developing adenomas in the pouch has been reported to be up to 75% at 15 years. Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients. A meta-analysis of quality of life following restorative proctocolectomy and IPAA has suggested that FAP patients do marginally better than inflammatory bowel disease patients in terms of fistula formation, pouchitis, stool frequency, and seepage.
Specific cyclooxygenase II (COX-2) inhibitors such as celecoxib and rofecoxib, or nonspecific COX-2 inhibitors, such as sulindac, have been associated with a decrease in polyp size and number in FAP patients, suggesting a role for chemopreventive agents in the treatment of this disorder. Celecoxib is currently approved by the U.S. Food and Drug Administration as an adjunct to endoscopic surveillance following subtotal colectomy in patients with FAP. Celecoxib reduced the number of polyps by 28% from baseline, and the sum of the polyp diameters by 30.7% in patients with FAP; however, it is unknown whether this will translate into reductions in CRC incidence or mortality, or improvements in quality of life. Rofecoxib has also been shown to modestly reduce the number of polyps in patients after subtotal colectomy. Rofecoxib (25 mg/day) reduced the number of polyps by 6.8% from baseline in 21 patients after 9 months of treatment.
A small, randomized, placebo-controlled, dose-escalation trial of celecoxib in a pediatric population (aged 10–14 years) demonstrated the safety of celecoxib at all dosing levels when administered over a 3-month period. This study found a dose-dependent reduction in adenomatous polyp burden. At a dose of 16 mg/kg/day (which approximates the approved dose of 400 mg twice daily in adults), the reduction in polyp burden paralleled that demonstrated with celecoxib in adults.
Omega-3-polyunsaturated fatty acid eicosapentaenoic acid in the free fatty acid form has been shown to reduce rectal polyp number and size in a small study of patients with FAP post subtotal colectomy. Although not directly compared in a randomized trial, the effect appeared to be similar in magnitude to that previously observed with celecoxib.
It is unclear at present how to incorporate COX-2 inhibitors into the management of FAP patients who have not yet undergone risk-reducing surgery. A double-blind placebo-controlled trial in 41 APC mutation carrier children and young adults who had not yet manifested polyposis demonstrated that sulindac may not be effective as a primary treatment in FAP. There were no statistically significant differences between the sulindac and placebo groups over 4 years of treatment in incidence, number, or size of polyps.
Consistent with the effects of COX-2 inhibitors on colonic polyps, in a randomized, prospective, double-blind, placebo-controlled trial, celecoxib (400 mg, administered orally twice daily) reduced, but did not eliminate, the number of duodenal polyps in 32 patients with FAP after a 6-month course of treatment. Of importance, a statistically significant effect was seen only in individuals who had more than 5% of the duodenum involved with polyps at baseline and with an oral dose of 400 mg, given twice daily. A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps. The same issues surrounding the use of COX-2 inhibitors for the treatment of colonic polyps apply for their use for the treatment of duodenal polyps (e.g., only partial elimination of the polyps, complications secondary to the COX-2 inhibitors, and loss of effect after the medication is discontinued).
Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib, it is unclear whether this class of agents will be safe for long-term use for patients with FAP and in the general population. Also, because of the short-term (6 months) nature of these trials, there is currently no clinical information about cardiac events in FAP patients taking COX-2 inhibitors on a long-term basis.
Level of evidence for celecoxib study: 1
One cohort study has demonstrated regression of colonic and rectal adenomas with sulindac (an NSAID) treatment in FAP. The reported outcome of this trial was the number and size of polyps, a surrogate for the clinical outcome of main interest, CRC incidence.
Level of evidence for sulindac study: 1
Patients who carry APC germline mutations are at increased risk of other types of malignancies, including thyroid cancer, small bowel cancer, hepatoblastoma, and brain tumors. The risk of these tumors, however, is much lower than that for colon cancer, and the only surveillance recommendation by experts in the field is upper endoscopy of the gastric and duodenal mucosa. The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma. (Refer to the Duodenum/small bowel tumors section and the Other tumors section in the Major Genetic Syndromes section of this summary for more information about screening for extracolonic malignancies in patients with FAP.)
Attenuated Familial Adenomatous Polyposis (AFAP)
AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. It was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, though they ranged in number from a few to hundreds. Adenomas in AFAP are believed to form in the mid-twenties to late twenties. Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years. Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (fundic gland polyps, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoids.
AFAP is associated with particular subsets of APC mutations, including missense changes. Three groups of site-specific APC mutations causing AFAP have been characterized: 
- Mutations associated with the 5’ end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper gastrointestinal polyps.
- Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
- 3’ region mutations in which patients have very few adenomas (<50).
APC gene testing is an important component of the evaluation of patients suspected of having AFAP. It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided. The role for and timing of risk-reducing colectomy in AFAP is controversial. If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.
Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.  In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), LS, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or LS.
MYH-Associated Polyposis (MAP)
MAP is an autosomal recessive inherited polyposis syndrome. The MYH gene was first identified in 2002 in three siblings with multiple colonic adenomas and CRC but no APC mutation. MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and LS. MAP patients tend to develop fewer adenomas at a later age than patients with APC mutations  and also carry a high risk of CRC (35%–53%). This broad clinical presentation results from the MYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.
Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients. The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC. The Mallorca group and National Comprehensive Cancer Network (NCCN) have established clinical management guidelines based on available literature. These guidelines are generally consistent but have some differences related to age at initiation of surveillance. NCCN recommends beginning initiation at age 25 to 30 years repeated at 3 to 5 year intervals, while the Mallorca group recommends surveillance beginning at age 18 to 20 years with upper-tract surveillance beginning at age 25 to 30 years. The recommended surveillance interval can be based on the burden of involvement according to Spigelman criteria. Total colectomy with ileorectal anastomosis may be appropriate for patients with MYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.
Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, and thyroid and skin cancers including melanoma, squamous epithelial, and basal cell carcinomas. Additionally, extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors. Female MAP patients have an increased risk of breast cancer. These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or LS.
Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying a biallelic MYH mutation and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.
The clinical phenotype of monoallelic MYH mutations is less well characterized with respect to incidence and associated clinical phenotypes, and their role in pathogenesis of polyposis coli and colorectal carcinoma remains controversial. Approximately 1% to 2% of the general population carry a deleterious mutation in MYH. In one cohort of 215 APC mutation-negative patients, eight monoallelic MYH mutation carriers had a later mean age at diagnosis (average 48 years compared with 43 years in MAP) and a high CRC incidence rate of 50%. Monoallelic mutations were found in four patients with polyposis coli with 10 to 100 adenomas and in four patients with fewer than 10 adenomas; none of the monoallelic MYH mutation carriers had manifestation in the upper GI tract. This is in contrast to past reports of extracolonic polyposis in 22% of monoallelic MYH mutation carriers. The literature reports up to 4.4% frequency of monoallelic MYH carriers in CRC patients. This incidence rate is above the carrier frequency in the general population (0%–2.1%), suggesting a causative involvement in CRC. The risk of CRC in heterozygous carriers of single MYH mutations who are relatives of patients with MAP is comparable with that of first-degree relatives of patients with sporadic CRC. Screening measures for monoallelic carriers could be based on this modest increase in risk (standardized incidence ratio [SIR] = 2.12; 95% confidence interval [CI], 1.30–3.28). However, a 2007 meta-analysis of all previous case-control studies failed to support an increased risk of CRC in monoallelic MYH mutation carriers.
MMR genes may interact with MYH and increase the risk of CRC. An association between MYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 mutations in monoallelic MYH mutation carriers with CRC compared to noncarriers (11.5% vs. 0%; P = .037).
Lynch Syndrome (LS)
Between 1900 and 1990, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset; high risk of second primary tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as Lynch 1 (families with CRC only), Lynch 2 (families with CRC and extracolonic tumors), cancer family syndrome, and later, hereditary nonpolyposis colorectal cancer (HNPCC), were commonly employed.
By 1990, the need for enhanced surveillance (colonoscopy at an early age and repeated frequently) was recognized. However, the need to limit this aggressive regimen to families most likely to have an inherited susceptibility or “true” HNPCC led to development of the so-called Amsterdam criteria: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50 years, and no evidence of FAP.
At about this same time, a chromosomal abnormality on 5q led to detecting genetic linkage between FAP and this genomic region, from which the APC gene was eventually cloned. This led to searches for similar linkage in HNPCC. The APC gene was one of several genes (along with DCC and MCC) evaluated and to which no HNPCC linkage was found. An extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large HNPCC families in 1993. Once the first HNPCC gene was sequenced, MSH2, it was evident (from the somatic mutation patterns in the tumors) that a family of genes, the MMR family, was likely involved. Shortly thereafter, additional MMR genes were identified, including MLH1, MSH6, and PMS2.
Concurrent with the linkage studies, somatic genetic studies of HNPCC tumors showed evidence of characteristic mutations in microsatellite regions of numerous genes, which appeared to be a molecular marker of MMR deficiency. This was characterized with synonyms such as ubiquitous somatic mutations, replication errors, and eventually, the currently-employed term microsatellite instability (MSI). In HNPCC-related tumors showing MSI, there is typically loss of immunohistochemical expression for one or more of the proteins associated with the MMR genes. Since immunohistochemistry (IHC) is relatively easy to perform, it can serve to complement or even supplant MSI screening of suspected HNPCC cases. Although MSI characterizes nearly all HNPCC tumors, it can also occur sporadically in about 12% of CRCs. These cases clearly do not have the inherited disorder HNPCC, since further studies have shown that the MSI is caused by somatic inactivation of the MLH1 protein by hypermethylation of the MLH1 promoter; the sporadic nature of these cases can be confirmed by concurrent detection of somatic BRAF mutations in CRC tumor tissue.
Mutational testing for germline alterations has been somewhat disappointing, as no more than half of suspected HNPCC cases have detectable pathologic mutations. Because of this, and the lack of sufficiently specific clinical features, various genetic screening strategies have emerged to improve the yield of genetic testing. A sufficiently compelling family history, ideally complemented by the presence of MSI, warrants mutational testing, and most clinical practice guidelines provide for such an approach. The Bethesda guidelines are a combination of clinical, pathologic, and family history features that are sufficiently predictive to warrant MSI/IHC screening. Computer risk-assessment profiles have been developed to do this same work more quantifiably and can estimate mutation risk likelihood with or without the intermediate step of using MSI/IHC.
Against this background of potential clinical selection criteria for mutation testing, population studies have emerged that can estimate HNPCC frequency (1%–3%) and determine the performance characteristics of these same selection tools when implemented in otherwise unselected cases.
The combination of genetic counseling/testing strategies with clinical screening/treatment measures has led to the development of consensus clinical practice guidelines. These guidelines can be used by providers and patients alike to better understand the available options and key decision-points that exist. Refer to Table 9 for more information about practice guidelines for diagnosis and colon surveillance in LS.
Terminology related to familial CRC has certainly evolved. Most in the field use the term Lynch syndrome (LS) as a preferred synonym over HNPCC, since HNPCC is both excessively wordy and misleading—many patients do have polyps and many others have tumors other than CRC. In addition, entities such as Muir-Torre syndrome are now recognized as phenotypic variants of LS. Even Turcot syndrome, which was initially thought to only be an FAP variant, is now known to be an LS variant when it presents with glioblastomas and an FAP variant when it presents with medulloblastomas. It has been suggested that the term Lynch syndrome be applied to cases in which the genetic basis can be confidently linked to a germline mutation in a DNA MMR gene (either a germline mutation is present or can be confidently inferred based on the clinical presentation combined with MSI/IHC).
The term familial colorectal cancer type X was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities. Maybe a better term will emerge—there are many conditions with “X” in them—but it survives for now since workers in the field at least agree to use it to describe these cases.
In LS, unlike FAP, most patients do not have an unusual number of polyps. LS accounts for about 3% to 5% of all CRCs. LS is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors. LS is caused by mutations in the DNA MMR genes, namely MLH1, MSH2, MSH6, and PMS2. Mutations of the EPCAM gene that result in hypermethylation and silencing of MSH2 have also been described. (Refer to the MSI section in the Major Genetic Syndromes section of this summary for more information.) The average age of CRC diagnosis in LS mutation carriers is 44 to 52 years and 71 years in sporadic CRC. Even though LS is characterized by an early age of onset of CRC, in mutation-positive families when probands were excluded and both affected and non-affected relatives were ascertained, the average age at diagnosis of CRC was reported to be 61 years.
The lifetime risk of CRC in MLH1 and MSH2 mutation carriers was 68.7% in males and 52% in females. However, in a meta-analysis of three population-based studies and one clinic-based study, the lifetime risk of CRC in MLH1 and MSH2 mutation carriers was reported to be 53% in males and 33% in females. In a study of 113 families with MSH6 mutation carriers, the estimated cumulative risk of CRC in males was 22% and 10% in females. PMS2 lifetime CRC risk to age 70 years has been reported to be 20% in males and 15% in females. A large registry-based study from France estimated CRC risk at age 70 years to be 41% for MLH1 mutation carriers, 48% for MSH2 mutation carriers, and 12% for MSH6 mutation carriers.
These data have been largely retrospective and potentially include some biases for that reason. Some prospective data do exist, however. The Colon Cancer Family Registry program followed 446 carriers prospectively and found a 10-year risk of CRC of 8%.
Patients with LS can have synchronous and metachronous colorectal neoplasms and other primary extracolonic malignancies. LS mutation carriers have an increased risk of developing colon adenomas (hazard ratio [HR], 3.4), and the onset of adenomas appears to occur at a younger age than in nonmutation carriers from the same families. Unlike patients with sporadic cancers, whose cancer develops most often in the left side of the colon, approximately two-thirds of LS cancers develop in the right side of the colon, defined as proximal to the splenic flexure.
In addition to CRC, LS patients and their relatives are at risk of a wide variety of other cancers. The most common is endometrial adenocarcinoma, which affects at least one female member in about 50% of LS pedigrees. The lifetime risk of endometrial cancer in MLH1 and MSH2 mutation carriers has been estimated at 44% to 54%. Families with a MSH6 mutation have been reported to have an endometrial cancer predominance. Lifetime risk of endometrial cancer in MSH6 mutation carriers in 113 families was estimated to be 26% at age 70 years and 44% at age 80 years. In PMS2 mutation carriers, the endometrial cancer risk at age 70 years has been reported to be 15%. The same prospective data collection in the Colon Cancer Family Registry program yielded 5- and 10-year endometrial cancer risks of about 3% and 10%, respectively, in women from this cohort. Endometrial cancer can be the index cancer in female LS patients. LS-associated endometrial cancer is not limited to the endometrioid subtype. Endometrial adenocarcinoma, clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed Müllerian tumors are part of the spectrum of uterine tumors in LS.
Several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis, and cancers of the stomach, small intestine, liver and biliary tract, brain, breast, and ovary. The largest prospective study to date is of 446 unaffected mutation carriers from the Colon Cancer Family Registry. Participants who were followed for up to 10 years demonstrated an increased standardized incidence ratio (SIR) for colorectal, endometrial, ovarian, gastric, renal, bladder, pancreatic, and breast cancers. With the exception of colorectal, endometrial, and breast cancers, the number of observed cases was very small for most cancers (i.e., two to three cases), resulting in very wide 95% confidence intervals.
The issue of breast cancer risk in LS has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with LS; one of these studies evaluated breast cancer risk in individuals with LS and found that it is not elevated. However, the largest prospective study to date of 446 unaffected mutation carriers from the Colon Cancer Family Registry  who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001). The same group subsequently analyzed data on 764 MMR gene mutation carriers with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59). However, further studies are needed to define absolute risks and age distribution before surveillance guidelines for breast cancer can be developed for MMR mutation carriers.
Muir-Torre syndrome is considered a variant of LS and includes a phenotype of multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas). The skin lesions and CRC define the phenotype, and clinical variability is common. Both mutations in the MSH2 and MLH1 genes have been found in Muir-Torre families. A study of 1,914 MSH2 and MLH1 unrelated probands found MSH2 to be more common in individuals with the Muir-Torre syndrome phenotype.
Criteria for defining LS families
The research criteria for defining LS families were established by the International Collaborative Group (ICG) meeting in Amsterdam in 1990, and are known as the Amsterdam criteria.
- Amsterdam criteria:
- One member diagnosed with CRC before age 50 years.
- Two affected generations.
- Three affected relatives, one of them a first-degree relative of the other two.
- FAP should be excluded.
- Tumors should be verified by pathological examination.
These criteria provide a general approach to identifying LS families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline MMR gene mutations, have been reported.
To address these issues and to improve the diagnosis of LS clinically, the ICG developed revised criteria in 1999; these are known as Amsterdam criteria II.
- There should be at least three relatives with a LS-associated cancer (CRC or cancer of the endometrium, small bowel, ureter, or renal pelvis).
- One should be a first-degree relative of the other two.
- At least two successive generations should be affected.
- At least one should be diagnosed before age 50 years.
- FAP should be excluded in the CRC cases.
- Tumors should be verified by pathological examination.
Although these criteria are among the most stringent used to identify potential candidates for microsatellite and germline testing, it must be cautioned that by definition, familial CRC type X includes families meeting Amsterdam criteria but in whom there is no evidence of MSI. (Refer to the Familial CRC type X section in the Major Genetic Syndromes section of this summary for more information.)
A third set of clinical criteria that can be used to identify LS families is the revised Bethesda guidelines. The criteria was expanded to improve sensitivity in identifying families. The Bethesda guidelines are the least stringent for identifying families with germline mutations in one of the MMR genes. Because of lack of specificity for LS, the Bethesda guidelines are utilized to identify individuals whose colorectal tumors should be tested for MSI and/or IHC, rather than to identify families that meet clinical criteria for LS. (Refer to the Genetic/Molecular Testing for LS section in the Major Genetic Syndromes section of this summary for more information about testing for MSI and IHC.)
- Revised Bethesda Guidelines for Testing of Colorectal Tumors for MSI:
- CRC diagnosed in an individual younger than 50 years.
- Presence of synchronous, metachronous colorectal, or other LS-associated tumors.*
- CRC with MSI-high (MSI-H) pathologic associated features diagnosed in an individual younger than 60 years. Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.
- CRC or LS-associated tumor* diagnosed in at least one first-degree relative younger than 50 years.
- CRC or LS-associated tumor* diagnosed at any age in two first-degree or second-degree relatives.
*LS-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.
Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations in MSH6. While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.
Genetic/Molecular testing for LS
Genetic risk assessment of LS generally considers the cancer family history and age at diagnosis of CRC and/or other LS-associated cancers in the patient. Studies of gene testing using DNA sequencing in suspected LS probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative MSH2 or MLH1 mutation, allowing genetically informed management strategies to be developed for the family. Computer models analogous to BRCAPro predict the probability of a MMR gene mutation. PREMM1, PREMM2, PREMM6, and the MMRPro models are easy to use and have been validated. Although these models can predict mutation even in the absence of MSI or IHC information, they can incorporate those data as available. All three computer prediction models take family history of endometrial cancer into account. The mutation detection rate is higher for patients with more striking family histories or with informative tumor testing.
In the absence of additional family or personal history suggestive of LS, isolated cases of CRC diagnosed prior to age 36 years are uncommonly associated with MMR gene mutations. One study found MMR mutations in only 6.5% of such individuals. Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline mutation analysis.
MSI/IHC in adenomas
Current practice is to offer colonoscopy surveillance to those with strong family histories but no prior genetic or tumor testing. At times, adenomas are detected during these colonoscopies. In the instance when an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR mutations found 8 of 12 adenomas to have both MSI and IHC protein loss. However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude LS.
Microsatellites are short, repetitive sequences of DNA (often mononucleotides, dinucleotides, or trinucleotides) located throughout the genome, primarily in intronic sequences. The term microsatellite instability (MSI) is used when tumor DNA shows alterations in microsatellite regions when compared to normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic or germline mutations or epigenetic alterations. In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all MSI-H tumors.
Certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. These histologic features have been combined into computational scores that have high predictive value in identifying MSI CRCs.
Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma showing MSI depends, in part, on the detection of a specified percentage of unstable loci from a panel of dinucleotide and mononucleotide repeats that were selected at a National Institutes of Health Consensus conference. If more than 30% of a tumor's markers are unstable, it is scored as MSI-H; if at least one, but fewer than 30% of markers are unstable, the tumor is designated MSI-low (MSI-L). If no loci are unstable, the tumor is designated MSS. Most tumors arising in the setting of LS will be MSI-H. The clinical relevance of MSI-L tumors remains controversial at this point. The probability of finding a germline mutation in a MMR gene in this setting is very small. One distinction is that people with germline mutations in MSH6 do not necessarily manifest the MSI-H phenotype. One study presented evidence that MSH6 mutations were associated with cancers having an MSI-L phenotype. However, a second study found that 18/21 (86%) of CRCs in MSH6 carriers showed MSI-H. In addition, in sporadic cancers with MSI-L phenotype, MSH6 mutations were not found.
(Refer to the Diagnostic strategies for all individuals diagnosed with CRC (universal testing) section of this summary for information about the utilization of MSI status in the diagnostic work-up of a patient with suspected LS.)
(Refer to the Issues With Informed Consent for MSI and IHC Tumor Testing section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for information about educational strategies and issues related to informed consent for MSI and IHC testing.)
The complexity of aberrant methylation of MMR genes
Aberrant MLH1 methylation in sporadic CRC
The presence of an MSI-H tumor associated with loss of MSH2, MSH6, or PMS2 protein expression strongly supports a diagnosis of LS. However, MSI-H tumors with absent MLH1 protein expression present a more complex scenario. MSI occurs in approximately 10% to 15% of sporadic CRC (generally, patients aged >50 years and with little or no family history). In sporadic CRC, absent MLH1 protein expression is a consequence of aberrant MLH1 methylation, a somatic event confined to the tumor that in the vast majority of cases is not heritable. Since loss of MLH1 protein expression occurs in both LS and sporadic tumors, its specificity for predicting germline MMR gene mutations is lower than for the other MMR proteins.
Because of this uncertainty, additional molecular testing is often necessary to clarify the etiology of MLH1 absence in these cases. Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals with germline mutations in one of the MMR genes are BRAF mutations and MLH1 promoter methylation.
Aberrant methylation of MLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers. Other mechanisms such as somatic MLH1 mutations may be responsible for the minority of cases where aberrant MLH1 methylation is absent. In most studies, aberrant MLH1 methylation has been detected in only a small percentage of LS colon cancers in individuals with germline mutations in MLH1.  Thus, detection of aberrantly methylated MLH1 in colon cancer is more suggestive of a sporadic MSI tumor. Since assays of methylation are complex and resource-intensive, surrogate markers of MLH1 methylation have been examined. One study found that loss of immunohistochemical staining for p16 correlated strongly with both MLH1 methylation and BRAF V600E mutations (BRAF mutations are discussed in detail in the following paragraphs). However, only 30% of sporadic tumors examined in this study exhibited loss of p16 expression, limiting the utility of this assay.
BRAF mutations have been detected predominantly in sporadic MSI tumors. This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing. MLH1 hypermethylation and/or BRAF mutation testing are increasingly utilized in universal LS testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caued by hypermethylation and germline MLH1 mutations.
(Refer to the Diagnostic strategies for all individuals diagnosed with CRC (universal testing) section of this summary for more information about the clinical role of BRAF and hypermethylation testing.)
Germline MLH1 hypermethylation
Reports of patients with germline MLH1 hypermethylation should not be confused with EPCAM mutation-induced hypermethylation of MSH2, as described below. Prior paragraphs have emphasized the issues associated with the common, acquired somatic hypermethylation of the MLH1 promoter. However, examples of hypermethylation of the MLH1 promoter described in the germline have generally not been associated with a stable Mendelian inheritance.
A comprehensive review of MLH1 constitutional epigenetic alterations involving hypermethylation of one MLH1 allele has been published. Such epimutations are seen in patients with early-onset LS and/or multiple tumors of the LS type. Germline sequence variations or rearrangements are not seen in these patients, although the tumors show MSI-H, loss of MLH1 protein expression, and an absence of BRAF V600E mutations. These patients commonly have no family history of LS-like tumors. Interestingly, inheritance appears to be maternal, and therefore non-Mendelian. The constitutional monoallelic hypermethylation may appear as a mosaic, involving different tissues to a varying extent. In addition, the constitutional epimutation is typically reversible in the course of meiosis, such that offspring are usually unaffected. Because inheritance has been demonstrated in very few families, performing genetic counseling and genetic testing (which requires specialized research techniques) is particularly challenging.
Tumors with MSI and loss of MSH2 protein expression are generally indicative of an underlying MSH2 germline mutation (inferred MSH2 mutation). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter. Nevertheless, in at least 30% to 40% of these cases of inferred MSH2 mutation, no germline mutation can be detected with state of the art technology. One Chinese family with tumors showing MSH2 loss was found to have allele-specific hypermethylation that appeared to have been an inherited phenomenon. Another study of a family with MSH2-deficient MSI-high tumors employed the commonly used diagnostic MLPA analysis of MSH6 and also showed reduced expression of MSH6. In doing so, a decrease in signal was observed for exon 9 of the EPCAM (TACSTD1) gene, which is near MSH2. Use of additional MLPA probes located between exon 3 of EPCAM and exon 1 of MSH2 demonstrated that the deletion spanned most 3’ exons of EPCAM, but spared the MSH2 promoter. The mutation in EPCAM was found to induce the observed methylation of the MSH2 promoter by transcription across a CpG island within the promoter region. The presence of EPCAM mutations showing similar methylation-mediated MSH2 loss was found at about the same time in families from Hungary.. On the strength of these observations, EPCAM testing has already been introduced clinically for patients with loss of MSH2 protein expression in their CRCs who lack detectable MSH2 germline mutation. One study of two families with the same EPCAM deletion found few extracolonic cancers and no endometrial cancers.
A complementary and perhaps even alternative approach to MSI is to test the tumor by IHC for protein expression using monoclonal antibodies of the MSH2, MLH1, MSH6, and PMS2 proteins. Loss of expression of these proteins appears to correlate with the presence of MSI and may suggest which specific MMR gene is altered in a particular patient.
(Refer to the Issues With Informed Consent for MSI and IHC Tumor Testing section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for information about educational strategies and issues related to informed consent for MSI and IHC testing.)
Tumor testing for suspected LS
It appears that clinical practice has shifted from reliance on MSI in the early days of tumor testing to increasing, and in many cases exclusive, reliance on IHC currently. Using both of these tests increases the sensitivity of the initial screen and improves quality assurance; therefore, many laboratories assess both MSI and IHC initially. However, because these tests are so commonly regarded as simple alternatives, cost-effectiveness considerations seem to support IHC and account for its preferential use. Part of this rationale is that the information provided by IHC may direct testing toward a specific MMR gene (the one with loss of protein expression) as opposed to comprehensive testing that would be necessitated by the use of MSI alone. Arguments for a sequential approach to increase efficiency have been made. A German consortium has proposed an algorithm suggesting a sequential approach; this is likely to depend on the different costs of MSI and IHC and the prior probability of a mutation. Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories. To identify a more efficient screening approach, the strategy of performing IHC staining only for PMS2 and MSH6 has been considered, on the assumption that negative staining of either of these would, in most instances, detect the majority of cases of LS. This approach may be more appropriate when all tumors are being screened (universal testing). Although this strategy appears attractive from the standpoint of efficiency, staining for all four MMR proteins remains the current standard of care. Further studies are necessary to validate the utility of the two-protein approach. (Refer to the Diagnostic Strategies for all individuals diagnosed with CRC (universal testing) section of this summary for more information.)
Even in centers that rely exclusively on IHC testing, there may be a role for subsequent MSI testing in cases where the clinical picture suggests LS, notwithstanding the results of IHC.
If greatest weight is given to clinical selection considerations (i.e., Bethesda guidelines being met), then IHC combined with MSI may be appropriate. In fact, in a truly high-risk population (Amsterdam criteria being met), any strategy may be acceptable, including germline testing without the benefit of tumor testing first. (Refer to the Genetic/Molecular Testing for LS section of this summary for information about models.) However, as more institutions are adopting universal testing using MSI or IHC, perhaps in part based on some of the outlier (older, family history-negative) cases reported  or in part based on prognostic considerations (MSI-H having better prognosis), concerns about cost effectiveness of screening commonly dictate a more truncated approach. Thus, in a relatively low-risk population of patients with CRC, a screen with IHC or MSI alone may be adequate in cases of normal staining or MSS tumor.
(Refer to the Issues With Informed Consent for MSI and IHC Tumor Testing section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for information about educational strategies and issues related to informed consent for MSI and IHC testing.)
In instances where tumor is not available from individuals to test for MSI and/or MMR protein IHC, germline mutation analysis of MLH1, MSH2, and MSH6 may be considered. This approach is, however, time consuming and expensive. Strategies to screen for mutations using heteroduplex analysis-based techniques have been explored. These techniques are limited by the need to perform DNA sequencing as a subsequent step on all aberrant samples detected in screening. Additionally, such techniques frequently detect numerous variants of uncertain significance. They cannot, therefore, be recommended for routine clinical use at this time.
Genetic testing for germline mutations in MLH1, MSH2, MSH6, and PMS2 can help formulate appropriate intervention strategies for the affected mutation-positive individual and at-risk family members.
If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members (referred to as predictive testing). Family members who test negative for the familial mutation are generally not at increased risk of CRC or other LS-associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial mutation should follow surveillance and management guidelines for LS. (Refer to the Interventions/LS section of this summary for more information.)
If no mutation is identified in the affected family member, then testing is considered uninformative for the individual and at-risk family members. This would not exclude an inherited susceptibility to colon cancer in the family, but rather could indicate that current gene testing technology is not sensitive enough to detect the mutation in the genes tested. The current sensitivity of testing is between 50% and 95%, depending on the methodology used. Mutation testing utilizing sequencing alone will not detect large genomic rearrangements in MSH2 or MLH1 that may be present in a significant number of LS probands. An assessment of 365 probands with suspected LS showed 153 probands with germline mutations in MLH1 or MSH2, 12 of 67 (17.9%) and 39 of 86 (45.3%) of which were large genomic alterations in MLH1 and MSH2, respectively. Such mutations can be detected by MLPA or Southern blotting (MLPA has largely replaced Southern blotting). MLPA analysis of MLH1, MSH2, and MSH6 is commercially available and should be performed in cases where no mutation is detected by sequence analysis.
Alternatively, the family could have a mutation in a yet-unidentified gene that causes LS or a predisposition to colon cancer. Another explanation for a negative mutation test is that, by chance, the individual tested in the family has developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case), while the other cases in the family are really due to a germline mutation. If this scenario is suspected, testing another affected individual is recommended. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis. If no mutation can be identified in an affected family member, testing should not be offered to at-risk members. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions/LS section of this summary for more information.)
MLH1 and MSH2 make up the majority of LS mutations. Up to 50% of mutation-positive LS families harbor a MLH1 mutation, with some geographic variation.
MLH1 mutations have been associated with the entire spectrum of malignancies associated with LS. The lifetime risk of CRC in MLH1 mutation carriers is estimated to be 41% to 68%. The lifetime risk of endometrial cancer is estimated to be approximately 40%. Muir-Torre syndrome is less commonly associated with MLH1 mutations than are MSH2 mutations.
Practices and pitfalls in testing
In contrast to the scenario of MSI associated with loss of expression of MSH2, MSH6 or PMS2, absence of MLH1 expression is not specific to LS. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Therefore, absent MLH1 expression is less specific for LS than absence of the other MMR proteins. In addition, rare instances of inherited germline MLH1 methylation have added additional complexity to the interpretation of MSI associated with absence of MLH1 expression. (Refer to the Microsatellite instability (MSI) section for more information about germline MLH1 hypermethylation.)
The prevalence of MSH2 mutations in individuals or families with LS has varied across studies. MSH2 mutations were reported in 38% to 54% of LS families in studies including large cancer registries, cohorts of early-onset CRC (<55 years), and registries around the world.
The lifetime risk of colon cancer associated with MSH2 mutations is estimated to be between 48% and 68%. In a case series of LS patients, those carrying germline MSH2 mutations (49 individuals, 45% females) had a lifetime (cutoff of age 60 years) risk of extracolonic cancers of 48% compared with 11% for MLH1 carriers (56 individuals, 50% females). In addition, the same group reported a significantly higher prevalence of poorly differentiated CRCs (44% for MSH2 carriers vs. 14% for MLH1 carriers; P = .002) and Crohn-like reaction (49% for MSH2 carriers vs. 27% for MLH1 carriers; P = .049). Another study reported no significant differences between the prevalence of colorectal and extracolonic cancers in 22 families with germline MLH1 mutations and in 12 families with germline MSH2 mutations.
Multiple groups have reported that MSH2 and MSH6 carriers have a greater chance of presenting with endometrial cancers before CRCs than do MLH1 carriers. The average age at diagnosis of endometrial cancers differed with genotype in two studies: age 41 years for MSH2 , age 49 years for MLH1, and age 55 years for MSH6 carriers.
Practices and pitfalls in testing
In patients with absence of MSH2 and MSH6 protein expression who have undergone genetic testing with no mutation found by the currently available standard techniques, germline mutation testing for EPCAM/TACSTD1 should be considered. It has been reported that approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 mutation identified will have germline deletions in EPCAM/TACSTD1. The latter mechanism accounts for approximately 5% of all LS cases. (Refer to the EPCAM/TACSTD1 section of this summary for more information.)
Most series show a prevalence of germline MSH6 mutations in approximately 10% of LS families. However, the reported range (5%–52%) is large. This wide variation is likely a result of small sample sizes, referral bias, and ascertainment bias.
The lifetime risk of colon cancer associated with MSH6 mutations is estimated to be between 12% and 22%. It appears that the lifetime risk of CRC might be lower in MSH6 carriers than in MSH2 and MLH1 carriers. Initial studies have suggested that inactivating germline mutations of MSH6 might be more frequent in persons with a later average age at onset of CRC whose tumors exhibit a non-MSI-high phenotype.
One study reported on 146 MSH6 carriers (59 men and 87 women) from 20 families, all of whom had truncating mutations in MSH6. While the prevalence of CRCs by age 70 years was not significantly different between MSH6 and MLH1 or MSH2 carriers (P = .0854), the mean age at diagnosis for colorectal carcinoma in male MSH6 mutation carriers was 55 years (n = 21; range, 26–84 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively. The prevalence of CRC was significantly lower in women with MSH6 germline mutations than in MLH1 or MSH2 carriers (P = .0049). The mean age at diagnosis for colorectal carcinoma in female MSH6 mutation carriers was 57 years (n = 15; range, 41–81 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively.
In addition, endometrial cancer has been reported to be more common in MSH6 families. In the same study, the cumulative risk of uterine cancer was significantly higher in MSH6 mutation carriers (71%) than in MLH1 (27%) and MSH2 (40%) mutation carriers (P = .02). The mean age at diagnosis of endometrial carcinoma was 54 years in MSH6 mutation carriers (n = 29; range, 43–65 years) versus 48 years and 49 years in MLH1 and MSH2 mutation carriers, respectively. A group of researchers reported on ten MSH6 kindreds with LS in which 70% of females had been diagnosed with endometrial cancer compared with 31% and 29% in MLH1 and MSH2 carriers, respectively. One study found the prevalence of endometrial carcinoma to be 58% in 12 MSH6 families with a mean age at diagnosis of 57 years.
One group of researchers assembled the largest series of MSH6 mutation carrier families to estimate penetrance of cancers. A total of 113 families of MSH6 mutation carriers from five countries were ascertained through family cancer clinics and population-based cancer registries. The families contained an estimated 1,043 mutation carriers. By age 70 years, 22% (95% CI, 14%–32%) of male MSH6 mutation carriers developed CRC compared with 10% (95% CI, 5%–17%) of female MSH6 mutation carriers. By age 80 years, 44% (95% CI, 28%–62%) of male MSH6 mutation carriers were diagnosed with CRC, compared with 20% (95% CI, 11%–35%) of female MSH6 mutation carriers. For all MSH6 mutation carriers, the increased risk of CRC, relative to that of the general population, across all age groups was statistically significantly elevated (HR, 7.6; 95% CI, 5.4–10.8; P < .001). By ages 70 years and 80 years, 26% (95% CI, 18%–36%) and 44% (95% CI, 30%–58%), respectively, of women would be diagnosed with endometrial cancer. Female MSH6 mutation carriers had an endometrial cancer risk that was about 25 times higher than women in the general population (HR, 25.5; 95% CI, 16.8–38.7; P < .001).
In the same study, female MSH6 mutation carriers had a cumulative risk of other Lynch cancers (i.e., ovarian, stomach, small intestine, kidney, ureter, or brain) of 11% (95% CI, 6%–19%) by age 70 years and 22% (95% CI, 12%–38%) by age 80 years. The risk of LS cancers, excluding colorectal and endometrial cancers, was six times that of the general population (HR, 6.0; 95% CI, 3.4–10.7; P < .001). Male MSH6 mutation carriers showed no evidence of an increased risk of these cancers (HR, 0.8; 95% CI, 0.1–8.8; P = .9). The authors estimated that 24% (95% CI, 16%–37%) of men and 40% (95% CI, 32%–52%) of women harboring deleterious MSH6 mutations would be diagnosed with any LS cancer by age 70 years and that these values will increase to 47% (95% CI, 2%– 66%) of men and 65% (95% CI, 53%–78%) of women by age 80 years.
Practices and pitfalls in testing
One study reported that of 42 population-based probands harboring deleterious MSH6 germline mutations who were ascertained independent of their family cancer history, 30 (71%) had a family cancer history that did not meet the Amsterdam II criteria.
MSH6 colorectal tumors can be MSI-high, MSI-low, or MSS. This pitfall illustrates the utility of IHC for the MMR protein expression. Eighteen of 21 (86%) of the colorectal tumors showed an MSI-high phenotype. Of the 16 endometrial tumors tested, 11 were MSI-high (69%); four were MSI-low (25%), and one was microsatellite stable (6%).
The prevalence of PMS2 germline mutations has been underappreciated for many reasons. It is the most recent of the major genes to be identified, probably has the lowest prevalence, was not felt to be worthy of serious investigation, and commercial testing is not widely available. One registry study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected LS. A population-based study reported a prevalence of approximately 5% (1 of 18).
A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 mutations, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.
In one study, patients with PMS2 mutations presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 mutations. However, these families were small and did not fulfill Amsterdam criteria.
Diagnostic strategies for all individuals diagnosed with CRC (universal testing)
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention, formed a working group to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The Working Group was commissioned to address the following question: Do risk assessment and MMR gene mutation testing in individuals with newly diagnosed CRC lead to improved outcomes for the patient or relatives, or are they useful in medical, personal, or public health decision-making? The Working Group constructed economic models to assist in analyzing available evidence on clinical utility in estimating how various testing strategies might function in practice. These included mutation frequency, sensitivity and specificity of both IHC and MSI testing, and the cost of these tests. The performance of these tests is based on the risk of positivity of carrying a mutation including family history, age at diagnosis, and extracolonic cancers. In 2009, the Working Group reported that there was sufficient evidence to recommend offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives. They concluded that there was insufficient evidence to recommend a specific gene-testing strategy among the following four strategies tested:
- All individuals with CRC tested for germline mutations in MSH2, MLH1, and MSH6. The average cost per LS detected was estimated to be $111,825.
- All tumors tested for MSI, followed by germline mutation analysis of MSH2, MLH1, and MSH6 offered to those with MSI-H tumors. The average cost per LS detected was estimated to be $47,268.
- All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2, followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. The average cost per LS detected was estimated to be $21,315.
- All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF mutation–negative tumors. The average cost per LS detected was estimated to be $18,863.
The EGAPP analysis made several assumptions, including (1) IHC and MSI will not detect all LS patients and (2) not all patients with CRC will opt for testing.
Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify LS among persons with newly diagnosed CRC. The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline mutation testing followed by directed screening and risk-reducing surgery. Similar to the EGAPP working group, IHC followed by BRAF mutation testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life year gained resulted from this strategy. In this model, the number of relatives tested (3 to 4) per proband was a critical determinant of both effectiveness and cost-effectiveness.
A different approach based on risk assessments of 100,000 simulated individuals representative of the U.S. population who were tracked from age 20 and exposed to 20 different screening strategies has been reported. In this study, the strategies involved risk assessment at different ages utilizing the PREMM126 model followed by mutation analysis for MLH1, MSH2, MSH6, and PMS2 in individuals whose mutation risk threshold exceeded 0%, 2.5%, 5%, or 10%. In individuals whose risk assessment (starting at age 25, 30, or 35 years) for carrying a mutation exceeded 5%, colorectal and endometrial cancers in mutation carriers were reduced by 12.4% and 8.8%, respectively. In the whole population, this strategy increased the quality adjusted life-years by 135 years per 100,000 individuals with an average cost-effectiveness ratio of $26,000. The authors suggested that the outlined strategy was more cost effective than current practice and could improve health care outcomes.
Diagnostic strategies for all individuals diagnosed with endometrial cancer
Based on a Markov mathematical model, a strategy of performing IHC for MMR protein expression in all patients with endometrial cancer, irrespective of the age at diagnosis, who have a first-degree relative with endometrial cancer, was reported to be cost-effective in the detection of LS in patients with LS-related cancer. (Refer to the Genetic testing section of this summary for more information about performing IHC for MMR protein expression.) In this study, incremental cost-effectiveness ratio (ICER) was defined as the additional cost of a specific strategy divided by its health benefit compared to an alternative strategy. In this model, the strategy of performing IHC on the tumor from all patients diagnosed with LS-related cancer who have a first-degree relative with endometrial cancer had an incremental cost ratio of $9,126 per year of life gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer younger than 50 years with at least one first-degree relative with LS-related cancer.
The model predicted that if all endometrial cancers in the United States (estimated to be 45,000 new cases in 2010) underwent IHC screening, 827 women (1.84%) would be diagnosed as LS patients. However, applying the strategy of testing only those endometrial tumors of patients with at least a first-degree relative with LS-related cancer, 755 affected individuals (1.68%) would be identified. If the Amsterdam II criteria were applied, 539 carriers (1.2%) would be identified. The authors stated that the incremental benefit of the most cost-effective strategy was only associated with an average life expectancy gain of 1 day compared with testing by Amsterdam II criteria. However, they argue that this may be significant, as it is comparable to the life expectancy gain from triennial cervical cancer screening, which is a current recommendation from the American College of Obstetricians and Gynecologists for women older than 30 years in the general population.
Several aspects of the biologic behavior of LS suggest how the approach to surveillance should differ from that for average-risk people:
- CRCs in LS occur earlier in life than do sporadic cancers. For MLH1 and MSH2 mutation carriers, the estimated risk of CRC at age 40 years is 31% for females and 32% for males; at age 50 years, the estimated risks are 52% and 57%, respectively. This suggests that screening should begin earlier in life.
- A larger proportion of LS CRCs (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Annual colonoscopic surveillance is recommended.
- The progression from normal mucosa to adenoma to cancer is accelerated, suggesting that screening should be done at shorter intervals (every 1–2 years) and with colonoscopy. Because patients with LS have an ordinary, or slightly increased, frequency of polyps but a substantially increased rate of cancer, it is clear that a larger proportion of polyps progress to cancer. It has been demonstrated that MMR gene mutation carriers develop adenomas at an earlier age than noncarriers. The mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23–63.2 years), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2–57.6 years).
- Incidence of CRC through life is substantially higher, suggesting that the most sensitive test available should be used.
- Patients with LS are at an increased risk of other cancers, especially those of the endometrium and ovary. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population. There is some evidence that the rate of individual cancers varies from kindred to kindred. Expert consensus suggests consideration of endometrial cancer screening by age 25 years.
Evidence-based reviews of surveillance colonoscopy in LS have been reported. There is only one controlled trial of CRC screening in LS. In a study from Finland, 252 at-risk members of 22 families with LS were offered screening for 15 years. One hundred thirty-three individuals accepted screening by either colonoscopy or barium enema and sigmoidoscopy, and 123 of the at-risk members (93%) completed screening. One hundred nineteen did not accept advice to be screened, although 24 (20%) had screening examinations outside the study. Once genetic testing was performed in these families (starting in 1996, 14 years after the beginning of screening), screening was recommended for mutation-positive controls, 63% of whom chose to begin active screening. The screened group had 62% fewer cancers (P < .03) and 65% fewer CRC deaths (10 vs. 26, P = .003). All of the CRCs detected in the screened population were local and caused no deaths, compared with nine deaths from CRC in the control group. The results, while biologically plausible, are of limited validity, primarily because the main comparison was between compliant and noncompliant patients, and compliant patients have been shown to have an inherently better prognosis, independent of intervention. This assertion is supported by the observed low rates of all causes of mortality. It is noteworthy, however, that these differences were observed in spite of the fact that most mutation-positive controls ultimately entered a screening program.
The data from this Finnish trial were subsequently updated. Over the course of the study (early 1980s to present), the approach to colonoscopy surveillance has evolved. Colonoscopy was the approach used for MMR mutation carriers when this information was obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years. The series limited its attention to subjects with no prior diagnosis of adenoma or cancer. The 420 mutation carriers, at a mean age of 36 years, underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about half were located proximal to the splenic flexure. While the rates for CRC despite colonoscopy surveillance appear high, it must be emphasized that the recommended short intervals were not regularly adhered to in this nonrandomized series. These authors concluded by recommending surveillance at 2-year intervals. The appropriate colonoscopy surveillance interval remains every 1 to 2 years according to most consensus guidelines. (Refer to Table 9 of this summary for more information.) Analysis of surveillance data in 242 patients 10 years after mutation testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with mutation-negative relatives. However, this may be attributable to the modest sample size of the study.
In other series, the risk of developing adenomas in an MMR gene mutation carrier has been reported to be 3.6 times higher than the risk in noncarriers. By age 60 years, 70% of the carriers developed adenomas, compared with 20% of noncarriers. As previously mentioned, these mutation carriers developed adenomas at an earlier age than noncarriers. Most of the adenomas in carriers had absence of MMR protein expression and were more likely to have dysplastic features, compared with adenomas from control subjects. Given that colonoscopy is the accepted measure for colon cancer surveillance, preliminary data suggest that the use of chromoendoscopy, such as with indigo carmine, may increase the detection of diminutive, histologically advanced adenomas.
Although screening the intact colon is usually recommended for at-risk LS family members, some patients, faced with the high risk of CRC and the fallibility of screening, elect to undergo risk-reducing colectomy. However, there is a risk of developing cancer in the remaining rectum.
Level of evidence: 3a
Table 9 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance for LS.Table 9. Practice Guidelines for Diagnosis and Colon Surveillance of Lynch Syndrome Organization Tumor MSITumor IHCMMR Mutation TestingAge Screening InitiatedFrequencyMethodCommentsC = colonoscopy; GI = gastrointestinal; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; NA = not addressed; NCCN = National Comprehensive Cancer Network.aGI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.American Cancer Society NA NA Counseling to consider genetic testing 21 y1–2 y until age 40 y, then annuallyC American Society of Colon and Rectal Surgeons   YesYesYesNANANAEurope Mallorca Group YesYesYes20–25 y; consider stopping at age 80 y1–2 y C Despite acknowledging that existing data support a 3 y screening interval, this group elected to recommend a shorter screening interval. GI Societiesa NA NANA20–25 y 1–2 y C NCCN YesYesYes20–25 y OR 2–5 y prior to the youngest age at diagnosis in the family if it is before age 25 y; whichever comes first1–2 yCFamilies in whom a tumor has shown informative IHC and MSI, but no germline mutation found, should have at-risk relatives screened as if they were mutation carriers.
Chemoprevention in LS
The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with LS who were in surveillance programs at a number of international centers. The study randomly assigned 861 participants to aspirin (600 mg/day), aspirin placebo, resistant starch (30 g/day), or starch placebo for up to 4 years. At a mean follow-up of 55.7 months (range: 1–128 mo), 53 primary CRCs developed in 48 participants (18 of 427 in the aspirin group and 30 of 434 in the aspirin placebo group). Seventy-six patients who refused randomization to the aspirin groups (due to aspirin sensitivity or history of peptic ulcer disease) were randomly assigned to receive resistant starch or resistant starch placebo. The intention-to-treat analysis yielded an HR for CRC of 0.63 (95% CI, 0.35–1.13; P = .12). However, five of the patients who developed CRC developed two primary colon cancers. A Poisson regression was performed to account for the effect of the multiple primary CRCs and yielded a protective effect for aspirin (incidence rate ratio [IRR], 0.56; 95% CI, 0.32–0.99; P = .05). For participants who completed at least 2 years of treatment, the per-protocol analysis yielded an HR of 0.41 (95% CI, 0.19–0.86; P = .02) and an IRR of 0.37 (0.18–0.78; P = .008). An analysis of all LS cancers (endometrial, ovarian, pancreatic, small bowel, gall bladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin versus placebo (HR, 0.65; 95% CI, 0.42–1.00; P = .05). There were no significant differences in adverse events between the aspirin and placebo groups, and no serious adverse effects were noted with any treatment. The authors concluded that 600 mg of aspirin per day for a mean of 25 months substantially reduced cancer incidence in LS patients. A limitation of the trial is that the frequency of surveillance studies at the various centers was not reported as being standardized. Earlier CAPP2 trial results for 746 LS patients enrolled in the study were published in 2008  and failed to show a significant preventive effect on incident colonic adenomas or carcinomas (relative risk [RR], 1.0; 95% CI, 0.7–1.4) with a shorter mean follow-up of 29 months (range: 7–74 mo). The CAPP3 trial, which will evaluate the effect of lower doses of aspirin, is expected to begin in 2013.
Screening for endometrial cancer in LS families
Note: A separate PDQ summary on Endometrial Cancer Screening in the general population is also available.
Cancer of the endometrium is the second most common cancer observed in LS families with initial estimates of cumulative risk in LS carriers of 30% to 39% by age 70 years. In a large Finnish study of 293 putative LS gene carriers, the cumulative lifetime risk of endometrial cancer was 43%. Endometrial cancer risk was directly related to age, ranging from 3.7% at age 40 years to 42.6% by age 80 years, compared with a 3% endometrial cancer risk in the general population. The maximal risk of endometrial cancer in LS families occurs 15 years earlier than in the general population, with the highest risk occurring between ages 55 and 65 years. In a community study of unselected endometrial cancer patients in central Ohio, at least 1.8% (95% CI, 0.9%–3.5%) of newly diagnosed patients had LS. Adenocarcinomas of the lower uterine segment may carry a greater risk of manifesting LS.
In the general population, the diagnosis of endometrial cancer is generally made when women present with symptoms including abnormal or postmenopausal bleeding. An office endometrial sampling, or a dilatation and curettage (D&C), is then performed, providing a histologic specimen for diagnosis. Eighty percent of women with endometrial cancer present with stage I disease due to the presenting symptoms. There is no data suggesting the clinical presentation in women with LS differs from the general population.
Given their substantial increased risk of endometrial cancer, endometrial screening for women with LS has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. Although the Pap test occasionally leads to a diagnosis of endometrial cancer, the sensitivity is too low for it to be a useful screening test. The presence of endometrial cells in a Pap smear obtained from a postmenopausal woman not taking hormone replacement therapy is abnormal and warrants further investigation. Two studies have examined the use of TVUS in endometrial screening for women with LS. In one study of 292 women from LS or LS-like families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women. In a second study, 41 women with LS were enrolled in a TVUS screening program. Of 179 TVUS procedures performed, there were 17 abnormal scans. Three of the 17 women had complex atypical hyperplasia on endometrial sampling, while 14 had normal endometrial sampling. However, TVUS failed to identify one patient who presented 8 months after a normal TVUS with abnormal vaginal bleeding, and was found to have stage IB endometrial cancer. Both of these studies concluded that TVUS is neither sensitive or specific. A study of 175 women with LS, which included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity over TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS. While this cohort study demonstrates that endometrial sampling may have benefits over TVUS for endometrial screening, there is no data that predicts screening with any other modality has benefits for endometrial cancer survival in women with LS. Given the favorable survival for endometrial cancer diagnosed by symptoms, it is unlikely that a sufficiently powered screening study will be able to demonstrate a survival advantage. Certainly, women with LS should be counseled that abnormal or postmenopausal vaginal bleeding warrants an endometrial sampling or D&C.
Routine screening for endometrial cancer has not been shown to be beneficial in the general population, but expert consensus suggests that it be considered in women who are members of high-risk LS families. Some studies suggest that women with a clinical or genetic diagnosis of LS do not universally adopt intensive gynecologic screening. (Refer to the Gynecologic cancer screening in LS section of this summary for more information.) Despite absence of a survival advantage, a task force organized by the National Institutes of Health (NIH) has suggested annual endometrial sampling beginning at age 30 to 35 years. TVUS can also be considered annually to evaluate the ovaries.
The published literature on TVUS for endometrial cancer screening has shown it to be insensitive and nonspecific, but because there may still be a role for TVUS in ovarian cancer screening, clinical practice guidelines have been reluctant to date to recommend against TVUS.
Level of evidence: 5
Surgical management in LS
There have been no controlled studies of the benefit of risk-reducing surgery in at-risk MMR gene mutation carriers. Recommendations based upon expert opinion, however, have been formulated by a panel convened by an NIH research consortium. The expert panel recommended consideration of risk-reducing subtotal colectomy as an option for persons with LS having adenomas at surveillance because of their risk of additional adenomas and cancer. In addition, the panel recommended presenting risk-reducing subtotal colectomy as an option for persons with LS who are not willing or are unable to undergo periodic colonic surveillance. Patients should be counseled, however, that the efficacy of these interventions is unknown.
The expert panel recommended that risk-reducing hysterectomy (RRH) and bilateral salpingo-oophorectomy (RRSO) be presented as options for women with LS, and that counseling include thoughtful discussion of childbearing plans, psychosocial effects of risk-reducing surgery, long-term effects of prolonged estrogen replacement therapy, and uncertainties concerning the efficacy of risk-reducing surgery as a means to reduce the risk of endometrial or ovarian cancer.
Level of evidence for colon cancer: 5
A retrospective study of 315 female patients with germline mutations associated with LS reported no occurrences of endometrial, ovarian, or primary peritoneal cancers in women who underwent RRH with or without RRSO compared with women who had no risk-reducing surgery. Sixty-nine of 210 women developed endometrial cancer, and 12 of 223 women developed ovarian cancer in the control group. In the risk-reducing surgery group, 61 and 47 women underwent RRH or RRSO, respectively. The authors suggested that RRH with RRSO is an effective strategy for preventing endometrial and ovarian cancer in women with LS. There were no data on survival benefit from risk-reducing surgical intervention in this study.
Level of evidence: 3di
The surgical management of a patient with LS must be individualized. Management of these patients can be subdivided into patients with newly diagnosed CRC, those with CRC treated with segmental resection, and those who are at risk of developing CRC or who are mutation carriers. Because of the increased incidence of synchronous and metachronous colorectal neoplasms, many experts have advocated that the treatment of choice for a LS patient with newly diagnosed colon cancer is a subtotal colectomy with anastomosis of the ileum to either the sigmoid colon or the rectum. The risk of metachronous CRCs has been estimated to be as high as 40% at 10 years after less than a subtotal colectomy, and up to 72% at 40 years after the diagnosis of CRC. There are no prospective data, however, to suggest a survival benefit from a subtotal colectomy over a segmental resection. In a decision analysis model, one study showed that performing a subtotal colectomy at a young age (27 and 47 years) led to an increased life expectancy of 1 to 2.3 years compared with a segmental resection. In this model, the potential benefit in life expectancy depended on the age of the patient and stage of the cancer at diagnosis. The older the patient and/or the more advanced cancer at diagnosis, the less theoretical benefit in terms of life expectancy from a subtotal colectomy as opposed to a segmental resection. This model did not take into account quality of life and was reported in absolute years. In a Markov decision analysis model taking into account both survival and quality of life based on assumptions obtained from published literature, the mean survival of a male aged 30 years with LS was 0.7 years better in an individual who underwent a total abdominal colectomy versus a segmental resection. When quality-adjusted life years (QALYs) were taken into account in this model, patients undergoing segmental resection had 21.5 QALYs, whereas patients undergoing an abdominal colectomy had 21.2 QALYs. Because the data underpinning these models are not likely to be validated and this topic is controversial, most surgeons choose to individualize the surgical decision based on patient-centered considerations.
Aside from the diagnosis of LS, other factors to consider in individualizing the surgical decision are age at diagnosis and the stage of the primary CRC. Most surgeons would consider loss of protein expression or MSI in the tumor in patients younger than age 50 years as evidence of LS even if germline mutational testing is uninformative or cannot be done before surgery. After more extensive resections, younger individuals tend to adapt better in terms of bowel function than older individuals undergoing similar procedures. In a cross-sectional quality-of-life and functional outcome survey of LS patients with more extensive (subtotal colectomy) or less extensive (segmental resection or hemicolectomy) resections, global quality-of-life outcomes were comparable, although patients with greater extent of resection described more frequent bowel movements and related dysfunction. This parallels the experience in FAP in which objectively measured dysfunction in ileal pouch patients does not appear to translate into an inferior quality-of-life assessment, compared with patients with abdominal colectomy and ileorectal anastomosis.
Similar results regarding a decrease in the number of metachronous CRCs after subtotal or total abdominal colectomy at the time of diagnosis of first CRC were reported by retrospective studies from Creighton University and the Cancer Family Registries. No survival advantage was demonstrated when performing a more extensive procedure compared to a segmental resection in these studies.
When considering the surgical options, it is important to recognize that a subtotal colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant following a subtotal colectomy has been reported to be 12% at 12 years postcolectomy. In addition to the general complications of surgery, there are the potential risks of urinary and sexual dysfunction and diarrhea following a subtotal colectomy, with these risks being greater the more distal the anastomosis. Therefore, the choice of surgery must be made on an individual basis by the surgeon and the patient. In all LS patients who have undergone a partial surgical resection of the colon, endoscopic surveillance should be the mainstay of follow-up.
The data on a decrease in metachronous CRC, and thus, a decrease in the number of surgeries, support the notion of routine subtotal colectomy in patients with LS. However, it appears that this has not penetrated surgical practice where functional outcomes weigh heavily in decision making. While young patients will in theory live longer and therefore be at a higher risk of metachronous CRC and in general will adapt better functionally than older patients, the majority of young patients with LS and CRC undergo segmental resection.
Advances in Endoscopic Imaging in Hereditary CRC
Performance of endoscopic therapies for adenomas in FAP and LS, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and LS the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in LS.
The need for sensitive means to endoscopically detect subtle polyps has increased with the recognition of flat adenomas and sessile serrated polyps in otherwise average-risk subjects, very attenuated adenoma phenotypes in attenuated adenomatous polyposis (AFAP), and subtle flat adenomas in LS. Modern high-resolution endoscopes improve adenoma detection yield, but the use of various vital dyes, especially indigo carmine dye-spray, has further improved detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue), with or without magnification, or possibly newer imaging techniques such as narrow-band imaging, may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper gastrointestinal endoscopy may be informative if duodenal adenomas or fundic gland polyps with surface dysplasia are found. Such findings will increase the likelihood of mutation detection if APC or MYH testing is pursued.
In various large series of average-risk populations, subtle flat lesions were detected in about 5% to 10% of cases, including adenomas with high-grade dysplasia and invasive adenocarcinoma. Some of these studies involved tandem procedures—white-light exam followed by randomization to “intensive” (> 20-minute pull-back from cecum) inspection versus chromoendoscopy—with significantly more adenomas detected in the chromoendoscopy group. However, in several randomized trials, no significant difference in yield was seen.
In a randomized trial of subjects with LS, standard colonoscopy, with polypectomy as indicated, was followed by either indigo carmine chromoendoscopy or repeat “intensive” white-light colonoscopy (a design very nearly identical to the average-risk screening group noted above). In this series, no significant difference in adenoma yield between the chromoendoscopy and intensive white-light groups was detected. However, these patients were younger and in many cases had undergone several previous exams that might have resulted in polyp clearing.
In a German study, one series of LS patients underwent white-light exam followed by chromoendoscopy, while a second series underwent colonoscopy with narrow-band imaging followed by chromoendoscopy. Significant differences in flat polyp detection favored chromoendoscopy in both series, although some of the detected lesions were hyperplastic. In a French series of LS subjects that also employed white-light exam followed by chromoendoscopy, significantly more adenomas were detected with chromoendoscopy.
Fewer evaluations of chromoendoscopy have been performed in attenuated FAP than in LS. One study examined four patients with presumed AFAP and fewer than 20 adenomas upon white-light examination. All had more than 1,000 diminutive adenomas found on chromoendoscopy, in agreement with pathology evaluation after colectomy.
A similar role for chromoendoscopy has been suggested to evaluate the duodenum in FAP. One study from Holland that used indigo carmine dye-spray to detect duodenal adenomas showed an increase in the number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.
Small Bowel Imaging
Patients with PJS and juvenile polyposis syndrome are at greater risk of disease-related complications in the small bowel (e.g., bleeding, obstruction, intussusception, or cancer). FAP patients, although at great risk of duodenal neoplasia, have a relatively low risk of jejunoileal involvement. The RR of small bowel malignancy is very high in LS, but absolute risk is less than 10%. Although the risks of small bowel neoplasia are high enough to warrant consideration of surveillance in each disease, the technical challenges of doing so have been daunting. Because of the technical challenges and relatively low prevalences, there is virtually no evidence base for small-bowel screening in LS.
Historically, the relative endoscopic inaccessibility of the mid and distal small bowel required radiographic measures for its evaluation, including the barium small bowel series or a variant called tube enteroclysis, in which a nasogastroduodenal tube is placed so that all of the contrast goes into the small intestine for more precise imaging. None of these measures were sensitive for small lesions. Any therapeutic undertaking required laparotomy. This entailed resection in most cases, although intraoperative endoscopy, with or without enterotomy for scope access, has been available for many years. Peroral enteroscopy (aided by stiffening overtubes with two balloons, one balloon, or spiral ribs) has been employed to overcome the technical problem of excessive looping, enabling deep jejunal access with therapeutic (polypectomy) potential.
Most data relate to PJS with double-balloon enteroscopy as the preferred method for endoscopy of the small bowel. This may involve only peroral enteroscopy, although subsequent retrograde enteroscopy has been described for more complete evaluation of the total small bowel. Because these procedures are time-consuming and involve some risk of complication, deep enteroscopy is usually preceded by more noninvasive imaging, including traditional barium exams, capsule endoscopy, and CT or magnetic resonance enterography.
In FAP, data from capsule endoscopy  show a 50% to 100% prevalence of jejunal and/or ileal polyps in patients with Spigelman stage III or stage IV duodenal involvement, but virtually no such polyps in Spigelman stage I or stage II disease. All polyps were smaller than 10 mm and were not biopsied or removed. Consequently, their clinical significance remains uncertain but is likely limited, given the infrequency of jejunoileal cancer reports in FAP.
Capsule endoscopy in the small series of PJS patients described above  showed the presence of a similar frequency (50%–100%) of polyps, but the prevalent polyps were much larger than in FAP, were more likely to become symptomatic, and warranted endoscopic or surgical excision. Capsule studies were suggested as an appropriate replacement for radiographic studies because of the sensitivity of capsule.
An estimated 7% to 10% of people have a first-degree relative with CRC, and approximately twice that many have either a first-degree or a second-degree relative with CRC. A simple family history of CRC (defined as one or more close relatives with CRC in the absence of a known hereditary colon cancer) confers a twofold to sixfold increase in risk. The risk associated with family history varies greatly according to the age of onset of CRC in the family members, the number of affected relatives, the closeness of the genetic relationship (e.g., first-degree relatives), and whether cancers have occurred across generations. A positive family history of CRC appears to increase the risk of CRC earlier in life such that at age 45 years, the annual incidence is more than three times higher than that in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals. The incidence in a 35- to 40-year-old is about the same as that of an average-risk person at age 50 years. There is no evidence to suggest that CRC in people with one affected first-degree relative is more likely to be proximal or is more rapidly progressive.
A personal history of adenomatous polyps confers a 15% to 20% risk of subsequently developing polyps  and increases the risk of CRC in relatives. The RR of CRC, adjusted for the year of birth and sex, was 1.78 (95% CI, 1.18–2.67) for the parents and siblings of the patients with adenomas as compared with the spouse controls. The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% CI, 1.46–4.58), compared with the siblings of patients who were 60 years or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex, with a parental history of CRC.
While familial clusters account for approximately 20% of all CRC cases in developed countries, the rare and highly penetrant Mendelian CRC diseases contribute to only a fraction of familial cases, which suggests that other genes and/or shared environmental factors may contribute to the remainder of the cancers. Two studies attempted to determine the degree to which hereditary factors contribute to familial CRCs.
The first study utilized the Swedish, Danish, and Finnish twin registries that cumulatively provided 44,788 pairs of same-sex twins (for men: 7,231 monozygotic [MZ] and 13,769 dizygotic [DZ] pairs; for women: 8,437 MZ and 15,351 DZ pairs) to study the contribution of heritable and environmental factors involved in 11 different cancers. The twins included in the study all resided in their respective countries of origin into adulthood (>50 years). Cancers were identified through their respective national cancer registries in 10,803 individuals from 9,512 pairs of twins. The premise of the study was based on the fact that MZ twins share 100% and DZ twins share 50% of their genes on average for any individual twin pair. This study calculated that heritable factors accounted for 35%, shared environmental factors for 5%, and nonshared environmental factors for 60% of the risk of CRC. For CRC, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that although nonshared environmental factors constitute the major risk of familial CRC, heredity plays a larger-than-expected role.
The second study utilized the Swedish Family-Cancer Database, which contained 6,773 and 31,100 CRCs in offspring and their parents, respectively, from 1991 to 2000. The database included 253,467 pairs of spouses, who were married and lived together for at least 30 years, and who were used to control for common environmental effects on cancer risk. The overall SIR for cancers of the colon, rectum, and colon and rectum combined in the offspring of an affected parent was 1.81 (95% CI, 1.62–2.02), 1.74 (95% CI, 1.53–1.96), and 1.78 (95% CI, 1.53–1.96), respectively. The risk conferred by affected siblings was also significantly elevated. Because there was no significantly increased risk of CRC conferred between spouses, the authors concluded that heredity plays a significant role in familial CRCs; however, controls for shared environmental effects among siblings were absent in this study.
Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members, but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for LS. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of familial CRC remains a research challenge.
Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families, with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas. A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2. A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.
Familial CRC type X
Families meeting Amsterdam-I criteria for LS who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic LS and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as familial CRC type X, and it has been suggested that these families be classified as a distinct group.
Age of CRC onset in LS ranges from 44 years (registry series) to a mean of 52 years (population-based series). There are no corresponding population-based data for familial CRC type X, as familial CRC type X by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between familial CRC type X and LS have suggested that the age of onset is slightly older in familial CRC type X, but the lifetime risk of cancer is substantially lower. The SIR for CRC among families with intact MMR (type X families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective MMR (LS families). The risk of extracolonic tumors was also not found to be elevated for the type X families, suggesting that enhanced surveillance for CRC was sufficient. Although further studies are required, tumors arising within type X families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those from families with LS.
Interventions/family history of CRC
There are no controlled comparisons of screening in people with a mild or modest family history of CRC. Most experts, if they accept that average-risk people should be screened starting at age 50 years, suggest that screening should begin earlier in life (e.g., at age 35 to 40 years) when the magnitude of risk is comparable to that of a 50-year-old. Because the risk increases with the extent of family history, there is room for clinical judgment in favor of even earlier screening, depending on the details of the family history. Some experts suggest shortening the frequency of the screening interval to every 5 years, rather than every 10 years.
A common but unproven clinical practice is to initiate CRC screening 10 years before the age of the youngest CRC case in the family. There is neither direct evidence nor a strong rational argument for using aggressive screening methods simply because of a modest family history of CRC.
These issues were weighed by a panel of experts convened by the American Gastroenterological Association before publishing clinical guidelines for CRC screening, including those for persons with a positive family history of CRC. These guidelines have been endorsed by a number of other organizations.
The American Cancer Society and the United States Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals. These guidelines address screening issues related to modest family history of CRC or adenomas. Given the heterogeneity of this grouping, it is beyond the scope of this more targeted discussion of major gene conditions.
Rare Colon Cancer Syndromes
Peutz-Jeghers syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, and the perioral and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous. Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families. (Refer to the Peutz-Jeghers Gene(s) section in the PDQ summary on Genetics of Colorectal Cancer for more information.) The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancy. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS. Table 10 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome in the PDQ summary on Genetics of Colorectal Cancer.
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in over-estimates of these risks should be considered.Table 10. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified AgeaSiteAge (y)Cumulative Risk (%)bReference(s)GI = Gastrointestinal.aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology , copyright 2010.bAll cumulative risks were increased compared to the general population (P < .05) with the exception of cervix and testes.cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.dWesterman et al.: GI cancer does not include pancreatic cancer.eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.Any cancer60–7037–93GI cancerc,d60–7038–66Gynecological cancer60–7013–18Per originStomach6529Small bowel6513Colorectum6539Pancreas65–7011–36Lung65–707–17Breast60–7032–54Uterus659Ovary6521Cervixe6510Testese659
Juvenile polyposis syndrome (JPS)
JPS is a genetically heterogeneous, rare, childhood-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract and can present with diarrhea, GI tract hemorrhage, and protein-losing enteropathy. While most patients with juvenile polyposis appear to represent sporadic illness, this may be due to reduced penetrance. Juvenile polyposis syndrome is due to germline mutations in the MADH4 gene, also known as SMAD4/DPC4, at chromosome 18q21  in approximately 15% to 20% of cases, and to mutations in the gene-encoding bone morphogenic protein receptor 1A (BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases. The lifetime CRC risk in JPS has been reported to be 39%.
A severe form of JPS, in which polyposis develops in the first few years of life, is referred to as JPS of infancy. JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN. (Refer to the Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s) section of this summary for more information about PTEN.) The phenotype often includes features such as macrocephaly and developmental delay, possibly as a result of loss of PTEN function. Recurrent gastrointestinal bleeding, diarrhea, exudative enteropathy, in addition to associated developmental delay, are associated with a very high rate of morbidity and mortality in these infants, thereby limiting the heritability of such cases.
Hereditary mixed polyposis syndrome (HMPS)
HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas; atypical juvenile polyps; and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14. While there is considerable phenotypic overlap between JPS and HMPS, one large family has been linked to a locus on chromosome 15, raising the possibility that this may be a distinct disorder.
Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene. Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.
Similar results were obtained in another study conducted in Poland. In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.
Hyperplastic polyposis syndrome (HPPS)
Isolated and multiple hyperplastic polyps (HP) (typically white, flat, and small) are common in the general population and their presence does not suggest an underlying genetic disorder. The clinical diagnosis of hyperplastic polyposis syndrome (HPPS), as defined by the World Health Organization (WHO), must satisfy one of the following criteria:
- At least five histologically diagnosed HP occurring proximal to the sigmoid colon (of which at least two are greater than 10 mm in diameter).
- One HP occurring proximal to the sigmoid colon in an individual who has at least one first-degree relative with hyperplastic polyposis.
- Greater than 30 HPs distributed throughout the colon.
These WHO criteria are based on expert opinion; there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Although the vast majority of cases of HPPS lack a family history of HPs, approximately half of HPPS cases have a positive family history for CRC. Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for HPPS is 50% or more.
Only one study to date has linked a germline mutation with HPPS. In a recent study of 38 patients with more than 20 HPs, a large (>1 cm) HP, or HPs in the proximal colon, molecular alterations were sought in the base-excision repair genes MBD4 and MYH. One patient was found to have biallelic MYH mutations, and thus was diagnosed with MYH-associated polyposis. No pathogenic mutations were detected in MBD4 among 27 patients tested. However, six patients had single nucleotide polymorphisms of uncertain significance. Only two patients had a known family history of HPPS, and ten of the 38 patients developed CRC. This series presumably included patients with sporadic HPs mixed in with other patients who may have HPPS.
In a cohort of 40 HPPS patients, defined as having more than five HPs or more than three HPs, two of which were larger than 1 cm in diameter, one patient was found to have a germline mutation in the EPHB2 gene (D861N). The patient had serrated adenomas and more than 100 HPs in her colon at age 58 years, and her mother died of colon cancer at age 36 years. EPHB2 germline mutations were not found in 100 additional patients with a personal history of CRC or in 200 population-matched healthy control patients.
The EPHB2 gene is a target of the Wnt/beta-catenin signaling pathway and is important in the compartmentalization of intestinal epithelial cell proliferation to the intestinal crypts. When mice with disruption of the Ephb2 gene were bred with Apcmin/+ mice, tumor progression was accelerated suggesting that Ephb2 is a tumor suppressor whose loss of expression in the colon enhances adenoma progression.
Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in HPPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF mutation (V600E) was found in polyp tissue. Fifty percent (20 of 40) of HPs from these patients demonstrated the V600E BRAF mutation. The HPs from these patients also demonstrated significantly higher CpG island methylation phenotypes (CIMP-high), and fewer KRAS mutations than left-sided sporadic HPs. In a previous study from this group, HPs from patients with HPPS showed a loss of chromosome 1p in 21% (16 of 76) versus 0% in HPs from patients with large HPs (>1 cm), or only five to ten HPs.
Many of the genetic and histological alterations found in HPs of patients with HPPS are common with the recently defined CIMP pathway of colorectal adenocarcinoma. The CIMP pathway (identified molecularly by hypermethylation of specific genes such as CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) is characterized histologically by a hyperplastic polyp-serrated adenoma-adenocarcinoma sequence. BRAF mutations are more commonly associated with the right colon and methylation of p16INK and MINT31.
Interventions/rare colon cancer syndromes
Individuals with Peutz-Jeghers and juvenile polyposis syndromes are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Due to the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion). One's best clinical judgment must be used in making screening recommendations based on published guidelines.Table 11. Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome Organization/ Author STK11 Gene Testing RecommendedaAge Colon Screening InitiatedFrequencyMethodExtracolonic Screening RecommendationsCommentACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; FS = flexible sigmoidoscopy; NCCN = National Comprehensive Cancer Network. aSTK11 mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing. bLung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.ACPGBI18 y3 yC or FS + BENo mention of extracolonic screeningNo mention of genetic testing; need to consider STK11/LKB1 testingBrosens et al. Yes, age not specifiedLate teens or at symptoms 3 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach, TestesGenetic testing at late teens or at symptomsGiardiello and Trimbath Yes, at age 8 y18 y2–3 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach, TestesNCCN No specific recommendationLate teens2–3 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Lungb, Pancreas, Small Intestine, Stomach, Testes Refer to specialized teamvan Lier et al.  25–30 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, StomachZbuk and Eng 18 y 3 yCBreast, Gynecologic (Cervix, Ovaries), Pancreas, Small Intestine, Stomach, Testes
Level of evidence: 5Table 12. Clinical Practice Guidelines for the Diagnosis of Colon Cancer in Familial Juvenile Polyposis Syndrome (JPS)Organization/ AuthorSMAD4/BMPR1A Testing Recommendeda Age Screening InitiatedFrequencyMethodCommentACGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; NCCN = National Comprehensive Cancer Network. aSMAD4/BMPR1A mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing.bYounger, if patient has presented with symptoms.ACGBI 15–18 yb1–2 yC or FS + BEGene carriers and affected surveillance until age 70 y and discussion of prophylactic surgeryBrosens et al. Yes, genetic testing preferred over colonoscopy15 y or at symptomsYearly until polyp free then every 2–3 yCProphylactic surgery if >50–100 polyps, unable to manage endoscopically, severe GI bleeding, JPS with adenomatous changes, strong family history of CRCNCCN No specific recommendation~15 y2–3 y or 1 y if polyps are foundCRefer to specialized teamZbuk and Eng 15 y3 yC, EGDSome families with SMAD4 mutation also have HHT; these individuals may need to be screened for HHT
Level of evidence: 51Bussey HJ: Familial Polyposis Coli: Family Studies, Histopathology, Differential Diagnosis, and Results of Treatment. Baltimore, Md: The Johns Hopkins University Press, 1975.2Burt RW, Leppert MF, Slattery ML, et al.: Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology 127 (2): 444-51, 2004.3Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996.4Stoffel E, Mukherjee B, Raymond VM, et al.: Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 137 (5): 1621-7, 2009.5Aretz S, Uhlhaas S, Goergens H, et al.: MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer 119 (4): 807-14, 2006.6Hearle N, Schumacher V, Menko FH, et al.: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12 (10): 3209-15, 2006.7Coburn MC, Pricolo VE, DeLuca FG, et al.: Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 2 (5): 386-91, 1995.8Desai DC, Neale KF, Talbot IC, et al.: Juvenile polyposis. Br J Surg 82 (1): 14-7, 1995.9Herrera L, ed.: Familial Adenomatous Polyposis. New York, NY: Alan R. Liss Inc, 1990.10Bülow S: Familial polyposis coli. Dan Med Bull 34 (1): 1-15, 1987.11Campbell WJ, Spence RA, Parks TG: Familial adenomatous polyposis. Br J Surg 81 (12): 1722-33, 1994.12Giardiello FM, Offerhaus JG: Phenotype and cancer risk of various polyposis syndromes. Eur J Cancer 31A (7-8): 1085-7, 1995 Jul-Aug.13Jagelman DG, DeCosse JJ, Bussey HJ: Upper gastrointestinal cancer in familial adenomatous polyposis. Lancet 1 (8595): 1149-51, 1988.14Sturt NJ, Gallagher MC, Bassett P, et al.: Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation. Gut 53 (12): 1832-6, 2004.15Lynch HT, Fitzgibbons R Jr: Surgery, desmoid tumors, and familial adenomatous polyposis: case report and literature review. Am J Gastroenterol 91 (12): 2598-601, 1996.16Bülow S, Björk J, Christensen IJ, et al.: Duodenal adenomatosis in familial adenomatous polyposis. Gut 53 (3): 381-6, 2004.17Burt RW: Colon cancer screening. Gastroenterology 119 (3): 837-53, 2000.18Galiatsatos P, Foulkes WD: Familial adenomatous polyposis. Am J Gastroenterol 101 (2): 385-98, 2006.19Bisgaard ML, Bülow S: Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts. Am J Med Genet A 140 (3): 200-4, 2006.20Berk T, Cohen Z, Bapat B, et al.: Negative genetic test result in familial adenomatous polyposis: clinical screening implications. Dis Colon Rectum 42 (3): 307-10; discussion 310-2, 1999.21Petersen GM, Slack J, Nakamura Y: Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 100 (6): 1658-64, 1991.22Jagelman DG: Clinical management of familial adenomatous polyposis. Cancer Surv 8 (1): 159-67, 1989.23Neale K, Ritchie S, Thomson JP: Screening of offspring of patients with familial adenomatous polyposis: the St. Mark's Hospital polyposis register experience. In: Herrera L, ed.: Familial Adenomatous Polyposis. New York, NY: Alan R. Liss Inc, 1990, pp 61-66.24Patenaude AF: Cancer susceptibility testing: risks, benefits, and personal beliefs. In: Clarke A, ed.: The Genetic Testing of Children. Oxford, England: BIOS Scientific, 1998, pp 145-156.25Anthony T, Rodriguez-Bigas MA, Weber TK, et al.: Desmoid tumors. J Am Coll Surg 182 (4): 369-77, 1996.26Eccles DM, van der Luijt R, Breukel C, et al.: Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet 59 (6): 1193-201, 1996.27Bertario L, Russo A, Sala P, et al.: Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 95 (2): 102-7, 2001.28Lynch HT: Desmoid tumors: genotype-phenotype differences in familial adenomatous polyposis--a nosological dilemma. Am J Hum Genet 59 (6): 1184-5, 1996.29Scott RJ, Froggatt NJ, Trembath RC, et al.: Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet 5 (12): 1921-4, 1996.30Caspari R, Olschwang S, Friedl W, et al.: Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet 4 (3): 337-40, 1995.31Davies DR, Armstrong JG, Thakker N, et al.: Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 57 (5): 1151-8, 1995.32Bertario L, Russo A, Sala P, et al.: Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 21 (9): 1698-707, 2003.33Elayi E, Manilich E, Church J: Polishing the crystal ball: knowing genotype improves ability to predict desmoid disease in patients with familial adenomatous polyposis. Dis Colon Rectum 52 (10): 1762-6, 2009.34Nieuwenhuis MH, Lefevre JH, Bülow S, et al.: Family history, surgery, and APC mutation are risk factors for desmoid tumors in familial adenomatous polyposis: an international cohort study. Dis Colon Rectum 54 (10): 1229-34, 2011.35Clark SK, Smith TG, Katz DE, et al.: Identification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis. Br J Surg 85 (7): 970-3, 1998.36Hodgson SV, Maher ER: Gastro-intestinal system. In: Hodgson SV, Maher ER: A Practical Guide to Human Cancer Genetics. 2nd ed. New York, NY: Cambridge University Press, 1999, pp 167-175.37Rodriguez-Bigas MA, Mahoney MC, Karakousis CP, et al.: Desmoid tumors in patients with familial adenomatous polyposis. Cancer 74 (4): 1270-4, 1994.38Clark SK, Neale KF, Landgrebe JC, et al.: Desmoid tumours complicating familial adenomatous polyposis. Br J Surg 86 (9): 1185-9, 1999.39Belchetz LA, Berk T, Bapat BV, et al.: Changing causes of mortality in patients with familial adenomatous polyposis. Dis Colon Rectum 39 (4): 384-7, 1996.40Iwama T, Tamura K, Morita T, et al.: A clinical overview of familial adenomatous polyposis derived from the database of the Polyposis Registry of Japan. Int J Clin Oncol 9 (4): 308-16, 2004.41Church J, Berk T, Boman BM, et al.: Staging intra-abdominal desmoid tumors in familial adenomatous polyposis: a search for a uniform approach to a troubling disease. Dis Colon Rectum 48 (8): 1528-34, 2005.42Parc Y, Piquard A, Dozois RR, et al.: Long-term outcome of familial adenomatous polyposis patients after restorative coloproctectomy. Ann Surg 239 (3): 378-82, 2004.43Tonelli F, Ficari F, Valanzano R, et al.: Treatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene. Tumori 89 (4): 391-6, 2003 Jul-Aug.44Hansmann A, Adolph C, Vogel T, et al.: High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 100 (3): 612-20, 2004.45Lindor NM, Dozois R, Nelson H, et al.: Desmoid tumors in familial adenomatous polyposis: a pilot project evaluating efficacy of treatment with pirfenidone. Am J Gastroenterol 98 (8): 1868-74, 2003.46Mace J, Sybil Biermann J, Sondak V, et al.: Response of extraabdominal desmoid tumors to therapy with imatinib mesylate. Cancer 95 (11): 2373-9, 2002.47Gega M, Yanagi H, Yoshikawa R, et al.: Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 24 (1): 102-5, 2006.48Heiskanen I, Järvinen HJ: Occurrence of desmoid tumours in familial adenomatous polyposis and results of treatment. Int J Colorectal Dis 11 (4): 157-62, 1996.49Latchford AR, Sturt NJ, Neale K, et al.: A 10-year review of surgery for desmoid disease associated with familial adenomatous polyposis. Br J Surg 93 (10): 1258-64, 2006.50Church JM, McGannon E, Hull-Boiner S, et al.: Gastroduodenal polyps in patients with familial adenomatous polyposis. Dis Colon Rectum 35 (12): 1170-3, 1992.51Sarre RG, Frost AG, Jagelman DG, et al.: Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut 28 (3): 306-14, 1987.52Watanabe H, Enjoji M, Yao T, et al.: Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. Hum Pathol 9 (3): 269-83, 1978.53Weston BR, Helper DJ, Rex DK: Positive predictive value of endoscopic features deemed typical of gastric fundic gland polyps. J Clin Gastroenterol 36 (5): 399-402, 2003 May-Jun.54Abraham SC, Nobukawa B, Giardiello FM, et al.: Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations. Am J Pathol 157 (3): 747-54, 2000.55Odze RD, Marcial MA, Antonioli D: Gastric fundic gland polyps: a morphological study including mucin histochemistry, stereometry, and MIB-1 immunohistochemistry. Hum Pathol 27 (9): 896-903, 1996.56Wu TT, Kornacki S, Rashid A, et al.: Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis. Am J Surg Pathol 22 (3): 293-8, 1998.57Burt RW: Gastric fundic gland polyps. Gastroenterology 125 (5): 1462-9, 2003.58Bianchi LK, Burke CA, Bennett AE, et al.: Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clin Gastroenterol Hepatol 6 (2): 180-5, 2008.59Jalving M, Koornstra JJ, Wesseling J, et al.: Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 24 (9): 1341-8, 2006.60Leggett B: FAP: another indication to treat H pylori. Gut 51 (4): 463-4, 2002.61Nakamura S, Matsumoto T, Kobori Y, et al.: Impact of Helicobacter pylori infection and mucosal atrophy on gastric lesions in patients with familial adenomatous polyposis. Gut 51 (4): 485-9, 2002.62Iida M, Yao T, Itoh H, et al.: Natural history of gastric adenomas in patients with familial adenomatosis coli/Gardner's syndrome. Cancer 61 (3): 605-11, 1988.63Bülow S, Alm T, Fausa O, et al.: Duodenal adenomatosis in familial adenomatous polyposis. DAF Project Group. Int J Colorectal Dis 10 (1): 43-6, 1995.64Park JG, Park KJ, Ahn YO, et al.: Risk of gastric cancer among Korean familial adenomatous polyposis patients. Report of three cases. Dis Colon Rectum 35 (10): 996-8, 1992.65Iwama T, Mishima Y, Utsunomiya J: The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment. Ann Surg 217 (2): 101-8, 1993.66Offerhaus GJ, Giardiello FM, Krush AJ, et al.: The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 102 (6): 1980-2, 1992.67Brosens LA, Keller JJ, Offerhaus GJ, et al.: Prevention and management of duodenal polyps in familial adenomatous polyposis. Gut 54 (7): 1034-43, 2005.68Perzin KH, Bridge MF: Adenomas of the small intestine: a clinicopathologic review of 51 cases and a study of their relationship to carcinoma. Cancer 48 (3): 799-819, 1981.69Ranzi T, Castagnone D, Velio P, et al.: Gastric and duodenal polyps in familial polyposis coli. Gut 22 (5): 363-7, 1981.70Vasen HF, Bülow S, Myrhøj T, et al.: Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis. Gut 40 (6): 716-9, 1997.71Groves CJ, Saunders BP, Spigelman AD, et al.: Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut 50 (5): 636-41, 2002.72Burke CA, Santisi J, Church J, et al.: The utility of capsule endoscopy small bowel surveillance in patients with polyposis. Am J Gastroenterol 100 (7): 1498-502, 2005.73Tescher P, Macrae FA, Speer T, et al.: Surveillance of FAP: a prospective blinded comparison of capsule endoscopy and other GI imaging to detect small bowel polyps. Hered Cancer Clin Pract 8 (1): 3, 2010.74Eliakim R: Video capsule endoscopy of the small bowel. Curr Opin Gastroenterol 26 (2): 129-33, 2010.75Taylor SA, Halligan S, Moore L, et al.: Multidetector-row CT duodenography in familial adenomatous polyposis: a pilot study. Clin Radiol 59 (10): 939-45, 2004.76Bleau BL, Gostout CJ: Endoscopic treatment of ampullary adenomas in familial adenomatous polyposis. J Clin Gastroenterol 22 (3): 237-41, 1996.77Norton ID, Gostout CJ: Management of periampullary adenoma. Dig Dis 16 (5): 266-73, 1998 Sep-Oct.78Norton ID, Gostout CJ, Baron TH, et al.: Safety and outcome of endoscopic snare excision of the major duodenal papilla. Gastrointest Endosc 56 (2): 239-43, 2002.79Saurin JC, Gutknecht C, Napoleon B, et al.: Surveillance of duodenal adenomas in familial adenomatous polyposis reveals high cumulative risk of advanced disease. J Clin Oncol 22 (3): 493-8, 2004.80Spigelman AD, Williams CB, Talbot IC, et al.: Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet 2 (8666): 783-5, 1989.81Park JS, Choi GS, Kim HJ, et al.: Natural orifice specimen extraction versus conventional laparoscopically assisted right hemicolectomy. Br J Surg 98 (5): 710-5, 2011.82Johnson MD, Mackey R, Brown N, et al.: Outcome based on management for duodenal adenomas: sporadic versus familial disease. J Gastrointest Surg 14 (2): 229-35, 2010.83de Vos tot Nederveen Cappel WH, Järvinen HJ, Björk J, et al.: Worldwide survey among polyposis registries of surgical management of severe duodenal adenomatosis in familial adenomatous polyposis. Br J Surg 90 (6): 705-10, 2003.84National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 2.2012. Rockledge, PA: National Comprehensive Cancer Network, 2012. Available online with free registration. Last accessed February 04, 2013.85Ahmad NA, Kochman ML, Long WB, et al.: Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: a study of 101 cases. Gastrointest Endosc 55 (3): 390-6, 2002.86Heiskanen I, Kellokumpu I, Järvinen H: Management of duodenal adenomas in 98 patients with familial adenomatous polyposis. Endoscopy 31 (6): 412-6, 1999.87Penna C, Phillips RK, Tiret E, et al.: Surgical polypectomy of duodenal adenomas in familial adenomatous polyposis: experience of two European centres. Br J Surg 80 (8): 1027-9, 1993.88Mackey R, Walsh RM, Chung R, et al.: Pancreas-sparing duodenectomy is effective management for familial adenomatous polyposis. J Gastrointest Surg 9 (8): 1088-93; discussion 1093, 2005.89Lepistö A, Kiviluoto T, Halttunen J, et al.: Surveillance and treatment of duodenal adenomatosis in familial adenomatous polyposis. Endoscopy 41 (6): 504-9, 2009.90Wallace MH, Phillips RK: Upper gastrointestinal disease in patients with familial adenomatous polyposis. Br J Surg 85 (6): 742-50, 1998.91Parc Y, Mabrut JY, Shields C, et al.: Surgical management of the duodenal manifestations of familial adenomatous polyposis. Br J Surg 98 (4): 480-4, 2011.92Penna C, Bataille N, Balladur P, et al.: Surgical treatment of severe duodenal polyposis in familial adenomatous polyposis. Br J Surg 85 (5): 665-8, 1998.93Hirasawa R, Iishi H, Tatsuta M, et al.: Clinicopathologic features and endoscopic resection of duodenal adenocarcinomas and adenomas with the submucosal saline injection technique. Gastrointest Endosc 46 (6): 507-13, 1997.94Catalano MF, Linder JD, Chak A, et al.: Endoscopic management of adenoma of the major duodenal papilla. Gastrointest Endosc 59 (2): 225-32, 2004.95Alarcon FJ, Burke CA, Church JM, et al.: Familial adenomatous polyposis: efficacy of endoscopic and surgical treatment for advanced duodenal adenomas. Dis Colon Rectum 42 (12): 1533-6, 1999.96Biasco G, Nobili E, Calabrese C, et al.: Impact of surgery on the development of duodenal cancer in patients with familial adenomatous polyposis. Dis Colon Rectum 49 (12): 1860-6, 2006.97Chung RS, Church JM, vanStolk R: Pancreas-sparing duodenectomy: indications, surgical technique, and results. Surgery 117 (3): 254-9, 1995.98Tsiotos GG, Sarr MG: Pancreas-preserving total duodenectomy. Dig Surg 15 (5): 398-403, 1998.99Sarmiento JM, Thompson GB, Nagorney DM, et al.: Pancreas-sparing duodenectomy for duodenal polyposis. Arch Surg 137 (5): 557-62; discussion 562-3, 2002.100Kalady MF, Clary BM, Tyler DS, et al.: Pancreas-preserving duodenectomy in the management of duodenal familial adenomatous polyposis. J Gastrointest Surg 6 (1): 82-7, 2002 Jan-Feb.101Eisenberger CF, Knoefel WT, Peiper M, et al.: Pancreas-sparing duodenectomy in duodenal pathology: indications and results. Hepatogastroenterology 51 (57): 727-31, 2004 May-Jun.102Cetta F, Montalto G, Gori M, et al.: Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. J Clin Endocrinol Metab 85 (1): 286-92, 2000.103Cetta F, Curia MC, Montalto G, et al.: Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene. J Clin Endocrinol Metab 86 (1): 427-32, 2001.104Jasperson KW, Tuohy TM, Neklason DW, et al.: Hereditary and familial colon cancer. Gastroenterology 138 (6): 2044-58, 2010.105Jarrar AM, Milas M, Mitchell J, et al.: Screening for thyroid cancer in patients with familial adenomatous polyposis. Ann Surg 253 (3): 515-21, 2011.106Seki M, Tanaka K, Kikuchi-Yanoshita R, et al.: Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis. Hum Genet 89 (3): 298-300, 1992.107Marchesa P, Fazio VW, Church JM, et al.: Adrenal masses in patients with familial adenomatous polyposis. Dis Colon Rectum 40 (9): 1023-8, 1997.108Cetta F, Mazzarella L, Bon G, et al.: Genetic alterations in hepatoblastoma and hepatocellular carcinoma associated with familial adenomatous polyposis. Med Pediatr Oncol 41 (5): 496-7, 2003.109Young J, Barker M, Robertson T, et al.: A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis. J Clin Pathol 55 (3): 230-1, 2002.110Cetta F, Montalto G, Petracci M: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 41 (3): 417, 1997.111Giardiello FM, Petersen GM, Brensinger JD, et al.: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 39 (96): 867-9, 1996.112Ding SF, Michail NE, Habib NA: Genetic changes in hepatoblastoma. J Hepatol 20 (5): 672-5, 1994.113Hughes LJ, Michels VV: Risk of hepatoblastoma in familial adenomatous polyposis. Am J Med Genet 43 (6): 1023-5, 1992.114Bernstein IT, Bülow S, Mauritzen K: Hepatoblastoma in two cousins in a family with adenomatous polyposis. Report of two cases. Dis Colon Rectum 35 (4): 373-4, 1992.115Giardiello FM, Offerhaus GJ, Krush AJ, et al.: Risk of hepatoblastoma in familial adenomatous polyposis. J Pediatr 119 (5): 766-8, 1991.116Perilongo G: Link confirmed between FAP and hepatoblastoma. Oncology (Huntingt) 5 (7): 14, 1991.117Toyama WM, Wagner S: Hepatoblastoma with familial polyposis coli: another case and corrected pedigree. Surgery 108 (1): 123-4, 1990.118Kurahashi H, Takami K, Oue T, et al.: Biallelic inactivation of the APC gene in hepatoblastoma. Cancer Res 55 (21): 5007-11, 1995.119Hirschman BA, Pollock BH, Tomlinson GE: The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 147 (2): 263-6, 2005.120Aretz S, Koch A, Uhlhaas S, et al.: Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations? Pediatr Blood Cancer 47 (6): 811-8, 2006.121Hamilton SR, Liu B, Parsons RE, et al.: The molecular basis of Turcot's syndrome. N Engl J Med 332 (13): 839-47, 1995.122Petersen GM, Francomano C, Kinzler K, et al.: Presymptomatic direct detection of adenomatous polyposis coli (APC) gene mutations in familial adenomatous polyposis. Hum Genet 91 (4): 307-11, 1993.123Fearnhead NS, Britton MP, Bodmer WF: The ABC of APC. Hum Mol Genet 10 (7): 721-33, 2001.124Sieber OM, Lamlum H, Crabtree MD, et al.: Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. Proc Natl Acad Sci U S A 99 (5): 2954-8, 2002.125Michils G, Tejpar S, Thoelen R, et al.: Large deletions of the APC gene in 15% of mutation-negative patients with classical polyposis (FAP): a Belgian study. Hum Mutat 25 (2): 125-34, 2005.126Meuller J, Kanter-Smoler G, Nygren AO, et al.: Identification of genomic deletions of the APC gene in familial adenomatous polyposis by two independent quantitative techniques. Genet Test 8 (3): 248-56, 2004.127Sieber OM, Lipton L, Crabtree M, et al.: Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348 (9): 791-9, 2003.128Fearnhead NS: Familial adenomatous polyposis and MYH. Lancet 362 (9377): 5-6, 2003.129Al-Tassan N, Chmiel NH, Maynard J, et al.: Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet 30 (2): 227-32, 2002.130Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003.131Dunlop MG; British Society for Gastroenterology.Association of Coloproctology for Great Britain and Ireland.: Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 51 (Suppl 5): V21-7, 2002.132Lynch HT, Smyrk TC: Classification of familial adenomatous polyposis: a diagnostic nightmare. Am J Hum Genet 62 (6): 1288-9, 1998.133Smith RA, Cokkinides V, von Eschenbach AC, et al.: American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 52 (1): 8-22, 2002 Jan-Feb.134Church J, Simmang C; Standards Task Force., American Society of Colon and Rectal Surgeons.Collaborative Group of the Americas on Inherited Colorectal Cancer and the Standards Committee of The American Society of Colon and Rectal Surgeons., et al.: Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum 46 (8): 1001-12, 2003.135Church J, Lowry A, Simmang C, et al.: Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. Dis Colon Rectum 44 (10): 1404-12, 2001.136Standard Task Force., American Society of Colon and Rectal Surgeons., Collaborative Group of the Americas on Inherited Colorectal Cancer.: Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer. Dis Colon Rectum 44 (10): 1403, 2001.137Petersen GM: Genetic testing and counseling in familial adenomatous polyposis. Oncology (Huntingt) 10 (1): 89-94; discussion 97-8, 1996.138Church J, Burke C, McGannon E, et al.: Risk of rectal cancer in patients after colectomy and ileorectal anastomosis for familial adenomatous polyposis: a function of available surgical options. Dis Colon Rectum 46 (9): 1175-81, 2003.139Guillem JG, Wood WC, Moley JF, et al.: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. Ann Surg Oncol 13 (10): 1296-321, 2006.140Bertario L, Russo A, Radice P, et al.: Genotype and phenotype factors as determinants for rectal stump cancer in patients with familial adenomatous polyposis. Hereditary Colorectal Tumors Registry. Ann Surg 231 (4): 538-43, 2000.141Heiskanen I, Järvinen HJ: Fate of the rectal stump after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Int J Colorectal Dis 12 (1): 9-13, 1997.142Bassuini MM, Billings PJ: Carcinoma in an ileoanal pouch after restorative proctocolectomy for familial adenomatous polyposis. Br J Surg 83 (4): 506, 1996.143Vrouenraets BC, Van Duijvendijk P, Bemelman WA, et al.: Adenocarcinoma in the anal canal after ileal pouch-anal anastomosis for familial adenomatous polyposis using a double-stapled technique: report of two cases. Dis Colon Rectum 47 (4): 530-4, 2004.144De Cosse JJ, Bülow S, Neale K, et al.: Rectal cancer risk in patients treated for familial adenomatous polyposis. The Leeds Castle Polyposis Group. Br J Surg 79 (12): 1372-5, 1992.145Nugent KP, Phillips RK: Rectal cancer risk in older patients with familial adenomatous polyposis and an ileorectal anastomosis: a cause for concern. Br J Surg 79 (11): 1204-6, 1992.146Bess MA, Adson MA, Elveback LR, et al.: Rectal cancer following colectomy for polyposis. Arch Surg 115 (4): 460-7, 1980.147Iwama T, Mishima Y: Factors affecting the risk of rectal cancer following rectum-preserving surgery in patients with familial adenomatous polyposis. Dis Colon Rectum 37 (10): 1024-6, 1994.148Setti-Carraro P, Nicholls RJ: Choice of prophylactic surgery for the large bowel component of familial adenomatous polyposis. Br J Surg 83 (7): 885-92, 1996.149Vasen HF, van der Luijt RB, Slors JF, et al.: Molecular genetic tests as a guide to surgical management of familial adenomatous polyposis. Lancet 348 (9025): 433-5, 1996.150Wu JS, Paul P, McGannon EA, et al.: APC genotype, polyp number, and surgical options in familial adenomatous polyposis. Ann Surg 227 (1): 57-62, 1998.151Church J, Burke C, McGannon E, et al.: Predicting polyposis severity by proctoscopy: how reliable is it? Dis Colon Rectum 44 (9): 1249-54, 2001.152Nieuwenhuis MH, Bülow S, Björk J, et al.: Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the choice of surgery. Dis Colon Rectum 52 (7): 1259-63, 2009.153Nieuwenhuis MH, Mathus-Vliegen LM, Slors FJ, et al.: Genotype-phenotype correlations as a guide in the management of familial adenomatous polyposis. Clin Gastroenterol Hepatol 5 (3): 374-8, 2007.154Parc YR, Olschwang S, Desaint B, et al.: Familial adenomatous polyposis: prevalence of adenomas in the ileal pouch after restorative proctocolectomy. Ann Surg 233 (3): 360-4, 2001.155Groves CJ, Beveridge G, Swain DJ, et al.: Prevalence and morphology of pouch and ileal adenomas in familial adenomatous polyposis. Dis Colon Rectum 48 (4): 816-23, 2005.156Ooi BS, Remzi FH, Gramlich T, et al.: Anal transitional zone cancer after restorative proctocolectomy and ileoanal anastomosis in familial adenomatous polyposis: report of two cases. Dis Colon Rectum 46 (10): 1418-23; discussion 1422-3, 2003.157Lovegrove RE, Tilney HS, Heriot AG, et al.: A comparison of adverse events and functional outcomes after restorative proctocolectomy for familial adenomatous polyposis and ulcerative colitis. Dis Colon Rectum 49 (9): 1293-306, 2006.158NDA 21-156 CELEBREX (Celecoxib) Indicated for the Reduction and Regression of Adenomatous Colorectal Polyps in FAP Patients. In: Food and Drug Administration, Center for Drug Evaluation and Research.: Sixty-Fourth Meeting of the Oncologic Drugs Advisory committee, Dec. 14, 1999. Rockville, Md: FDA/CDER, 1999, [p. 81]. Available online. Last accessed February 22, 2013.159Steinbach G, Lynch PM, Phillips RK, et al.: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342 (26): 1946-52, 2000.160Giardiello FM, Yang VW, Hylind LM, et al.: Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 346 (14): 1054-9, 2002.161Higuchi T, Iwama T, Yoshinaga K, et al.: A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res 9 (13): 4756-60, 2003.162Lynch PM, Ayers GD, Hawk E, et al.: The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol 105 (6): 1437-43, 2010.163West NJ, Clark SK, Phillips RK, et al.: Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut 59 (7): 918-25, 2010.164Phillips RK, Wallace MH, Lynch PM, et al.: A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50 (6): 857-60, 2002.165Nugent KP, Farmer KC, Spigelman AD, et al.: Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 80 (12): 1618-9, 1993.166Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med 351 (17): 1709-11, 2004.167NIH Halts Use of COX-2 Inhibitor in Large Cancer Prevention Trial. Bethesda, Md: National Cancer Institute, 2004. Available online. Last accessed February 22, 2013.168Solomon SD, McMurray JJ, Pfeffer MA, et al.: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352 (11): 1071-80, 2005.169Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352 (11): 1092-102, 2005.170Giardiello FM, Hamilton SR, Krush AJ, et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328 (18): 1313-6, 1993.171Leppert M, Burt R, Hughes JP, et al.: Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 322 (13): 904-8, 1990.172Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75 (5): 951-7, 1993.173Brensinger JD, Laken SJ, Luce MC, et al.: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 43 (4): 548-52, 1998.174Giardiello FM, Brensinger JD, Luce MC, et al.: Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene. Ann Intern Med 126 (7): 514-9, 1997.175Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62 (6): 1290-301, 1998.176Pedemonte S, Sciallero S, Gismondi V, et al.: Novel germline APC variants in patients with multiple adenomas. Genes Chromosomes Cancer 22 (4): 257-67, 1998.177White S, Bubb VJ, Wyllie AH: Germline APC mutation (Gln1317) in a cancer-prone family that does not result in familial adenomatous polyposis. Genes Chromosomes Cancer 15 (2): 122-8, 1996.178Gonçalves V, Theisen P, Antunes O, et al.: A missense mutation in the APC tumor suppressor gene disrupts an ASF/SF2 splicing enhancer motif and causes pathogenic skipping of exon 14. Mutat Res 662 (1-2): 33-6, 2009.179Knudsen AL, Bisgaard ML, Bülow S: Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer 2 (1): 43-55, 2003.180Nieuwenhuis MH, Vasen HF: Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 61 (2): 153-61, 2007.181Scott RJ, Meldrum C, Crooks R, et al.: Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity. Gut 48 (4): 508-14, 2001.182Hampel H: Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am 18 (4): 687-703, 2009.183Jones N, Vogt S, Nielsen M, et al.: Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 137 (2): 489-94, 494.e1; quiz 725-6, 2009.184Sampson JR, Dolwani S, Jones S, et al.: Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362 (9377): 39-41, 2003.185Morak M, Laner A, Bacher U, et al.: MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet 78 (4): 353-63, 2010.186Nielsen M, Morreau H, Vasen HF, et al.: MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 79 (1): 1-16, 2011.187Vasen HF, Möslein G, Alonso A, et al.: Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 57 (5): 704-13, 2008.188Nascimbeni R, Pucciarelli S, Di Lorenzo D, et al.: Rectum-sparing surgery may be appropriate for biallelic MutYH-associated polyposis. Dis Colon Rectum 53 (12): 1670-5, 2010.189Win AK, Cleary SP, Dowty JG, et al.: Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer 129 (9): 2256-62, 2011.190Vogt S, Jones N, Christian D, et al.: Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 137 (6): 1976-85.e1-10, 2009.191Gismondi V, Meta M, Bonelli L, et al.: Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer 109 (5): 680-4, 2004.192Lefevre JH, Rodrigue CM, Mourra N, et al.: Implication of MYH in colorectal polyposis. Ann Surg 244 (6): 874-9; discussion 879-80, 2006.193Wasielewski M, Out AA, Vermeulen J, et al.: Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer. Breast Cancer Res Treat 124 (3): 635-41, 2010.194Poulsen ML, Bisgaard ML: MUTYH Associated Polyposis (MAP). Curr Genomics 9 (6): 420-35, 2008.195Goodenberger M, Lindor NM: Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol 45 (6): 488-500, 2011.196Nielsen M, Franken PF, Reinards TH, et al.: Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 42 (9): e54, 2005.197Russell AM, Zhang J, Luz J, et al.: Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients. Int J Cancer 118 (8): 1937-40, 2006.198Peterlongo P, Mitra N, Sanchez de Abajo A, et al.: Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis 27 (11): 2243-9, 2006.199Webb EL, Rudd MF, Houlston RS: Colorectal cancer risk in monoallelic carriers of MYH variants. Am J Hum Genet 79 (4): 768-71; author reply 771-2, 2006.200Balaguer F, Castellví-Bel S, Castells A, et al.: Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol 5 (3): 379-87, 2007.201Giráldez MD, Balaguer F, Caldés T, et al.: Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer 8 (4): 525-31, 2009.202Boland CR: Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4 (3): 211-8, 2005.203Boland CR: Hereditary nonpolyposis colorectal cancer. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. New York, NY: McGraw-Hill, 1998, pp 333-346.204Lynch HT, Lanspa S, Smyrk T, et al.: Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II). Genetics, pathology, natural history, and cancer control, Part I. Cancer Genet Cytogenet 53 (2): 143-60, 1991.205Lynch HT, Smyrk TC, Watson P, et al.: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104 (5): 1535-49, 1993.206Hampel H, Frankel WL, Martin E, et al.: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352 (18): 1851-60, 2005.207Hampel H, Frankel WL, Martin E, et al.: Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26 (35): 5783-8, 2008.208Vasen HF: Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer 4 (3): 219-25, 2005.209Jemal A, Siegel R, Xu J, et al.: Cancer statistics, 2010. CA Cancer J Clin 60 (5): 277-300, 2010 Sep-Oct.210Hampel H, Stephens JA, Pukkala E, et al.: Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 129 (2): 415-21, 2005.211Chen S, Wang W, Lee S, et al.: Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296 (12): 1479-87, 2006.212Quehenberger F, Vasen HF, van Houwelingen HC: Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 42 (6): 491-6, 2005.213Baglietto L, Lindor NM, Dowty JG, et al.: Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 102 (3): 193-201, 2010.214Senter L, Clendenning M, Sotamaa K, et al.: The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135 (2): 419-28, 2008.215Bonadona V, Bonaïti B, Olschwang S, et al.: Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305 (22): 2304-10, 2011.216Win AK, Young JP, Lindor NM, et al.: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30 (9): 958-64, 2012.217De Jong AE, Morreau H, Van Puijenbroek M, et al.: The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology 126 (1): 42-8, 2004.218Broaddus RR, Lynch HT, Chen LM, et al.: Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer 106 (1): 87-94, 2006.219Vasen HF, Offerhaus GJ, den Hartog Jager FC, et al.: The tumour spectrum in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the Netherlands. Int J Cancer 46 (1): 31-4, 1990.220Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71 (3): 677-85, 1993.221Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994.222Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995.223Ketabi Z, Bartuma K, Bernstein I, et al.: Ovarian cancer linked to Lynch syndrome typically presents as early-onset, non-serous epithelial tumors. Gynecol Oncol 121 (3): 462-5, 2011.224Jensen UB, Sunde L, Timshel S, et al.: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 120 (3): 777-82, 2010.225Shanley S, Fung C, Milliken J, et al.: Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer 8 (3): 251-5, 2009.226Walsh MD, Buchanan DD, Cummings MC, et al.: Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res 16 (7): 2214-24, 2010.227Buerki N, Gautier L, Kovac M, et al.: Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer 51 (1): 83-91, 2012.228Win AK, Lindor NM, Young JP, et al.: Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 104 (18): 1363-72, 2012.229Bapat B, Xia L, Madlensky L, et al.: The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Am J Hum Genet 59 (3): 736-9, 1996.230Lynch HT, Lynch PM, Pester J, et al.: The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre's syndrome. Arch Intern Med 141 (5): 607-11, 1981.231Suspiro A, Fidalgo P, Cravo M, et al.: The Muir-Torre syndrome: a rare variant of hereditary nonpolyposis colorectal cancer associated with hMSH2 mutation. Am J Gastroenterol 93 (9): 1572-4, 1998.232Kruse R, Rütten A, Lamberti C, et al.: Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Am J Hum Genet 63 (1): 63-70, 1998.233South CD, Hampel H, Comeras I, et al.: The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst 100 (4): 277-81, 2008.234Kastrinos F, Stoffel EM, Balmaña J, et al.: Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States. Cancer Epidemiol Biomarkers Prev 17 (8): 2044-51, 2008.235Vasen HF, Mecklin JP, Khan PM, et al.: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34 (5): 424-5, 1991.236Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 (4): 1146-58, 1997.237Beck NE, Tomlinson IP, Homfray T, et al.: Genetic testing is important in families with a history suggestive of hereditary non-polyposis colorectal cancer even if the Amsterdam criteria are not fulfilled. Br J Surg 84 (2): 233-7, 1997.238Vasen HF, Watson P, Mecklin JP, et al.: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116 (6): 1453-6, 1999.239Umar A, Boland CR, Terdiman JP, et al.: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96 (4): 261-8, 2004.240Laghi L, Bianchi P, Roncalli M, et al.: Re: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96 (18): 1402-3; author reply 1403-4, 2004.241Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997.242Akiyama Y, Sato H, Yamada T, et al.: Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57 (18): 3920-3, 1997.243Wu Y, Berends MJ, Mensink RG, et al.: Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet 65 (5): 1291-8, 1999.244Kolodner RD, Tytell JD, Schmeits JL, et al.: Germ-line msh6 mutations in colorectal cancer families. Cancer Res 59 (20): 5068-74, 1999.245Plaschke J, Engel C, Krüger S, et al.: Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 22 (22): 4486-94, 2004.246Wijnen JT, Vasen HF, Khan PM, et al.: Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339 (8): 511-8, 1998.247Syngal S, Fox EA, Li C, et al.: Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA 282 (3): 247-53, 1999.248Balmaña J, Stockwell DH, Steyerberg EW, et al.: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296 (12): 1469-78, 2006.249Barnetson RA, Tenesa A, Farrington SM, et al.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354 (26): 2751-63, 2006.250Kastrinos F, Allen JI, Stockwell DH, et al.: Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. Am J Gastroenterol 104 (6): 1508-18, 2009.251Khan O, Blanco A, Conrad P, et al.: Performance of Lynch syndrome predictive models in a multi-center US referral population. Am J Gastroenterol 106 (10): 1822-7; quiz 1828, 2011.252Jasperson KW, Vu TM, Schwab AL, et al.: Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis. Fam Cancer 9 (2): 99-107, 2010.253Müller A, Beckmann C, Westphal G, et al.: Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study. Int J Colorectal Dis 21 (7): 632-41, 2006.254Weber JL, May PE: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44 (3): 388-96, 1989.255Vilar E, Gruber SB: Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7 (3): 153-62, 2010.256Aaltonen LA, Peltomäki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 260 (5109): 812-6, 1993.257Jenkins MA, Hayashi S, O'Shea AM, et al.: Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 133 (1): 48-56, 2007.258Greenson JK, Bonner JD, Ben-Yzhak O, et al.: Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol 27 (5): 563-70, 2003.259Boland CR, Thibodeau SN, Hamilton SR, et al.: A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58 (22): 5248-57, 1998.260Hendriks YM, Wagner A, Morreau H, et al.: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 127 (1): 17-25, 2004.261Parc YR, Halling KC, Wang L, et al.: HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60 (8): 2225-31, 2000.262Cunningham JM, Kim CY, Christensen ER, et al.: The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69 (4): 780-90, 2001.263Yuen ST, Chan TL, Ho JW, et al.: Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 21 (49): 7585-92, 2002.264Raedle J, Trojan J, Brieger A, et al.: Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. Ann Intern Med 135 (8 Pt 1): 566-76, 2001.265Bouzourene H, Hutter P, Losi L, et al.: Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer 9 (2): 167-72, 2010.266Payá A, Alenda C, Pérez-Carbonell L, et al.: Utility of p16 immunohistochemistry for the identification of Lynch syndrome. Clin Cancer Res 15 (9): 3156-62, 2009.267Wang L, Cunningham JM, Winters JL, et al.: BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63 (17): 5209-12, 2003.268Domingo E, Espín E, Armengol M, et al.: Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer 39 (2): 138-42, 2004.269Deng G, Bell I, Crawley S, et al.: BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10 (1 Pt 1): 191-5, 2004.270Domingo E, Niessen RC, Oliveira C, et al.: BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene 24 (24): 3995-8, 2005.271Hitchins MP, Ward RL: Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet 46 (12): 793-802, 2009.272Chan AT, Zauber AG, Hsu M, et al.: Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma. Gastroenterology 136 (7): 2127-2136.e1, 2009.273Ligtenberg MJ, Kuiper RP, Chan TL, et al.: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet 41 (1): 112-7, 2009.274Kovacs ME, Papp J, Szentirmay Z, et al.: Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 30 (2): 197-203, 2009.275Lynch HT, Riegert-Johnson DL, Snyder C, et al.: Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol 106 (10): 1829-36, 2011.276Thibodeau SN, French AJ, Roche PC, et al.: Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 56 (21): 4836-40, 1996.277Cawkwell L, Gray S, Murgatroyd H, et al.: Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut 45 (3): 409-15, 1999.278Lindor NM, Burgart LJ, Leontovich O, et al.: Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20 (4): 1043-8, 2002.279de La Chapelle A: Microsatellite instability phenotype of tumors: genotyping or immunohistochemistry? The jury is still out. J Clin Oncol 20 (4): 897-9, 2002.280Piñol V, Castells A, Andreu M, et al.: Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 293 (16): 1986-94, 2005.281Baudhuin LM, Burgart LJ, Leontovich O, et al.: Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer 4 (3): 255-65, 2005.282Lagerstedt Robinson K, Liu T, Vandrovcova J, et al.: Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 99 (4): 291-9, 2007.283Schofield L, Watson N, Grieu F, et al.: Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer 124 (5): 1097-102, 2009.284Engel C, Forberg J, Holinski-Feder E, et al.: Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer 118 (1): 115-22, 2006.285Hall G, Clarkson A, Shi A, et al.: Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology 42 (5): 409-13, 2010.286Perez-Cabornero L, Velasco E, Infante M, et al.: A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR. Eur J Cancer 45 (8): 1485-93, 2009.287Charbonnier F, Olschwang S, Wang Q, et al.: MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res 62 (3): 848-53, 2002.288Wagner A, Barrows A, Wijnen JT, et al.: Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 72 (5): 1088-100, 2003.289Wang Y, Friedl W, Lamberti C, et al.: Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes. Int J Cancer 103 (5): 636-41, 2003.290Baudhuin LM, Ferber MJ, Winters JL, et al.: Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients. Gastroenterology 129 (3): 846-54, 2005.291Grabowski M, Mueller-Koch Y, Grasbon-Frodl E, et al.: Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. Genet Test 9 (2): 138-46, 2005.292Mangold E, Pagenstecher C, Friedl W, et al.: Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer 116 (5): 692-702, 2005.293Peltomäki P: Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21 (6): 1174-9, 2003.294Choi YH, Cotterchio M, McKeown-Eyssen G, et al.: Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario. Hered Cancer Clin Pract 7 (1): 14, 2009.295Lin KM, Shashidharan M, Thorson AG, et al.: Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer. J Gastrointest Surg 2 (1): 67-71, 1998 Jan-Feb.296Scott RJ, McPhillips M, Meldrum CJ, et al.: Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68 (1): 118-127, 2001.297Wijnen J, de Leeuw W, Vasen H, et al.: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23 (2): 142-4, 1999.298Goodfellow PJ, Buttin BM, Herzog TJ, et al.: Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A 100 (10): 5908-13, 2003.299de Leeuw WJ, Dierssen J, Vasen HF, et al.: Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol 192 (3): 328-35, 2000.300Rumilla K, Schowalter KV, Lindor NM, et al.: Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn 13 (1): 93-9, 2011.301Berends MJ, Wu Y, Sijmons RH, et al.: Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet 70 (1): 26-37, 2002.302Ramsoekh D, Wagner A, van Leerdam ME, et al.: A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut 57 (11): 1539-44, 2008.303Peltomäki P, Vasen H: Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20 (4-5): 269-76, 2004.304Peterlongo P, Nafa K, Lerman GS, et al.: MSH6 germline mutations are rare in colorectal cancer families. Int J Cancer 107 (4): 571-9, 2003.305Schweizer P, Moisio AL, Kuismanen SA, et al.: Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer. Cancer Res 61 (7): 2813-5, 2001.306Truninger K, Menigatti M, Luz J, et al.: Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128 (5): 1160-71, 2005.307Baudhuin LM, Mai M, French AJ, et al.: Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods. J Mol Diagn 7 (2): 226-35, 2005.308Nakagawa H, Lockman JC, Frankel WL, et al.: Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64 (14): 4721-7, 2004.309Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al.: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130 (2): 312-22, 2006.310Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.: Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11 (1): 35-41, 2009.311Palomaki GE, McClain MR, Melillo S, et al.: EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 11 (1): 42-65, 2009.312Ladabaum U, Wang G, Terdiman J, et al.: Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 155 (2): 69-79, 2011.313Dinh TA, Rosner BI, Atwood JC, et al.: Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res (Phila) 4 (1): 9-22, 2011.314Kwon JS, Scott JL, Gilks CB, et al.: Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol 29 (16): 2247-52, 2011.315Engel C, Rahner N, Schulmann K, et al.: Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 8 (2): 174-82, 2010.316Reitmair AH, Cai JC, Bjerknes M, et al.: MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis. Cancer Res 56 (13): 2922-6, 1996.317Järvinen HJ, Aarnio M, Mustonen H, et al.: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118 (5): 829-34, 2000.318Järvinen HJ, Mecklin JP, Sistonen P: Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 108 (5): 1405-11, 1995.319Voskuil DW, Vasen HF, Kampman E, et al.: Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC. Int J Cancer 72 (2): 205-9, 1997.320Heinimann K, Müller H, Weber W, et al.: Disease expression in Swiss hereditary non-polyposis colorectal cancer (HNPCC) kindreds. Int J Cancer 74 (3): 281-5, 1997.321Burke W, Petersen G, Lynch P, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 277 (11): 915-9, 1997.322Johnson PM, Gallinger S, McLeod RS: Surveillance colonoscopy in individuals at risk for hereditary nonpolyposis colorectal cancer: an evidence-based review. Dis Colon Rectum 49 (1): 80-93; discussion 94-5, 2006.323Lindor NM, Petersen GM, Hadley DW, et al.: Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 296 (12): 1507-17, 2006.324Friedman GD, Collen MF, Fireman BH: Multiphasic Health Checkup Evaluation: a 16-year follow-up. J Chronic Dis 39 (6): 453-63, 1986.325Mecklin JP, Aarnio M, Läärä E, et al.: Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology 133 (4): 1093-8, 2007.326Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, et al.: Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol 27 (28): 4793-7, 2009.327Hurlstone DP, Karajeh M, Cross SS, et al.: The role of high-magnification-chromoscopic colonoscopy in hereditary nonpolyposis colorectal cancer screening: a prospective "back-to-back" endoscopic study. Am J Gastroenterol 100 (10): 2167-73, 2005.328Lecomte T, Cellier C, Meatchi T, et al.: Chromoendoscopic colonoscopy for detecting preneoplastic lesions in hereditary nonpolyposis colorectal cancer syndrome. Clin Gastroenterol Hepatol 3 (9): 897-902, 2005.329Rodríguez-Bigas MA, Vasen HF, Pekka-Mecklin J, et al.: Rectal cancer risk in hereditary nonpolyposis colorectal cancer after abdominal colectomy. International Collaborative Group on HNPCC. Ann Surg 225 (2): 202-7, 1997.330Vasen HF, Möslein G, Alonso A, et al.: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44 (6): 353-62, 2007.331Burn J, Gerdes AM, Macrae F, et al.: Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378 (9809): 2081-7, 2011.332Burn J, Bishop DT, Mecklin JP, et al.: Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 359 (24): 2567-78, 2008.333Hampel H, Frankel W, Panescu J, et al.: Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66 (15): 7810-7, 2006.334Westin SN, Lacour RA, Urbauer DL, et al.: Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol 26 (36): 5965-71, 2008.335Ng AB, Reagan JW, Hawliczek S, et al.: Significance of endometrial cells in the detection of endometrial carcinoma and its precursors. Acta Cytol 18 (5): 356-61, 1974 Sep-Oct.336Yancey M, Magelssen D, Demaurez A, et al.: Classification of endometrial cells on cervical cytology. Obstet Gynecol 76 (6): 1000-5, 1990.337Dove-Edwin I, Boks D, Goff S, et al.: The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 94 (6): 1708-12, 2002.338Rijcken FE, Mourits MJ, Kleibeuker JH, et al.: Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 91 (1): 74-80, 2003.339Renkonen-Sinisalo L, Bützow R, Leminen A, et al.: Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer 120 (4): 821-4, 2007.340Yang K, Allen B, Conrad P, et al.: Awareness of gynecologic surveillance in women from hereditary non-polyposis colorectal cancer families. Fam Cancer 5 (4): 405-9, 2006.341Collins VR, Meiser B, Ukoumunne OC, et al.: The impact of predictive genetic testing for hereditary nonpolyposis colorectal cancer: three years after testing. Genet Med 9 (5): 290-7, 2007.342Schmeler KM, Lynch HT, Chen LM, et al.: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354 (3): 261-9, 2006.343Guillem JG, Wood WC, Moley JF, et al.: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24 (28): 4642-60, 2006.344Fitzgibbons RJ Jr, Lynch HT, Stanislav GV, et al.: Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). Ann Surg 206 (3): 289-95, 1987.345de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G, et al.: Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum 45 (12): 1588-94, 2002.346Parry S, Win AK, Parry B, et al.: Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 60 (7): 950-7, 2011.347de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, et al.: Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut 52 (12): 1752-5, 2003.348Maeda T, Cannom RR, Beart RW Jr, et al.: Decision model of segmental compared with total abdominal colectomy for colon cancer in hereditary nonpolyposis colorectal cancer. J Clin Oncol 28 (7): 1175-80, 2010.349You YN, Chua HK, Nelson H, et al.: Segmental vs. extended colectomy: measurable differences in morbidity, function, and quality of life. Dis Colon Rectum 51 (7): 1036-43, 2008.350Haanstra JF, de Vos Tot Nederveen Cappel WH, Gopie JP, et al.: Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy. Dis Colon Rectum 55 (6): 653-9, 2012.351Church JM, Fazio VW, Lavery IC, et al.: Quality of life after prophylactic colectomy and ileorectal anastomosis in patients with familial adenomatous polyposis. Dis Colon Rectum 39 (12): 1404-8, 1996.352Hassan I, Chua HK, Wolff BG, et al.: Quality of life after ileal pouch-anal anastomosis and ileorectal anastomosis in patients with familial adenomatous polyposis. Dis Colon Rectum 48 (11): 2032-7, 2005.353Aziz O, Athanasiou T, Fazio VW, et al.: Meta-analysis of observational studies of ileorectal versus ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 93 (4): 407-17, 2006.354Hurlstone DP, Cross SS, Slater R, et al.: Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy. Gut 53 (3): 376-80, 2004.355Saitoh Y, Waxman I, West AB, et al.: Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 120 (7): 1657-65, 2001.356Hurlstone DP, Cross SS, Adam I, et al.: Endoscopic morphological anticipation of submucosal invasion in flat and depressed colorectal lesions: clinical implications and subtype analysis of the kudo type V pit pattern using high-magnification-chromoscopic colonoscopy. Colorectal Dis 6 (5): 369-75, 2004.357Dacosta RS, Wilson BC, Marcon NE: New optical technologies for earlier endoscopic diagnosis of premalignant gastrointestinal lesions. J Gastroenterol Hepatol 17 (Suppl): S85-104, 2002.358Rembacken BJ, Fujii T, Cairns A, et al.: Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 355 (9211): 1211-4, 2000.359Tsuda S, Veress B, Tóth E, et al.: Flat and depressed colorectal tumours in a southern Swedish population: a prospective chromoendoscopic and histopathological study. Gut 51 (4): 550-5, 2002.360Rex DK, Helbig CC: High yields of small and flat adenomas with high-definition colonoscopes using either white light or narrow band imaging. Gastroenterology 133 (1): 42-7, 2007.361Soetikno RM, Kaltenbach T, Rouse RV, et al.: Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 299 (9): 1027-35, 2008.362Stoffel EM, Turgeon DK, Stockwell DH, et al.: Chromoendoscopy detects more adenomas than colonoscopy using intensive inspection without dye spraying. Cancer Prev Res (Phila) 1 (7): 507-13, 2008.363Le Rhun M, Coron E, Parlier D, et al.: High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study. Clin Gastroenterol Hepatol 4 (3): 349-54, 2006.364Brooker JC, Saunders BP, Shah SG, et al.: Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial. Gastrointest Endosc 56 (3): 333-8, 2002.365Stoffel EM, Turgeon DK, Stockwell DH, et al.: Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer). Cancer Prev Res (Phila) 1 (6): 470-5, 2008.366Hüneburg R, Lammert F, Rabe C, et al.: Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening. Endoscopy 41 (4): 316-22, 2009.367Wallace MH, Frayling IM, Clark SK, et al.: Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to dye-spray at colonoscopy. Dis Colon Rectum 42 (8): 1078-80, 1999.368Dekker E, Boparai KS, Poley JW, et al.: High resolution endoscopy and the additional value of chromoendoscopy in the evaluation of duodenal adenomatosis in patients with familial adenomatous polyposis. Endoscopy 41 (8): 666-9, 2009.369Sakamoto H, Yamamoto H, Hayashi Y, et al.: Nonsurgical management of small-bowel polyps in Peutz-Jeghers syndrome with extensive polypectomy by using double-balloon endoscopy. Gastrointest Endosc 74 (2): 328-33, 2011.370Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994.371Slattery ML, Kerber RA: Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 86 (21): 1618-26, 1994.372Butterworth AS, Higgins JP, Pharoah P: Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 42 (2): 216-27, 2006.373St John DJ, McDermott FT, Hopper JL, et al.: Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 118 (10): 785-90, 1993.374Zauber AG, Bond JH, Winawer SJ: Surveillance of patients with colorectal adenomas or cancer. In: Young GP, Rozen P, Levin B, eds.: Prevention and Early Detection of Colorectal Cancer. London, England: WB Saunders, 1996, pp 195-215.375Winawer SJ, Zauber AG, Gerdes H, et al.: Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 334 (2): 82-7, 1996.376Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348 (10): 919-32, 2003.377Lichtenstein P, Holm NV, Verkasalo PK, et al.: Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343 (2): 78-85, 2000.378Hemminki K, Chen B: Familial risk for colorectal cancers are mainly due to heritable causes. Cancer Epidemiol Biomarkers Prev 13 (7): 1253-6, 2004.379Woolf CM: A genetic study of carcinoma of the large intestine. Am J Hum Genet 10 (1): 42-7, 1958.380Negri E, Braga C, La Vecchia C, et al.: Family history of cancer and risk of colorectal cancer in Italy. Br J Cancer 77 (1): 174-9, 1998.381Duncan JL, Kyle J: Family incidence of carcinoma of the colon and rectum in north-east Scotland. Gut 23 (2): 169-71, 1982.382Rozen P, Fireman Z, Figer A, et al.: Family history of colorectal cancer as a marker of potential malignancy within a screening program. Cancer 60 (2): 248-54, 1987.383Houlston RS, Murday V, Harocopos C, et al.: Screening and genetic counselling for relatives of patients with colorectal cancer in a family cancer clinic. BMJ 301 (6748): 366-8, 1990 Aug 18-25.384Cannon-Albright LA, Skolnick MH, Bishop DT, et al.: Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 319 (9): 533-7, 1988.385Burt RW, Bishop DT, Cannon LA, et al.: Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med 312 (24): 1540-4, 1985.386Wiesner GL, Daley D, Lewis S, et al.: A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2. Proc Natl Acad Sci U S A 100 (22): 12961-5, 2003.387Djureinovic T, Skoglund J, Vandrovcova J, et al.: A genome wide linkage analysis in Swedish families with hereditary non-familial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer. Gut 55 (3): 362-6, 2006.388Lindor NM, Rabe K, Petersen GM, et al.: Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293 (16): 1979-85, 2005.389Mueller-Koch Y, Vogelsang H, Kopp R, et al.: Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54 (12): 1733-40, 2005.390Llor X, Pons E, Xicola RM, et al.: Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res 11 (20): 7304-10, 2005.391Valle L, Perea J, Carbonell P, et al.: Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol 25 (7): 781-6, 2007.392Jass JR: Hereditary Non-Polyposis Colorectal Cancer: the rise and fall of a confusing term. World J Gastroenterol 12 (31): 4943-50, 2006.393Smith RA, Cokkinides V, Eyre HJ: American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 56 (1): 11-25; quiz 49-50, 2006 Jan-Feb.394Levin B, Lieberman DA, McFarland B, et al.: Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58 (3): 130-60, 2008 May-Jun.395U.S. Preventive Services Task Force.: Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 149 (9): 627-37, 2008.396Rex DK, Johnson DA, Anderson JC, et al.: American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 104 (3): 739-50, 2009.397Peutz JL: On a very remarkable case of familial polyposis of the mucous membrane of the intestinal tract and nasopharynx accompanied by peculiar pigmentations of the skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921.398Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med 241(25): 993-1005, 1949.399Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989.400Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26 (6): 513-9, 2005.401Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.402Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998.403Boudeau J, Kieloch A, Alessi DR, et al.: Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. Hum Mutat 21 (2): 172, 2003.404Lim W, Hearle N, Shah B, et al.: Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89 (2): 308-13, 2003.405van Lier MG, Wagner A, Mathus-Vliegen EM, et al.: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105 (6): 1258-64; author reply 1265, 2010.406Westerman AM, Entius MM, de Baar E, et al.: Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 353 (9160): 1211-5, 1999.407Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000.408Mehenni H, Resta N, Park JG, et al.: Cancer risks in LKB1 germline mutation carriers. Gut 55 (7): 984-90, 2006.409Lim W, Olschwang S, Keller JJ, et al.: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126 (7): 1788-94, 2004.410Veale AM, McColl I, Bussey HJ, et al.: Juvenile polyposis coli. J Med Genet 3 (1): 5-16, 1966.411Chow E, Macrae F: A review of juvenile polyposis syndrome. J Gastroenterol Hepatol 20 (11): 1634-40, 2005.412Howe JR, Roth S, Ringold JC, et al.: Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280 (5366): 1086-8, 1998.413Howe JR, Bair JL, Sayed MG, et al.: Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28 (2): 184-7, 2001.414Zhou XP, Woodford-Richens K, Lehtonen R, et al.: Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 69 (4): 704-11, 2001.415Brosens LA, van Hattem A, Hylind LM, et al.: Risk of colorectal cancer in juvenile polyposis. Gut 56 (7): 965-7, 2007.416Dahdaleh FS, Carr JC, Calva D, et al.: Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet 81 (2): 110-6, 2012.417Jaeger EE, Woodford-Richens KL, Lockett M, et al.: An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am J Hum Genet 72 (5): 1261-7, 2003.418Thomas HJ, Whitelaw SC, Cottrell SE, et al.: Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q. Am J Hum Genet 58 (4): 770-6, 1996.419Meijers-Heijboer H, Wijnen J, Vasen H, et al.: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72 (5): 1308-14, 2003.420Cybulski C, Górski B, Huzarski T, et al.: CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75 (6): 1131-5, 2004.421de Jong MM, Nolte IM, Te Meerman GJ, et al.: Colorectal cancer and the CHEK2 1100delC mutation. Genes Chromosomes Cancer 43 (4): 377-82, 2005.422Cybulski C, Wokołorczyk D, Kładny J, et al.: Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations? Eur J Hum Genet 15 (2): 237-41, 2007.423Suchy J, Cybulski C, Wokołorczyk D, et al.: CHEK2 mutations and HNPCC-related colorectal cancer. Int J Cancer 126 (12): 3005-9, 2010.424Jass J: Hyperplastic Polyposis. In: Hamilton SR, Aaltonen LA: Pathology and Genetics of Tumours of the Digestive System. Lyon, France: International Agency for Research on Cancer, 2000, pp 135-6.425Chow E, Lipton L, Lynch E, et al.: Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH. Gastroenterology 131 (1): 30-9, 2006.426Lage P, Cravo M, Sousa R, et al.: Management of Portuguese patients with hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution for future guidelines based on a clinical study. Am J Gastroenterol 99 (9): 1779-84, 2004.427Leggett BA, Devereaux B, Biden K, et al.: Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 25 (2): 177-84, 2001.428Rashid A, Houlihan PS, Booker S, et al.: Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119 (2): 323-32, 2000.429Place RJ, Simmang CL: Hyperplastic-adenomatous polyposis syndrome. J Am Coll Surg 188 (5): 503-7, 1999.430Hyman NH, Anderson P, Blasyk H: Hyperplastic polyposis and the risk of colorectal cancer. Dis Colon Rectum 47 (12): 2101-4, 2004.431Koide N, Saito Y, Fujii T, et al.: A case of hyperplastic polyposis of the colon with adenocarcinomas in hyperplastic polyps after long-term follow-up. Endoscopy 34 (6): 499-502, 2002.432Jeevaratnam P, Cottier DS, Browett PJ, et al.: Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol 179 (1): 20-5, 1996.433Bengoechea O, Martínez-Peñuela JM, Larrínaga B, et al.: Hyperplastic polyposis of the colorectum and adenocarcinoma in a 24-year-old man. Am J Surg Pathol 11 (4): 323-7, 1987.434McCann BG: A case of metaplastic polyposis of the colon associated with focal adenomatous change and metachronous adenocarcinomas. Histopathology 13 (6): 700-2, 1988.435Kokko A, Laiho P, Lehtonen R, et al.: EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis. BMC Cancer 6: 145, 2006.436Batlle E, Bacani J, Begthel H, et al.: EphB receptor activity suppresses colorectal cancer progression. Nature 435 (7045): 1126-30, 2005.437Beach R, Chan AO, Wu TT, et al.: BRAF mutations in aberrant crypt foci and hyperplastic polyposis. Am J Pathol 166 (4): 1069-75, 2005.438Weisenberger DJ, Siegmund KD, Campan M, et al.: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38 (7): 787-93, 2006.439Burt R, Neklason DW: Genetic testing for inherited colon cancer. Gastroenterology 128 (6): 1696-716, 2005.440McGrath DR, Spigelman AD: Preventive measures in Peutz-Jeghers syndrome. Fam Cancer 1 (2): 121-5, 2001.441Giardiello FM, Trimbath JD: Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol 4 (4): 408-15, 2006.442Brosens LA, van Hattem WA, Jansen M, et al.: Gastrointestinal polyposis syndromes. Curr Mol Med 7 (1): 29-46, 2007.443Zbuk KM, Eng C: Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol 4 (9): 492-502, 2007.444Calva-Cerqueira D, Chinnathambi S, Pechman B, et al.: The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet 75 (1): 79-85, 2009.
Psychosocial Issues in Hereditary Colon Cancer Syndromes
Psychosocial research in cancer genetic counseling and testing focuses on the interest in testing among populations at varying levels of disease risk, psychological outcomes, interpersonal and familial effects, and cultural and community reactions. It also identifies behavioral factors that encourage or impede surveillance and other health behaviors. Data resulting from psychosocial research can guide clinician interactions with patients and may include:
- Decision-making about risk-reduction interventions, risk assessment, and genetic testing.
- Evaluation of psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification of genetic testing.
- Resolution of ethical concerns.
This section of the summary will focus on psychosocial aspects of genetic counseling and testing for Lynch syndrome (LS), familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), and familial colorectal cancer (CRC), including issues surrounding medical screening, risk-reducing surgery, and chemoprevention for these syndromes.
Interest in Genetic Counseling and Testing for Hereditary CRC in the General Population and High-Risk Families
Interest in genetic counseling and testing in the general population
Interest in genetic counseling and testing for hereditary CRC has been highest in studies involving general population samples (Tables 13 and 14). Initial random-digit-dial surveys that addressed this topic  showed that more than 80% of respondents indicated at least some interest in having a genetic test for hereditary CRC, and 40% to 47% indicated that they would be very interested. One study  reported that interest in genetic testing decreased from 81% to 67% when respondents were informed that only 1% of the population was estimated to inherit a CRC–predisposing gene. A 2002 study that evaluated the participant's intention to have a genetic test within a specific time frame (e.g., within the next month and within the next 6 months) found substantially lower levels of interest. Perceived risk of developing CRC was independently associated with greater interest in genetic testing across all studies. Other independent variables that were positively correlated with testing interest across studies included income, cancer worry, perceived benefits of testing, dispositional optimism and pessimism, and the perception that cancer runs in one’s family; perceived barriers of testing were negatively correlated with testing interest.
When respondents were asked about possible reactions if genetic testing showed that they were at high risk of CRC, the most common concerns included the lack of availability of preventive options, increased anxiety, and worry about cancer risks in family members, especially children. Virtually no concern was expressed regarding the potential impact of such information on insurance or employment discrimination. This finding contrasts with findings in some other studies of individuals who have gone through genetic counseling before deciding about testing. Additionally, individuals with health insurance coverage were most likely to be willing to share test results with others, primarily their physicians.
Participants in these studies were drawn from the general population and were not selected for known CRC risk factors; their interest in genetic testing was based on answers to largely hypothetical questions. Some findings indicate that interest in genetic testing may be high in the general population; however, the apparent interest may be due in part to a lack of awareness about the risks and limitations of testing or the view that genetic testing is similar to other more routine medical tests. Although these studies may help assess interest in genetic testing in the general population, it is possible that they overestimate the actual demand for such services.
Interest in genetic counseling and testing among CRC patients and their close relatives
Studies of CRC patients and their unaffected relatives showed varying levels of interest in or intention to undergo hereditary CRC genetic testing (Tables 13 and 14). Participants in these studies were recruited through tumor registries or familial colon cancer registries, oncology treatment centers, and the community. Study outcomes were reported as either testing interest or testing intention. Participants were not necessarily selected based on features that are characteristic of a hereditary CRC syndrome. Thus, when asking about intention or interest in genetic testing, most studies referred to testing in a general manner (e.g., testing for a hereditary colon cancer gene) rather than asking about testing for specific syndromes such as LS (also called hereditary nonpolyposis colorectal cancer [HNPCC]) or FAP. Some factors that were not consistently addressed in all studies (e.g., cost, test accuracy, or assuming that other relatives were gene mutation carriers) may account for some of the variability in findings regarding testing interest or intention.Table 13. Summary of Studies Evaluating Interest in or Intention to Have Genetic Counseling and Testing for Familial Colorectal Cancer (CRC)a Study PopulationNb Interest or Intention in GC or GTcFDR = first-degree relative; GC = genetic counseling; GT = genetic testing; HCCR = hereditary colon cancer registry.aAll studies used a cross-sectional design, with the exception of one study, which used focus groups. All studies were conducted in the United States, with the exception of one Canadian study. bIndicates number of participants older than 18 y, unless otherwise specified.cType of genetic test not specified.dRandom Digit Dial Survey with general population samples.eUnaffected = no previous diagnosis of CRC.General population (Utah), RDDSd 40147% very interested in GT; 35% somewhat interested in GTGeneral population (Utah), RDDS 38347% very interested in GT; 37% somewhat interested in GTUnaffectede FDRs of CRC patients from tumor registry 42646% GC intention; 26% definite GT intentionUnaffected FDRs of CRC patients from HCCR 1,37377% definite GT intention if free; 15% probableCRC patients from an oncology center and community 9852% definite GT interest; 20% probableUnaffected FDRs of CRC patients from an oncology center and community 9584% GT interestFocus groups of CRC patients and unaffected FDRs from an oncology center and community 28 CRCs CRCs: 96% GT interest before group; 89% after group33 FDRsFDRs: 82% before group; 42% after groupGeneral population (Ontario, Canada), RDDS 50181% interested in GT if test is 80% predictive; 77% interested if test is 90% accurate; 67% interested if 1% of population inherits a familial CRC gene mutationGeneral population (Vermont, New Hampshire, Maine), RDDS 1,836GT intention in next 6 months: 32% probably/definitely; 19% possibly GT intention in next month: 19% probably/definitely; 12% possiblyTable 14. Summary of Studies Evaluating Interest in or Intention to Have Genetic Counseling and Testing for Lynch Syndrome (LS)aStudy PopulationNbInterest or Intention in GC or GTc CRC = colorectal cancer; FDR = first-degree relative; GC = genetic counseling; GT = genetic testing; HCCR = hereditary colon cancer registry.aAll studies used a cross-sectional design, with the exception of one study, which used focus groups. All studies were conducted in the United States, with the exception of one German study. bIndicates number of participants older than 18 y, unless otherwise specified.cType of genetic test not specified.dUnaffected = no previous diagnosis of CRC.Unaffectedd FDRs of CRC patients undergoing treatment 4551% definite GT intention; 31% probable CRC patients and unaffected individuals undergoing LS GC  31 CRCs; 34 unaffectedPrecounseling: 100% (29). GT intention among CRCs who were aware of GT. 92% (30) GT intention among unaffected who were aware of GT Postcounseling: no one decided against testing, but 5 unaffected (18%); 1 CRC undecidedCRC patients, unaffected FDRs, and age/gender-matched controls recruited from HCCR and driver’s license/Medicare records 105If relative is a carrier: GT intention for 67% of CRCs; 75% of FDRs; 60% of controls If insurance covers cost: GT intention for 17% of CRCs; 75% of FDRs; 40% of controls
In several studies, higher perceived risk and worry of developing colorectal cancer were correlated with interest in or intention to have testing. Other correlates found in several studies included higher perceived risk and worry of developing colorectal cancer, higher education, greater family support, preference for making one’s own decision about testing, less advanced colorectal cancer, more frequent worries about colorectal cancer, belief that 50% or fewer of all colorectal cancers are hereditary, female gender, younger age, and ethnicity. Participants in these studies cited many reasons for and against undergoing genetic testing. Perceived advantages of having information as a result of genetic testing included the ability to help other family members, especially children; engage in more informed health decision-making, particularly in regard to screening; plan for the future; and gain reassurance. Disadvantages included the possibility of insurance discrimination if one is found to carry a cancer-predisposing mutation, adverse psychological outcomes, and costs associated with testing.
Interest in genetic testing for children
A key difference between genetic testing for CRC and FAP concerns the appropriateness of testing persons younger than 18 years. Genetic testing for adult-onset hereditary cancers is not recommended for minors because the medical and psychosocial benefits of such testing are not realized until adulthood. Genetic testing for FAP, however, is presently offered to children with affected parents, often at the age of 10 to 12 years, when endoscopic screening is recommended. Because it is often necessary to diagnose FAP before age 18 years to prevent colorectal cancer and because screening and possibly surgery are warranted at the time an individual is identified as an APC mutation carrier, genetic testing of minors is justified in this instance.
Nonetheless, it is important to consider the implications of testing decisions with regard to issues of informed consent for both children and their parents. Parents have the legal authority to make medical decisions on behalf of their children; however, there are justifications for increasing minors’ involvement in decision-making about genetic testing as they mature and become more capable of making decisions about their own welfare.
Studies conducted before the clinical availability of APC testing showed that most parents favored testing for FAP in early childhood. In one study, 94% of FAP-affected adults indicated that children should be tested for FAP at birth, though 79% stated that this condition should not be discussed with children until at least age 10 years. The majority of respondents wished to withhold information about FAP risk from their child for nearly a decade, suggesting that research is needed regarding the timing of disclosure of cancer genetic risk information to children.
In a survey conducted in the Netherlands of members of families with FAP, one-third (34%) believed that it was most suitable to offer APC gene testing of children prior to age 12 years, whereas 38% preferred to offer testing to children between the ages of 12 and 16 years, when children would be better able to understand the DNA testing process. Only 4% felt that children should not undergo DNA testing at all.
Results of qualitative interview data from 28 U.S. parents diagnosed with FAP showed that 61% favored genetic testing of APC mutations in their at-risk children (aged 10–17 years); 71% believed that their children should receive their test results. The primary reasons why parents chose to test their children included early detection and management, reduction in parental anxiety and uncertainty, and help with decision making regarding surveillance. Reasons provided for not testing focused on discrimination concerns and cost.
Interest in the use of assisted reproductive technology (ART)
The possibility of transmitting a mutation to a child may pose a concern to families affected by hereditary colorectal cancer syndromes to the extent that some carriers may avoid childbearing. These concerns also may prompt individuals to consider using prenatal diagnosis (PND) methods to help reduce the risk of transmission. PND is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling . Both procedures carry a small risk of miscarriage. Moreover, discovering the fetus is a carrier of a cancer susceptibility mutation may impose a difficult decision for couples regarding pregnancy continuation or termination and may require additional professional consultation and support.
An alternative to these tests is preimplantation genetic diagnosis (PGD), a procedure used to test fertilized embryos for genetic disorders prior to uterine implantation. Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGD can be used to detect mutations in hereditary cancer predisposing genes, including APC.27] and in the Netherlands..bParticipants were invited to complete questionnaires before clinical genetic testing for LS and at 3 months and 1 year after disclosure of genetic test results.cIndicates number of participants older than 18 y, unless otherwise specified.dRepresents the number who indicated that they were considering having children in the future, out of a total of 130 individuals who answered a questionnaire prior to genetic testing .FAP-affected individuals 2095% would consider prenatal GT for FAP; 90% would consider PGD; 75% would consider amniocentesis or chorionic villous samplingFAP-affected individuals 34133% would consider PND for FAP; 30% would consider PGD; 15% felt terminating pregnancy for FAP was acceptable 24% and 25% of patients did not respond to questions about attitudes toward PND and PGD, respectively.Individuals undergoing genetic testing for LS 48d21% would consider PND and/or PGD; 19% would consider only PND; 2% would consider only PGDAt 1 year after disclosure of GT results, two out of nine mutation carriers reported that they were considering PGD for future pregnancy.PJS-affected individualsa 5215% indicated that pregnancy termination was acceptable if PND identified a fetus with PJS; 52% indicated PGD was acceptable for persons with PJSTen (19%) individuals, nine of whome were female, reported that they had decided not to conceive a child because of PJS.
Issues With Informed Consent for Microsatellite Instability (MSI) and Immunohistochemical (IHC) Tumor Testing
Advocacy for universal screening of all colorectal tumors for MSI and IHC to detect the absence of MMR proteins has increased. This protocol could lead to increased identification of LS individuals and families; however, there is an ongoing discussion about best practices for the informed consent process for this tumor testing. MSI alone does not definitively establish a germline mutation in an MMR gene. IHC, on the other hand, can point to a specific underlying germline genetic defect because of the absent expression of a mismatch repair (MMR) protein (if methylation has been excluded). IHC results inform subsequent gene-specific mutation testing and therefore can be a surrogate for a LS diagnosis.
It is generally advised that identification of genetic predisposition to cancer mandates explicit informed consent because of concerns for the possibility of insurance discrimination (irrespective of the Genetic Information Nondiscrimination Act of 2008), adverse psychological outcomes, and costs associated with further testing. The Evaluation of Genomic Applications in Practice and Prevention working group specifically recommends obtaining informed consent for MSI or IHC testing. Nevertheless, debate about this issue continues, partially because of pragmatic concerns surrounding the feasibility of obtaining such consent prior to the procedure. One proposed approach suggests a preparatory conversation informing patients prior to their procedure that CRC runs in families and that if their tumor has features characteristic of a heritable type, they will be contacted by a genetic health care provider for further assessment of the genetic basis of their cancer. A cross-sectional survey of U.S. cancer programs (20 National Cancer Institute–designated comprehensive cancer centers and 49 community hospital cancer programs) found that, of those that performed MSI and/or IHC testing as part of standard pathologic evaluation at the time of colon cancer diagnosis in all or select cases, none required written informed consent prior to tumor testing.
(Refer to the Informed Consent section in the Cancer Genetics Risk Assessment and Counseling summary for more information.)
Participation in Genetic Counseling and Testing for Hereditary CRC
There are an increasing number of studies examining the actual uptake of genetic counseling and testing for LS (Table 16). Studies have included both colorectal cancer patients and unaffected, high-risk family members, recruited mainly from clinical settings and familial colon cancer registries. Most studies actively recruited participants for free genetic counseling and testing as part of research protocols. Participation or uptake was defined at various points in the process, including genetic counseling before testing; provision of a blood sample for testing; and genetic counseling for disclosure of test results.Table 16. Summary of Prospective Studies Evaluating Participation in Genetic Counseling and Testing for Hereditary Colorectal Cancer (CRC)a,b,c SyndromeStudy PopulationNdGC and GT ParticipationeFAP = familial adenomatous polyposis; FDR = first-degree relative; GC = genetic counseling; GT = genetic testing; HCCR = hereditary colon cancer registry; LS = Lynch syndrome.aAll studies used a prospective, observational design with the exception of one randomized trial evaluating two recruitment methods.bAll studies offered free GC and GT, with the exception of one study.cAll studies were conducted in the United States, with the exception of one Finnish study and one German study.dIndicates number of participants older than 18 years, unless otherwise specified.eGC = participated in pretest or posttest genetic counseling; GT = participated in genetic testing and received results; GT (blood) = only provided blood sample for genetic testing. fAffected = current or previous colorectal cancer diagnosis; Unaffected = no previous diagnosis of colorectal cancer.LSAffectedf and unaffectedf members of four extended families from HCCR with a known LS mutation in kindred 21959% pretest GC; posttest GC, GT LSUnaffected FDRs of CRC patients from HCCR 50521% pretest GC; 26% pending pretest GC; 15% GT (blood); 4% pending GT (blood) LSAffected and unaffected members of four extended families from HCCR with a known LS mutation in kindred 20847% pretest GC; 43% posttest GC, GTLSCRC patients from an oncology clinic and HCCR 51089% GT (blood) LSUnaffected members of 36 Finnish families with a known LS mutation in kindred 44678% pretest GC; 75% posttest GC, GTLS and familial CRCAffected and unaffected persons who underwent GC in a high-risk colon cancer clinic 57 (LS); 91 (familial CRC)LS: 14% posttest GC, GTAPCI130K: 85% posttest GC, GT LSCRC patients diagnosed age <60 y with affected FDR or second-degree relative, recruited through physicians 10147% pretest GC; 36% posttest GC, GT LSUnaffected FDRs of known LS mutation carriers  11151% pretest GC; 50% posttest GC, GT LSCRC patients from HCCR, relatives, and spouses 14026% pretest GCFAPUnaffected persons from HCCR age >5 y, with FAP-affected parent and known APC mutation in family 57 adults; 38 minors87% pretest GC; posttest GC, GT (82% adults; 95% minors)
Participation in both pretest genetic counseling and posttest counseling for disclosure of results ranged from 14% to 59% across studies (Table 16). The wide range of uptake rates suggests that factors such as cost, test characteristics, and the context in which counseling and testing were offered may have influenced participants’ decisions. For example, among studies that offered free genetic counseling and testing in the context of a research protocol, counseling uptake ranged from 21% to 59% and testing uptake ranged from 36% to 59%. The majority of those who had participated in a free pretest counseling or education session almost always followed through with genetic testing. Further research is needed to evaluate LS genetic counseling and testing participation in the clinical setting.
Although limited in number, these studies offer insight into why individuals from families at risk of LS decide to undergo or decline genetic counseling and testing. Participation in LS genetic counseling was associated with having children, having a greater number of relatives affected by CRC, and greater social support. A study of CRC patients who had donated a blood sample for genetic testing also showed that those who intended to follow through with receiving results were more worried that they carried a LS-predisposing gene mutation, believed that testing would help family members, and more strongly endorsed the benefits and importance of having testing. Factors associated with both counseling and testing uptake included having: children, a greater number of affected relatives, a greater perceived risk of developing CRC, and more frequent thoughts about CRC.
Less is known about the characteristics of persons who decide to not undergo LS genetic counseling and testing. Studies have found that persons who declined counseling and testing reported to have a lower perceived risk of CRC, to have fewer first-degree relatives affected with cancer, to be less likely to have had a previous colonoscopy, to have a college education, to have previously participated in cancer genetics research, or to be employed. Psychological factors also may limit the uptake of genetic counseling and testing. Those who declined counseling and testing, especially women, reported lower perceived ability to cope with mutation-positive test results, and were more likely to report having depressive symptoms. Reasons cited for not seeking genetic counseling or testing have included concerns about potential insurance discrimination, how genetic testing would affect one's family, and how one would emotionally handle genetic test results.
In contrast to the LS genetic counseling and testing uptake studies that have been conducted in the United States, findings from similar studies conducted in other countries may differ. A Finnish study found that 75% of individuals at risk of developing LS underwent genetic testing and counseling for disclosure of test results. Being employed was the only factor that independently predicted test uptake. Fundamental differences between U.S. and Finnish health care systems may have accounted for the substantial differences in testing uptake in this study compared with similar ones conducted in the United States. In particular, the lower likelihood of health or life insurance discrimination in a European state such as Finland may have eliminated an important barrier to testing in that setting.
The majority of these studies that evaluated the uptake of genetic testing for LS have focused on genetic testing for MMR mutations associated with this syndrome. Few studies have examined uptake of MSI and IHC testing. One study reported low levels of knowledge and awareness of MSI testing among a sample of CRC patients who met the revised Bethesda guidelines for LS and were offered MSI testing. Patients in this study generally reported positive attitudes about the benefits of MSI testing; however, patients with higher levels of cancer-specific distress also perceived a greater number of barriers to having MSI testing.
Research is emerging on the usefulness of decision aids for LS genetic testing. One study showed that a decision aid, in booklet format, was effective in reducing uncertainty about the testing decision, assisting individuals to make an informed decision about testing, and improving testing knowledge among men. However, the decision aid did not appear to influence actual testing decisions. Another study evaluated the impact of an educational intervention in high-risk CRC patients prior to MSI and IHC testing but not MMR mutation testing. Patients who received a brief educational session delivered by a health educator plus a CD-ROM decision aid about MSI and IHC testing were found to have greater increases in knowledge about testing, higher satisfaction with preparation for decision-making about testing, lower decisional conflict, and greater decisional self-efficacy compared with patients who received only a brief educational session.
The uptake for genetic testing for FAP may be higher than testing for LS. A study of asymptomatic individuals in the United States at risk of FAP who were enrolled in a CRC registry and were offered genetic counseling found that 82% of adults and 95% of minors underwent genetic testing. Uptake rates close to 100% have been reported in the United Kingdom. A possible explanation for the greater uptake of APC genetic testing is that it may be more cost-effective than annual endoscopic screening  and can eliminate the burden of annual screening, which must often be initiated before puberty. The opportunity to eliminate worry about potential risk-reducing surgery is another possible benefit of genetic testing for FAP. The decision to have APC genetic testing may be viewed as a medical management decision; the potential psychosocial factors that may influence the testing decision are not as well studied for FAP as for other hereditary cancer syndromes.
The higher penetrance of APC mutations and earlier onset of disease also may influence the decision to undergo genetic testing for this condition, possibly due to a greater awareness of the disease and more experience with multiple family members being affected. Clinical observations suggest that children who have family members affected with FAP are very aware of the possibility of risk-reducing surgery, and focus on the test result as the factor that determines the need for such surgery. It is important to consider the timing of disclosure of genetic test results to children in regard to their age, developmental issues, and psychological concerns about FAP. Children who carry an FAP mutation have expressed concern regarding how they will be perceived by peers and might benefit from assistance in formulating an explanation for others that preserves self-esteem.
Psychological Impact of Participating in Hereditary CRC Genetic Counseling and Testing
Studies have examined the psychological status of individuals before, during, and after genetic counseling and testing for LS. Some studies have included only persons with no personal history of any LS-associated cancers, and others have included both CRC patients and cancer-unaffected persons who are at risk of having a LS mutation. Cross-sectional evaluations of the psychosocial characteristics of individuals undergoing LS genetic counseling and testing have indicated that mean pretest scores of psychological functioning for most participants are within normal limits, although one study comparing affected and unaffected individuals showed that affected individuals had greater distress and worry associated with LS.
Several longitudinal studies have evaluated psychological outcomes before genetic counseling and testing for LS and at multiple time periods in the year following disclosure of test results. One study examined changes in anxiety based on personal cancer history, gender, and age (younger than 50 years vs. older than 50 years) prior to and 2 weeks after a pretest genetic-counseling session. Affected and unaffected female participants in both age groups and affected men older than 50 years showed significant decreases in anxiety over time. Unaffected men younger than 50 years maintained low levels of anxiety; however, affected men younger than 50 years showed no reductions in the anxiety levels reported at the time of pretest counseling. A study that evaluated psychological distress 8 weeks postcounseling (prior to disclosure of test results) among both affected and unaffected individuals found a significant reduction in general anxiety, cancer worry, and distress. In general, findings from studies within the time period immediately following disclosure of mutation status (e.g., 2 weeks to 1 month) suggested that MMR mutation carriers may experience increased general distress, cancer-specific distress, or cancer worries  relative to their pretest measurements. Carriers often experienced significantly higher distress following disclosure of test results compared with individuals who do not carry a mutation previously identified in the family (noncarrier). However, in most cases, carriers’ distress levels subsided during the course of the year after disclosure  and did not differ from pretest distress levels at 1 year postdisclosure. Findings from these studies also indicated that noncarriers experienced a reduction or no change in distress up to a year following results disclosure. A study that included unaffected individuals and CRC patients found that distress levels among patients did not differ between carriers and individuals who received results that were uninformative or showed a variant of unknown significance at any point up to 1 year posttest and were similar compared with pretest distress levels.
Less is known about the long-term psychological impact of LS genetic counseling and testing beyond 1 year following notification of mutation carrier status. One study evaluated psychological outcomes up to 3 years after disclosure of mutation status. Carriers’ and noncarriers’ 3-year mean scores on measures of depression, state anxiety, and cancer-specific distress were similar to scores obtained prior to genetic testing, with one exception: noncarriers’ cancer-specific distress scores showed sustained decreased posttesting, and were significantly lower compared with their baseline scores and with carriers’ scores at 1 year posttesting, with a similar trend observed at 3 years posttesting. In another study, 70 LS mutation carriers (including both cancer affected and unaffected persons) completed a cross-sectional survey between 6 months and 8.5 years after disclosure of test results; higher levels of cancer worry were associated with higher levels of perceived risk.
Findings from some studies suggested that there may be subgroups of individuals at higher risk of psychological distress following disclosure of test results, including those who present with relatively higher scores on measures of general or cancer-specific distress before undergoing testing. A study of CRC patients who had donated blood for LS testing found that higher levels of depressive symptoms and/or anxiety were found among women, younger persons, nonwhites, and those with less formal education and fewer and less satisfactory sources of social support. A subgroup of individuals who showed higher levels of psychological distress and lower quality of life and social support were identified from the same population; in addition, this subgroup was more likely to worry about finding out that they were LS mutation carriers and being able to cope with learning their test results. In a follow-up report that evaluated psychological outcomes following disclosure of test results among both CRC patients and relatives at risk of having a LS mutation, a subgroup with the same psychosocial characteristics experienced higher levels of general distress and distress specific to the experience of having genetic testing within the year after disclosure, regardless of mutation status. Nonwhites and those with lower education had higher levels of depression and anxiety scores at all times compared with whites and those with higher education, respectively. Other studies have also found that a prior history of major or minor depression, higher pretest levels of cancer-specific distress, having a greater number of cancer-affected first-degree relatives, greater grief reactions, and greater emotional illness–related representations predicted higher levels of distress from 1 to 6 months after disclosure of test results. While further research is needed in this area, case studies indicate that it is important to identify persons who may be at risk of experiencing psychiatric distress and to provide psychological support and follow-up throughout the genetic counseling and genetic testing process.
Studies also have examined the effect of LS genetic counseling and testing on cancer risk comprehension. One study reported that nearly all mutation carriers and noncarriers could accurately recall the test result 1 year after disclosure. More noncarriers than carriers correctly identified their risk of developing CRC at both 1 month and 1 year following result disclosure. Mutation carriers who incorrectly identified their CRC risk were more likely to have had lower levels of pretest subjective risk perception compared with those who correctly identified their level of risk. Another study reported that accuracy of estimating colorectal and endometrial cancer risk improved following disclosure of mutation status in both carriers and noncarriers.
Studies evaluating psychological outcomes following genetic testing for FAP suggest that some individuals, particularly mutation carriers, may be at risk of experiencing increased distress. In a cross-sectional study of adults who had previously undergone APC genetic testing, those who were mutation carriers exhibited higher levels of state anxiety than noncarriers and were more likely to exhibit clinically significant anxiety levels. Lower optimism and lower self-esteem were associated with higher anxiety in this study, and FAP-related distress, perceived seriousness of FAP, and belief in the accuracy of genetic testing were associated with more state anxiety among carriers. However, in an earlier study that compared adults who had undergone genetic testing for FAP, Huntington disease, and hereditary breast/ovarian cancer syndrome, FAP-specific distress was somewhat elevated within 1 week after disclosure of either positive or negative test results and was lower overall than the other syndromes.
In a cross-sectional Australian study focusing on younger adults aged 18 to 35 years diagnosed with FAP (N = 88), participants most frequently reported the following FAP-related issues for which they perceived the need for moderate-to-high levels of support or assistance: anxiety regarding their children’s risk of developing FAP, fear about developing cancer, and uncertainty about the impact of FAP. Seventy-five percent indicated that they would consider prenatal testing for FAP; 61% would consider PGD, and 61% would prefer that their children undergo genetic testing at birth or before age 10 years. A small proportion of respondents (16%) reported experiencing some FAP-related discrimination, primarily indicating that attending to their medical or self-care needs (e.g., time off work for screening, need for frequent toilet breaks, and physical limitations) may engender negative attitudes in colleagues and managers.
Another large cross-sectional study of FAP families conducted in the Netherlands included persons aged 16 to 84 years who either had an FAP diagnosis, were at 50% risk of having an APC mutation, or were proven APC noncarriers. Of those who had APC testing, 48% had done so at least 5 years or longer prior to this study. Of persons with an FAP diagnosis, 76% had undergone preventive colectomy, and 78% of those were at least 5 years postsurgery. The study evaluated the prevalence of generalized psychological distress, distress related specifically to FAP, and cancer-related worries. Mean scores on the Mental Health Index-5, a subscale of the SF-36 that assessed generalized distress, were comparable to the general Dutch population. Twenty percent of respondents were classified as having moderate to high levels of FAP-specific distress as measured by the Impact of Event scale (IES), with 23% of those with an FAP diagnosis, 11% of those at risk of FAP, and 17% of noncarriers reporting scores in this range. Five percent reported scores on the IES that indicated severe and clinically relevant distress; of those, the majority (78%) had an FAP diagnosis. Overall, mean scores on the Cancer Worry Scale were comparable to those found in another study of families with LS. Persons with an FAP diagnosis were more likely to report more frequent cancer worries, and the most commonly reported worries were the potential need for additional surgery (26%) and the likelihood that they (17%) or a family member (14%) will develop cancer. In multivariate analysis, factors associated with higher levels of FAP-specific distress included greater perceived risk of developing cancer, more frequent discussion about FAP with family or friends, and having no children. Factors associated with higher levels of cancer-specific worries included being female, poorer family functioning, greater actual and desired discussion about FAP with family or friends, greater perceived cancer risk, poorer general health perceptions, and having been a caregiver for a family member with cancer. The authors noted that most factors that were associated with higher levels of cancer- and FAP-specific distress or worry were psychosocial factors, rather than clinical or demographic factors.
Another cross-sectional study conducted in the Netherlands found that among FAP patients, 37% indicated that the disease had influenced their desire to have children (i.e., wanting fewer or no children). Thirty-three percent indicated they would consider PND for FAP; 30% would consider PGD. Higher levels of guilt and more positive attitudes towards terminating pregnancy were associated with greater interest for both PND and PGD. In a separate U.S. study, predictors of willingness to consider prenatal testing included having an affected child and experiencing a first-degree relative’s death secondary to FAP.
The psychological vulnerability of children undergoing testing is of particular concern in genetic testing for FAP. Research findings suggest that most children do not experience clinically significant psychological distress following APC testing. As in studies involving adults, however, subgroups may be vulnerable to increased distress and would benefit from continued psychological support. A study of children who had undergone genetic testing for FAP found that their mood and behavior remained in the normal range after genetic counseling and disclosure of test results. Aspects of the family situation, including illness in the mother or a sibling were associated with subclinical increases in depressive symptoms. In a long-term follow-up study of 48 children undergoing testing for FAP, most children did not suffer psychological distress; however, a small proportion of children tested demonstrated clinically significant posttest distress. Another study found that although APC mutation–positive children’s perceived risk of developing the disease increased after disclosure of results, anxiety and depression levels remain unchanged in the year following disclosure. Mutation-negative children in this study experienced less anxiety and improved self-esteem over this same time period.
Psychosocial Aspects of Screening and Risk Reduction Interventions for LS and FAP
Colorectal screening for LS
Benefits of genetic counseling and testing for LS include the opportunity for individuals to learn about options for the early detection and prevention of cancer, including screening and risk-reducing surgery. Studies suggest that many persons at risk of LS may have had some CRC screening before genetic counseling and testing, but most are not likely to adhere to LS screening recommendations. Among persons aged 18 years or older who did not have a personal history of CRC and who participated in U.S.-based research protocols offering genetic counseling and testing for LS, between 52% and 62% reported ever having had a colonoscopy before genetic testing. Among cancer-unaffected persons who participated in similar research in Belgium and Australia, 51% and 68%, respectively, had ever had a colonoscopy before study entry.  Factors associated with ever having a colonoscopy before genetic testing included higher income and older age, higher perceived risk of developing CRC, higher education level, and being informed of increased risk of CRC.
In a study of cancer-affected and cancer-unaffected persons who fulfilled clinical criteria for LS, 92% reported having had a colonoscopy and/or flexible sigmoidoscopy at least once before genetic testing. Another study of unaffected individuals presenting for genetic risk assessment and possible consideration of LS, FAP, or APCI1307K genetic testing reported that 77% had undergone at least one screening exam (either colonoscopy, flexible sigmoidoscopy, or barium enema).
Several longitudinal studies examined the use of screening colonoscopy by cancer-unaffected persons after undergoing testing for a known LS mutation. These studies compared colonoscopy use before LS genetic testing with colonoscopy use within 1 year after disclosure of test results. One study reported that LS mutation carriers were more likely to have a colonoscopy than were noncarriers and those who declined testing (73% vs. 16% vs. 22%) and that colonoscopy use increased among carriers (36% vs. 73%) in the year after disclosure of results. Two other studies reported that carriers’ colonoscopy rates at 1 year after disclosure of results (71% and 53%) were not significantly different from rates before testing, though noncarriers’ colonoscopy rates decreased in the same time period. Factors associated with colonoscopy use at 1 year after results disclosure included carrying a LS-predisposing mutation, older age, and greater perceived control over CRC. These findings suggest that colonoscopy rates increase or are maintained among mutation carriers within the year after disclosure of results and that rates decrease among noncarriers. Data from a longitudinal study including 134 MMR mutation carriers with and without a prior LS-related cancer diagnosis found that those who did not undergo colonoscopy for surveillance within 6 months after receiving genetic test results were six times more likely to report clinically significant depressive symptoms as measured by the Center for Epidemiological Studies-Depression (CES-D) scale (OR, 6.06; 95% confidence interval [CI], 2.09–17.59). Higher levels of CRC worry measured prior to genetic testing also were associated with clinically significant depressive symptoms (OR, 1.53; 95% CI, 1.19–1.97).
Two studies examined the level of adherence to published screening guidelines after LS genetic testing, based on mutation status. One study reported a colonoscopy adherence rate of 100% among mutation carriers. Another study found that 35% of mutation carriers and 13% of noncarriers did not adhere to published guidelines for appropriate CRC screening; in both groups, about one-half screened more frequently than published guidelines recommend, and one-half screened less frequently.
The longitudinal studies described above examined colorectal screening behavior within a relatively short period of time (1 year) after receiving genetic test results, and less is known about longer-term use of screening behaviors. A longitudinal study (N = 73) that examined psychological and behavioral outcomes among cancer-unaffected persons at 3 years following disclosure of genetic test results found that all carriers (n = 19) had undergone at least one colonoscopy between 1 and 3 years postdisclosure. Ninety-four percent of carriers in one study stated an intention to have annual or biannual colonoscopy in the future; among noncarriers, 64% did not intend to have colonoscopy in the future or were unsure, and 33% intended to have colonoscopy at 5- to 6-year intervals or less frequently. A cross-sectional study conducted in the Netherlands examined the use of flexible sigmoidoscopy or colonoscopy among persons with CRC, endometrial cancer, or a clinical or genetic diagnosis of LS during a time that ranged from 2 years to 18 years after risk assessment and counseling. Eighty-six percent of LS mutation carriers, 68% of those who did not test or who had an uninformative LS genetic test result, and 73% of those with a clinical LS diagnosis were considered adherent with screening recommendations, based on data obtained from medical records. Participants also answered questions regarding screening adherence, and 16% of the overall sample reported that they had undergone screening less frequently than recommended. For the overall sample, greater perceived barriers to screening were associated with screening nonadherence as determined through medical record review, and embarrassment with screening procedures was associated with self-reported nonadherence. A second cross-sectional study, also conducted in the Netherlands, surveyed cancer-unaffected LS mutation carriers (n = 42) regarding their colorectal screening behaviors after learning their mutation status (range, 6 months–8.5 years). Thirty-one percent of respondents reported that they had undergone annual colonoscopy prior to LS genetic testing, and 88% reported that they had undergone colonoscopy since their genetic diagnosis (P < .001).
Gynecologic cancer screening in LS
A few studies have examined the use of screening for endometrial and ovarian cancers associated with LS. These studies have included relatively small numbers of women and suggest that screening rates for LS-associated gynecologic cancers are low before genetic counseling and testing. Two U.S. studies  reported that 14% of women with a family history of LS had undergone endometrial biopsy or 25% had undergone transvaginal ultrasound (TVUS) before genetic counseling and testing; among women who had seen a gynecologist in the preceding year, 50% had inadequate endometrial cancer screening.
Some studies suggest that women with a clinical or genetic diagnosis of LS do not universally adopt intensive gynecologic screening. In a Belgian study, 85% of female mutation carriers and 27% of noncarriers underwent TVUS within the year following disclosure of genetic test results. One Australian longitudinal study examined gynecologic screening behaviors before testing and 1 year after disclosure of results. They found that 30% of women had undergone TVUS and 7% had undergone an endometrial biopsy before testing. Forty-seven percent of carriers and 10% of noncarriers reported having had a TVUS in the 12 months following test result disclosure, while 53% of carriers and 5% of noncarriers had undergone endometrial biopsy in that same period.
A cross-sectional study conducted in the Netherlands assessed gynecologic screening behaviors in LS mutation carriers, who were surveyed 6 months to 8.5 years after their genetic diagnosis. Seventeen percent of respondents reported that they had undergone gynecologic screening prior to undergoing genetic testing, and 69% reported they had undergone gynecologic screening since their genetic diagnosis (P < .001). However, the screening interval and specific gynecologic tests were not described.
Risk-reducing surgery for LS
There is no consensus regarding the use of risk-reducing colectomy for LS, and little is known about decision-making and psychological sequelae surrounding risk-reducing colectomy for LS.
Among persons who received positive test results, a greater proportion indicated interest in having risk-reducing colectomy following disclosure of results as compared with baseline. This study also indicated that consideration of risk-reducing surgery for LS may motivate participation in genetic testing. Before receiving results, 46% indicated that they were considering risk-reducing colectomy, and 69% of women were considering risk-reducing total abdominal hysterectomy (RRH) and risk reducing bilateral salpingo-oophorectomy (RRSO); however, this study did not assess whether persons actually followed through with risk-reducing surgery after they received their test results. Prior to undergoing LS genetic counseling and testing, 5% of cancer-unaffected individuals at risk of a MMR mutation in a longitudinal study reported that they would consider colectomy, and 5% of women indicated that they would have an RRH and an RRSO, if they were found to be mutation-positive. At 3 years following disclosure of results, no participants had undergone risk-reducing colectomy. Two women who had undergone an RRH before genetic testing underwent RRSO within 1 year after testing, however, no other female mutation carriers in the study reported having either procedure at 3 years following test result disclosure.
Colorectal screening for FAP
Less is known about psychological aspects of screening for FAP. One study of a small number of persons (aged 17–53 years) with a family history of FAP who were offered participation in a genetic counseling and testing protocol found that among those who were asymptomatic, all reported undergoing at least one endoscopic surveillance before participation in the study. Only 33% (two of six patients) reported continuing screening at the recommended interval. Of the affected persons who had undergone colectomy, 92% (11 of 12 patients) were adherent to recommended colorectal surveillance. In a cross-sectional study of 150 persons with a clinical or genetic diagnosis of classic FAP or attenuated FAP (AFAP) and at-risk relatives, 52% of those with FAP and 46% of relatives at risk of FAP, had undergone recommended endoscopic screening. Among persons who had or were at risk of AFAP, 58% and 33%, respectively, had undergone screening. Compared with persons who had undergone screening within the recommended time interval, those who had not screened were less likely to recall provider recommendations for screening, more likely to lack health insurance or insurance reimbursement for screening, and more likely to believe that they are not at increased risk of CRC. Only 42% of the study population had ever undergone genetic counseling. A small percentage of participants (14%–19%) described screening as a “necessary evil,” indicating a dislike for the bowel preparation, or experienced pain and discomfort. Nineteen percent reported that these issues might pose barriers to undergoing future endoscopies. Nineteen percent reported that improved techniques and the use of anesthesia have improved tolerance for screening procedures.
Risk-reducing surgery for FAP
When persons at risk of FAP develop multiple polyps, risk-reducing surgery in the form of subtotal colectomy or proctocolectomy is the only effective way to reduce the risk of CRC. Most persons with FAP can avoid a permanent ostomy and preserve the anus and/or rectum, allowing some degree of bowel continence. Studies of bowel function after subtotal colectomy show that patients average four to five stools per day in the immediate postoperative period, decreasing to three stools per day by 1 year postsurgery.
Studies of risk-reducing surgery for FAP have found that general measures of quality of life have been within normal range, and the majority reported no negative impact on their body image. However, other studies suggest that risk-reducing surgery for FAP may have negative quality-of-life effects for at least some proportion of those affected. Twenty-nine percent of FAP-affected persons who had undergone subtotal colectomy reported that increased stool frequency adversely affected their activities, and 14% reported occasional liquid soiling. When FAP-specific quality-of-life domains were measured, one study indicated that persons undergoing ileal pouch anal anastomosis may experience more adverse outcomes for physical functioning, body image, sexual functioning, and negative affect compared with those who have not had surgery; and physical functioning and negative affect may be worse compared with persons who had an ileorectal anastomosis. Another study showed that 20% of those with good bowel function nonetheless reported fears about incontinence that affected their quality of life.
A large cross-sectional study of 525 persons from 145 families affected by or at high risk of FAP reported that surgically treated patients had significantly lower scores on several health-related quality-of-life domains, including physical functioning, social functioning, and defecation problems, as assessed by the Dutch version of the SF-36 Health Survey. Among surgically treated patients (n = 296) in this study, predictors of higher levels of physical functioning included being male and having no comorbid conditions or complications during surgery. Having a stoma predicted poorer body image. Worse problems with defecation were predicted by having had surgical complications or comorbid conditions, such as cardiovascular disease or diabetes mellitus. Those who reported better social functioning were more likely to have a higher educational level, have children, and not have a comorbid condition. The analyses controlled for clinical and sociodemographic variability including age at time of surgery, type of surgery, and personal cancer history (9% [n = 45] had a personal history of cancer at the time of the study).
A cross-sectional study of 209 adults with FAP participating in a Swedish registry who had undergone prophylactic colorectal surgery found that 91% of participants reported at least one (out of 21) symptom (e.g., diarrhea, stomach grumbling, and nighttime urge of defecation) from the Abdominal Symptom Questionnaire within the previous 3 months. All 21 symptoms were reported at least once by the participants. A higher number of symptoms were reported by women than men (P < .01); however, no differences were found between men and women in overall troublesomeness of symptoms. Self-reported number of symptoms was an independent predictor of physical and mental health with a high number of symptoms related to poor physical and mental health. For purposes of comparison, a population-based sample of Swedish adults (N = 1,290) responding to the Abdominal Symptom Questionnaire found 54% reported at least one abdominal symptom. Women within the population-based sample also reported significantly higher levels of symptoms than men, with the highest rates amongst young women.
Chemoprevention trials are currently under way to evaluate the effectiveness of various therapies for persons at risk of LS and FAP. In a sample of persons diagnosed with FAP who were invited to take part in a 5-year trial to evaluate the effects of vitamins and fiber on the development of adenomatous polyps, 55% agreed to participate. Participants were more likely to be younger, to have been more recently diagnosed with FAP, and to live farther from the trial center, but did not differ from nonparticipants on any other psychosocial variables.
Family communication about genetic testing for hereditary CRC susceptibility, and specifically about the results of such testing, is complex. It is generally accepted that communication about genetic risk information within families is largely the responsibility of family members themselves. A few studies have examined communication patterns in families who had been offered LS genetic counseling and testing. Studies have focused on whether individuals disclosed information about LS genetic testing to their family members, to whom they disclosed this information, and family-based characteristics or issues that might facilitate or inhibit such communication. These studies examined communication and disclosure processes in families after notification by health care professionals about a LS predisposition and have comprised relatively small samples.
Research findings indicate that persons generally are willing to share information about the presence of a LS-predisposing mutation within their families. Motivations for sharing genetic risk information include a desire to increase family awareness about personal risk, health promotion options and predictive genetic testing, a desire for emotional support, and a perceived moral obligation and responsibility to help others in the family. Findings across studies suggest that most study participants believed that LS genetic risk information is shared openly within families; however, such communication is more likely to occur with first-degree relatives (e.g., siblings, children) than with more distant relatives.
One Finnish study recruited parents aged 40 years or older and known to carry an MMR mutation to complete a questionnaire that investigated how parents shared knowledge of genetic risk with their adult and minor offspring. The study also identified challenges in the communication process. Of 248 parents, 87% reported that they had disclosed results to their children. Reasons for nondisclosure were consistent with previous studies (young age of offspring, socially distant relationships, or feelings of difficulty in discussing the topic ). Nearly all parents had informed their adult offspring about their genetic risk and the possibility of genetic testing, but nearly one-third were unsure of how their offspring had used the information. Parents identified discussing their children’s cancer risk as the most difficult aspect of the communication process. Of the 191 firstborn children informed, 69% had undergone genetic testing. One-third of the parents suggested that health professionals should be involved in disclosure of the information and that a family appointment at the genetics clinic should be made at the time of disclosure.
In regard to informing second- and third-degree relatives, individuals may favor a cascade approach; for example, it is assumed that once a relative is given information about the family’s risk of LS, he or she would then be responsible for informing his or her first-degree relatives. This cascade approach to communication is distinctly preferred in regard to informing relatives’ offspring, particularly those of minor age, and the consensus suggests that it would be inappropriate to disclose such information to a second-degree or third-degree relative without first proceeding through the family relational hierarchy. In one study, persons who had undergone testing and were found to carry a LS-predisposing mutation were more likely than persons who had received true negative or uninformative results to inform at least one second-degree or third-degree relative about their genetic test results.
While communication about genetic risk is generally viewed as an open process, some communication barriers were reported across studies. Reasons for not informing a relative included lack of a close relationship and lack of contact with the individual; in fact, emotional, rather than relational, closeness seemed to be a more important determinant of the degree of risk communication. A desire to not worry relatives with information about test results and the perception that relatives would not understand the meaning of this information also have been cited as communication barriers. Disclosure seemed less likely if at-risk individuals were considered too young to receive the information (i.e., children), if information about the hereditary cancer risk had previously created conflict in the family, or if it was assumed that relatives would be uninterested in information about testing. Prior existence of conflict seemed to inhibit discussions about hereditary cancer risk, particularly if such discussions involved disclosure of bad news.
For most participants in these studies, the news that the pattern of cancers in their families was attributable to a LS-predisposing mutation did not come as a surprise, as individuals had suspected a hereditary cause for the familial cancers or had prior family discussions about cancer. Identification of a LS-predisposing mutation in the family was considered a private matter but not necessarily a secret, and many individuals had discussed the family’s mutation status with someone outside of the family. Knowledge about the detection of a LS-predisposing mutation in the family was not viewed as stigmatizing, though individuals expressed concern about the potential impact of this information on insurance discrimination. Also, while there may be a willingness to disclose information about the presence of a mutation in the family, one study suggests a tendency to remain more private about the disclosure of individual results, distinguishing personal results from familial risk information. In a few cases, individuals reported that their relatives expressed anger, shock, or other negative emotional reactions after receiving news about the family’s LS risk; however, most indicated little to no difficulty in informing their relatives. It was suggested that families who are more comfortable and open with cancer-related discussions may be more receptive and accepting of news about genetic risk.
In some cases, probands reported feeling particularly obliged to inform family members about a hereditary cancer risk  and were often the strongest advocates for encouraging their family members to undergo genetic counseling and testing for the family mutation. Some gender and family role differences also emerged in regard to the dissemination of hereditary cancer risk information. One study reported that female probands were more comfortable discussing genetic information than were male probands and that male probands showed a greater need for professional support during the family communication process. Another study suggested that mothers may be particularly influential members of the family network in regard to communicating health risk information. Mutation-negative individuals, persons who chose not to be tested, and spouses of at-risk persons reported not feeling as personally involved with the risk communication process compared with probands and other at-risk persons who had undergone genetic testing.
Various modes of communication (e.g., in-person, telephone, or written contact) may typically be used to disclose genetic risk information within families.  In one study, communication aids such as a genetic counseling summary letter or LS booklet were viewed as helpful adjuncts to the communication process but were not considered central or necessary to its success. Studies have suggested that recommendations by health care providers to inform relatives about hereditary cancer risk may encourage communication about LS  and that support by health care professionals may be helpful in overcoming barriers to communicating such information to family members.
Much of the literature to date on family communication has focused on disclosure of test results; however, other elements of family communication are currently being explored. One study evaluated the role of older family members in providing various types of support (e.g., instrumental, emotional, crisis help, and dependability when needed) among individuals with LS and their family members (206 respondents from 33 families). Respondents completed interviews about their family social network (biological and non-biological relatives and others outside the family) and patterns of communication within their family. The average age of the respondents and the members of their family social network did not differ (~ age 43 years). The study found that 23% of the members of the family social network encouraged CRC screening (other types of support, such as social support, were reported much more frequently). Those who encouraged screening were older, female, and significant others or biological family members, rather than nonfamily members. Given that many of the members of the family social network did not live in the same household, the study points out the importance of extended family in the context of screening encouragement and support.1Croyle RT, Lerman C: Interest in genetic testing for colon cancer susceptibility: cognitive and emotional correlates. Prev Med 22 (2): 284-92, 1993.2Smith KR, Croyle RT: Attitudes toward genetic testing for colon cancer risk. Am J Public Health 85 (10): 1435-8, 1995.3Graham ID, Logan DM, Hughes-Benzie R, et al.: How interested is the public in genetic testing for colon cancer susceptibility? Report of a cross-sectional population survey. Cancer Prev Control 2 (4): 167-72, 1998.4Bunn JY, Bosompra K, Ashikaga T, et al.: Factors influencing intention to obtain a genetic test for colon cancer risk: a population-based study. Prev Med 34 (6): 567-77, 2002.5Meiser B, Dunn S: Psychological impact of genetic testing for Huntington's disease: an update of the literature. J Neurol Neurosurg Psychiatry 69 (5): 574-8, 2000.6Lerman C, Shields AE: Genetic testing for cancer susceptibility: the promise and the pitfalls. Nat Rev Cancer 4 (3): 235-41, 2004.7Petersen GM, Larkin E, Codori AM, et al.: Attitudes toward colon cancer gene testing: survey of relatives of colon cancer patients. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 337-44, 1999.8Glanz K, Grove J, Lerman C, et al.: Correlates of intentions to obtain genetic counseling and colorectal cancer gene testing among at-risk relatives from three ethnic groups. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 329-36, 1999.9Ramsey SD, Wilson S, Spencer A, et al.: Attitudes towards genetic screening for predisposition to colon cancer among cancer patients, their relatives and members of the community. Results of focus group interviews. Community Genet 6 (1): 29-36, 2003.10Keller M, Jost R, Kadmon M, et al.: Acceptance of and attitude toward genetic testing for hereditary nonpolyposis colorectal cancer: a comparison of participants and nonparticipants in genetic counseling. Dis Colon Rectum 47 (2): 153-62, 2004.11Lerman C, Marshall J, Audrain J, et al.: Genetic testing for colon cancer susceptibility: Anticipated reactions of patients and challenges to providers. Int J Cancer 69 (1): 58-61, 1996.12Kinney AY, Choi YA, DeVellis B, et al.: Attitudes toward genetic testing in patients with colorectal cancer. Cancer Pract 8 (4): 178-86, 2000 Jul-Aug.13Kinney AY, Choi YA, DeVellis B, et al.: Interest in genetic testing among first-degree relatives of colorectal cancer patients. Am J Prev Med 18 (3): 249-52, 2000.14Kinney AY, DeVellis BM, Skrzynia C, et al.: Genetic testing for colorectal carcinoma susceptibility: focus group responses of individuals with colorectal carcinoma and first-degree relatives. Cancer 91 (1): 57-65, 2001.15Keller M, Jost R, Haunstetter CM, et al.: Comprehensive genetic counseling for families at risk for HNPCC: impact on distress and perceptions. Genet Test 6 (4): 291-302, 2002.16Shiloh S, Koehly L, Jenkins J, et al.: Monitoring coping style moderates emotional reactions to genetic testing for hereditary nonpolyposis colorectal cancer: a longitudinal study. Psychooncology 17 (8): 746-55, 2008.17Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995.18Reliability of presymptomatic test for adenomatous polyposis coli. Lancet 337 (8750): 1171-2, 1991.19Whitelaw S, Northover JM, Hodgson SV: Attitudes to predictive DNA testing in familial adenomatous polyposis. J Med Genet 33 (7): 540-3, 1996.20Douma KF, Aaronson NK, Vasen HF, et al.: Attitudes toward genetic testing in childhood and reproductive decision-making for familial adenomatous polyposis. Eur J Hum Genet 18 (2): 186-93, 2010.21Levine FR, Coxworth JE, Stevenson DA, et al.: Parental attitudes, beliefs, and perceptions about genetic testing for FAP and colorectal cancer surveillance in minors. J Genet Couns 19 (3): 269-79, 2010.22Cunniff C; American Academy of Pediatrics Committee on Genetics.: Prenatal screening and diagnosis for pediatricians. Pediatrics 114 (3): 889-94, 2004.23Rappaport VJ: Prenatal diagnosis and genetic screening--integration into prenatal care. Obstet Gynecol Clin North Am 35 (3): 435-58, ix, 2008.24Eddleman KA, Malone FD, Sullivan L, et al.: Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol 108 (5): 1067-72, 2006.25Baruch S, Kaufman D, Hudson KL: Genetic testing of embryos: practices and perspectives of US in vitro fertilization clinics. Fertil Steril 89 (5): 1053-8, 2008.26Ogilvie CM, Braude PR, Scriven PN: Preimplantation genetic diagnosis--an overview. J Histochem Cytochem 53 (3): 255-60, 2005.27Kastrinos F, Stoffel EM, Balmaña J, et al.: Attitudes toward prenatal genetic testing in patients with familial adenomatous polyposis. Am J Gastroenterol 102 (6): 1284-90, 2007.28Simpson JL, Carson SA, Cisneros P: Preimplantation genetic diagnosis (PGD) for heritable neoplasia. J Natl Cancer Inst Monogr (34): 87-90, 2005.29Dewanwala A, Chittenden A, Rosenblatt M, et al.: Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch syndrome. Fam Cancer 10 (3): 549-56, 2011.30van Lier MG, Korsse SE, Mathus-Vliegen EM, et al.: Peutz-Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis. Eur J Hum Genet 20 (2): 236-9, 2012.31Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.: Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11 (1): 35-41, 2009.32Mvundura M, Grosse SD, Hampel H, et al.: The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med 12 (2): 93-104, 2010.33Hampel H, Frankel WL, Martin E, et al.: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352 (18): 1851-60, 2005.34Chubak B, Heald B, Sharp RR: Informed consent to microsatellite instability and immunohistochemistry screening for Lynch syndrome. Genet Med 13 (4): 356-60, 2011.35Piñol V, Castells A, Andreu M, et al.: Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 293 (16): 1986-94, 2005.36Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010.37Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012.38Beamer LC, Grant ML, Espenschied CR, et al.: Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 30 (10): 1058-63, 2012.39Codori AM, Petersen GM, Miglioretti DL, et al.: Attitudes toward colon cancer gene testing: factors predicting test uptake. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 345-51, 1999.40Lerman C, Hughes C, Trock BJ, et al.: Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA 281 (17): 1618-22, 1999.41Lynch HT, Lemon SJ, Karr B, et al.: Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications. Cancer Epidemiol Biomarkers Prev 6 (12): 987-91, 1997.42Vernon SW, Gritz ER, Peterson SK, et al.: Intention to learn results of genetic testing for hereditary colon cancer. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 353-60, 1999.43Aktan-Collan K, Mecklin JP, Järvinen H, et al.: Predictive genetic testing for hereditary non-polyposis colorectal cancer: uptake and long-term satisfaction. Int J Cancer 89 (1): 44-50, 2000.44Loader S, Shields C, Levenkron JC, et al.: Patient vs. physician as the target of educational outreach about screening for an inherited susceptibility to colorectal cancer. Genet Test 6 (4): 281-90, 2002.45Hadley DW, Jenkins J, Dimond E, et al.: Genetic counseling and testing in families with hereditary nonpolyposis colorectal cancer. Arch Intern Med 163 (5): 573-82, 2003.46Johnson KA, Rosenblum-Vos L, Petersen GM, et al.: Response to genetic counseling and testing for the APC I1307K mutation. Am J Med Genet 91 (3): 207-11, 2000.47Petersen GM, Boyd PA: Gene tests and counseling for colorectal cancer risk: lessons from familial polyposis. J Natl Cancer Inst Monogr (17): 67-71, 1995.48Esplen MJ, Madlensky L, Aronson M, et al.: Colorectal cancer survivors undergoing genetic testing for hereditary non-polyposis colorectal cancer: motivational factors and psychosocial functioning. Clin Genet 72 (5): 394-401, 2007.49Manne SL, Chung DC, Weinberg DS, et al.: Knowledge and attitudes about microsatellite instability testing among high-risk individuals diagnosed with colorectal cancer. Cancer Epidemiol Biomarkers Prev 16 (10): 2110-7, 2007.50Wakefield CE, Meiser B, Homewood J, et al.: Randomized trial of a decision aid for individuals considering genetic testing for hereditary nonpolyposis colorectal cancer risk. Cancer 113 (5): 956-65, 2008.51Manne SL, Meropol NJ, Weinberg DS, et al.: Facilitating informed decisions regarding microsatellite instability testing among high-risk individuals diagnosed with colorectal cancer. J Clin Oncol 28 (8): 1366-72, 2010.52Bapat B, Noorani H, Cohen Z, et al.: Cost comparison of predictive genetic testing versus conventional clinical screening for familial adenomatous polyposis. Gut 44 (5): 698-703, 1999.53Dudok deWit AC, Duivenvoorden HJ, Passchier J, et al.: Course of distress experienced by persons at risk for an autosomal dominant inheritable disorder participating in a predictive testing program: an explorative study. Rotterdam/Leiden Genetics Workgroup. Psychosom Med 60 (5): 543-9, 1998 Sep-Oct.54Collins VR, Meiser B, Ukoumunne OC, et al.: The impact of predictive genetic testing for hereditary nonpolyposis colorectal cancer: three years after testing. Genet Med 9 (5): 290-7, 2007.55Meiser B, Collins V, Warren R, et al.: Psychological impact of genetic testing for hereditary non-polyposis colorectal cancer. Clin Genet 66 (6): 502-11, 2004.56Aktan-Collan K, Haukkala A, Mecklin JP, et al.: Psychological consequences of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC): a prospective follow-up study. Int J Cancer 93 (4): 608-11, 2001.57Claes E, Denayer L, Evers-Kiebooms G, et al.: Predictive testing for hereditary nonpolyposis colorectal cancer: subjective perception regarding colorectal and endometrial cancer, distress, and health-related behavior at one year post-test. Genet Test 9 (1): 54-65, 2005.58Vernon SW, Gritz ER, Peterson SK, et al.: Correlates of psychologic distress in colorectal cancer patients undergoing genetic testing for hereditary colon cancer. Health Psychol 16 (1): 73-86, 1997.59Gritz ER, Vernon SW, Peterson SK, et al.: Distress in the cancer patient and its association with genetic testing and counseling for hereditary non-polyposis colon cancer. Cancer Research, Therapy and Control 8(1-2): 35-49, 1999.60Esplen MJ, Urquhart C, Butler K, et al.: The experience of loss and anticipation of distress in colorectal cancer patients undergoing genetic testing. J Psychosom Res 55 (5): 427-35, 2003.61Gritz ER, Peterson SK, Vernon SW, et al.: Psychological impact of genetic testing for hereditary nonpolyposis colorectal cancer. J Clin Oncol 23 (9): 1902-10, 2005.62Murakami Y, Okamura H, Sugano K, et al.: Psychologic distress after disclosure of genetic test results regarding hereditary nonpolyposis colorectal carcinoma. Cancer 101 (2): 395-403, 2004.63Keller M, Jost R, Haunstetter CM, et al.: Psychosocial outcome following genetic risk counselling for familial colorectal cancer. A comparison of affected patients and family members. Clin Genet 74 (5): 414-24, 2008.64Hasenbring MI, Kreddig N, Deges G, et al.: Psychological impact of genetic counseling for hereditary nonpolyposis colorectal cancer: the role of cancer history, gender, age, and psychological distress. Genet Test Mol Biomarkers 15 (4): 219-25, 2011.65Wagner A, van Kessel I, Kriege MG, et al.: Long term follow-up of HNPCC gene mutation carriers: compliance with screening and satisfaction with counseling and screening procedures. Fam Cancer 4 (4): 295-300, 2005.66van Oostrom I, Meijers-Heijboer H, Duivenvoorden HJ, et al.: Experience of parental cancer in childhood is a risk factor for psychological distress during genetic cancer susceptibility testing. Ann Oncol 17 (7): 1090-5, 2006.67Patenaude AF: Genetic Testing for Cancer: Psychological Approaches for Helping Patients and Families. Washington, DC: American Psychological Association, 2005.68Michie S, Bobrow M, Marteau TM: Predictive genetic testing in children and adults: a study of emotional impact. J Med Genet 38 (8): 519-26, 2001.69Michie S, Weinman J, Miller J, et al.: Predictive genetic testing: high risk expectations in the face of low risk information. J Behav Med 25 (1): 33-50, 2002.70Andrews L, Mireskandari S, Jessen J, et al.: Impact of familial adenomatous polyposis on young adults: attitudes toward genetic testing, support, and information needs. Genet Med 8 (11): 697-703, 2006.71Douma KF, Aaronson NK, Vasen HF, et al.: Psychological distress and use of psychosocial support in familial adenomatous polyposis. Psychooncology 19 (3): 289-98, 2010.72Codori AM, Petersen GM, Boyd PA, et al.: Genetic testing for cancer in children. Short-term psychological effect. Arch Pediatr Adolesc Med 150 (11): 1131-8, 1996.73Codori AM, Zawacki KL, Petersen GM, et al.: Genetic testing for hereditary colorectal cancer in children: long-term psychological effects. Am J Med Genet 116A (2): 117-28, 2003.74Hadley DW, Jenkins JF, Dimond E, et al.: Colon cancer screening practices after genetic counseling and testing for hereditary nonpolyposis colorectal cancer. J Clin Oncol 22 (1): 39-44, 2004.75Halbert CH, Lynch H, Lynch J, et al.: Colon cancer screening practices following genetic testing for hereditary nonpolyposis colon cancer (HNPCC) mutations. Arch Intern Med 164 (17): 1881-7, 2004.76Collins V, Meiser B, Gaff C, et al.: Screening and preventive behaviors one year after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma. Cancer 104 (2): 273-81, 2005.77Stoffel EM, Garber JE, Grover S, et al.: Cancer surveillance is often inadequate in people at high risk for colorectal cancer. J Med Genet 40 (5): e54, 2003.78Hadley DW, Ashida S, Jenkins JF, et al.: Colonoscopy use following mutation detection in Lynch syndrome: exploring a role for cancer screening in adaptation. Clin Genet 79 (4): 321-8, 2011.79Bleiker EM, Menko FH, Taal BG, et al.: Screening behavior of individuals at high risk for colorectal cancer. Gastroenterology 128 (2): 280-7, 2005.80Yang K, Allen B, Conrad P, et al.: Awareness of gynecologic surveillance in women from hereditary non-polyposis colorectal cancer families. Fam Cancer 5 (4): 405-9, 2006.81Kinney AY, Hicken B, Simonsen SE, et al.: Colorectal cancer surveillance behaviors among members of typical and attenuated FAP families. Am J Gastroenterol 102 (1): 153-62, 2007.82Eu KW, Lim SL, Seow-Choen F, et al.: Clinical outcome and bowel function following total abdominal colectomy and ileorectal anastomosis in the Oriental population. Dis Colon Rectum 41 (2): 215-8, 1998.83Van Duijvendijk P, Slors JF, Taat CW, et al.: Quality of life after total colectomy with ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 87 (5): 590-6, 2000.84Church JM: Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann Med 28 (6): 479-82, 1996.85Andrews L, Mireskandari S, Jessen J, et al.: Impact of familial adenomatous polyposis on young adults: quality of life outcomes. Dis Colon Rectum 50 (9): 1306-15, 2007.86Lim JF, Ho YH: Total colectomy with ileorectal anastomosis leads to appreciable loss in quality of life irrespective of primary diagnosis. Tech Coloproctol 5 (2): 79-83, 2001.87Douma KF, Bleiker EM, Vasen HF, et al.: Quality of life and consequences for daily life of familial adenomatous polyposis (FAP) family members. Colorectal Dis 13 (6): 669-77, 2011.88Fritzell K, Eriksson LE, Björk J, et al.: Self-reported abdominal symptoms in relation to health status in adult patients with familial adenomatous polyposis. Dis Colon Rectum 54 (7): 863-9, 2011.89Agréus L, Svärdsudd K, Nyrén O, et al.: The epidemiology of abdominal symptoms: prevalence and demographic characteristics in a Swedish adult population. A report from the Abdominal Symptom Study. Scand J Gastroenterol 29 (2): 102-9, 1994.90Hawk E, Lubet R, Limburg P: Chemoprevention in hereditary colorectal cancer syndromes. Cancer 86 (11 Suppl): 2551-63, 1999.91Celecoxib trials under Way J Natl Cancer Inst 92 (4): 299A-299, 2000.92Miller HH, Bauman LJ, Friedman DR, et al.: Psychosocial adjustment of familial polyposis patients and participation in a chemoprevention trial. Int J Psychiatry Med 16 (3): 211-30, 1986-87.93Peterson SK, Watts BG, Koehly LM, et al.: How families communicate about HNPCC genetic testing: findings from a qualitative study. Am J Med Genet C Semin Med Genet 119 (1): 78-86, 2003.94Gaff CL, Collins V, Symes T, et al.: Facilitating family communication about predictive genetic testing: probands' perceptions. J Genet Couns 14 (2): 133-40, 2005.95Mesters I, Ausems M, Eichhorn S, et al.: Informing one's family about genetic testing for hereditary non-polyposis colorectal cancer (HNPCC): a retrospective exploratory study. Fam Cancer 4 (2): 163-7, 2005.96Stoffel EM, Ford B, Mercado RC, et al.: Sharing genetic test results in Lynch syndrome: communication with close and distant relatives. Clin Gastroenterol Hepatol 6 (3): 333-8, 2008.97Aktan-Collan KI, Kääriäinen HA, Kolttola EM, et al.: Sharing genetic risk with next generation: mutation-positive parents' communication with their offspring in Lynch Syndrome. Fam Cancer 10 (1): 43-50, 2011.98Pentz RD, Peterson SK, Watts B, et al.: Hereditary nonpolyposis colorectal cancer family members' perceptions about the duty to inform and health professionals' role in disseminating genetic information. Genet Test 9 (3): 261-8, 2005.99Koehly LM, Peterson SK, Watts BG, et al.: A social network analysis of communication about hereditary nonpolyposis colorectal cancer genetic testing and family functioning. Cancer Epidemiol Biomarkers Prev 12 (4): 304-13, 2003.100Ashida S, Hadley DW, Goergen AF, et al.: The importance of older family members in providing social resources and promoting cancer screening in families with a hereditary cancer syndrome. Gerontologist 51 (6): 833-42, 2011.
Changes to This Summary (02/28/2013)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated statistics with estimated new cases and deaths for 2013 (cited American Cancer Society as reference 1).
Added text to state that even in Lynch syndrome (LS), a hereditary form of colon cancer, cigarette smoking has been identified as a risk factor for the development of colorectal adenomas (cited Winkels et al. as reference 66).
Colon Cancer Genes
Revised text to state that a variety of LS-associated mutations in MSH2 and MLH1 have been identified; these include founder mutations in the Ashkenazi Jewish, Finnish, Portuguese, and German American populations (cited Pinheiro et al. and Tomsic et al. as references 31 and 32, respectively).
Added De novo mutation rate as a new subsection.
Major Genetic Syndromes
Added Khan et al. as reference 251.
Added text to state that one study of two families with the same EPCAM deletion found few extracolonic cancers and no endometrial cancers (cited Lynch et al. as reference 275).
Added text about a more efficient screening strategy that has been suggested in which staining for only PMS2 and MSH6 are performed (cited Hall et al. as reference 285), although staining for all four mismatch repair proteins remains the current standard of care.
Added text to state that even in centers that rely exclusively on immunohistochemistry (IHC) testing, there may be a role for subsequent microsatellite instability (MSI) testing in cases where the clinical picture suggests LS, notwithstanding the results of IHC.
The Surgical management in LS subsection was renamed from Risk-reducing surgery in LS.
Added text about a quality-of-life and functional outcome survey of LS patients in which global quality-of-life outcomes were comparable among patients with more extensive and less extensive resections (cited Haanstra et al. as reference 350); this parallels the experience in familial adenomatous polyposis (FAP) patients (cited Church et al., Hassan et al., Aziz et al. as references 351, 352, and 353, respectively).
Added Chromoendoscopy as a new subsection.
Added Small Bowel Imaging as a new subsection.
Psychosocial Issues in Hereditary Colon Cancer Syndromes
This section was renamed from Psychosocial Issues in Hereditary Colon Cancer Syndromes: Lynch Syndrome and FAP.
Revised text to state that from the limited studies published to date, there appears to be interest in the use of assisted reproductive technology (ART) for FAP, LS, and Peutz-Jeghers syndrome (PJS) (cited Dewanwala et al. and van Lier et al. as references 29 and 30, respectively).
Revised Table 15, Summary of Studies Evaluating Attitudes Toward, Interest in, or Intention to Use ART for FAP, LS, and PJS, to include a study in LS patients and a study in PJS patients.
Added Issues With Informed Consent for MSI and IHC Tumor Testing as a new subsection.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of colorectal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Colorectal Cancer are:
- Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)
- Donald W. Hadley, MS, CGC (National Human Genome Research Institute)
- Jennifer Lynn Hay, PhD (Memorial Sloan-Kettering Cancer Center)
- Scott Kuwada, MD, AGAF, FACP (University of Hawaii)
- Patrick M. Lynch, MD, JD (University of Texas, M.D. Anderson Cancer Center)
- Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
- Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
- Miguel A. Rodriguez-Bigas, MD (University of Texas, M.D. Anderson Cancer Center)
- Danielle Kim Turgeon, MD (University of Michigan Comprehensive Cancer Center)
- Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
- Catharine Wang, PhD, MSc (Boston University School of Public Health)
- Kevin Zbuk, MD, FRCPC (Margaret and Charles Juravinski Cancer Centre)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Genetics of Colorectal Cancer. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site’s Contact Form.
Get More Information From NCI
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
- NCI Public Inquiries Office
- 9609 Medical Center Dr.
- Room 2E532 MSC 9760
- Bethesda, MD 20892-9760
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
This information was last updated on 2013-02-28