Genetics of Colorectal Cancer

Summary Type: Genetics
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the genetics of colorectal cancer, including information about specific genes and family cancer syndromes. The summary also contains information about screening for colorectal cancer and research aimed at prevention of this disease. Psychosocial issues associated with genetic testing and counseling of individuals who may have hereditary colorectal cancer syndrome are also discussed.

Genetics of Colorectal Cancer

Introduction

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.

Colorectal cancer is a commonly diagnosed cancer in both men and women. In 2007, an estimated 153,760 new cases will be diagnosed, and 52,180 deaths from colorectal cancer will occur.¹ Two kinds of observations indicate a genetic contribution to colorectal cancer risk: (1) increased incidence of colorectal cancer among persons with a family history of colorectal cancer; and (2) families in which multiple family members are affected with colorectal cancer, in a pattern indicating autosomal dominant inheritance of cancer susceptibility.^2,3,4,5,6 About 75% of patients with colorectal cancer have sporadic disease , with no apparent evidence of having inherited the disorder. The remaining 25% of patients have a family history of colorectal cancer that suggests a genetic 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 colorectal cancer cases overall. It is likely that other undiscovered major genes and background genetic factors contribute to the development of colorectal cancer, in conjunction with nongenetic risk factors.

Natural History of Colorectal Cancer

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 3 groups: nonneoplastic polyps, neoplastic polyps (adenomatous polyps, adenomas), and cancers. 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.^7,8 Specialized techniques may be needed to identify, biopsy, and remove such lesions.⁹ The nonneoplastic polyps include hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid polyps, which have not generally been thought of as precursors of cancer. Research, however, suggests increased colorectal cancer risk in some families with multiple members affected with juvenile polyposis and hyperplastic polyposis.^10,11,12

Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.¹³ Two complementary interpretations of this observation are (1) the adenoma may reflect an innate or acquired tendency of the colon to form tumors, and (2) adenomas are the primary precursor lesion of colon cancer. More than 95% of colorectal cancers 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 3 histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that most colorectal cancers arise from adenomas, adenocarcinomas are generally considered to arise from adenomas,^{14,15,16,17,18} based upon these important observations: (1) benign and malignant tissue occur within colorectal tumors;¹⁹ and (2) 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.²⁰ Also, 3 characteristics of adenomas that are highly correlated with the potential to transform into cancer include large size, villous pathology, and the degree of dysplasia within the adenoma.¹⁹ In addition, removal of adenomatous polyps is associated with reduced colorectal cancer incidence.^20,21

Molecular Events Associated With Colon Carcinogenesis

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.^22,23,24 This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.^25,26 At least 5 to 7 major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least 2 major pathways by which these molecular events can lead to colorectal cancer. About 85% of colorectal cancers are due to events that result in chromosomal instability (CIN) and the remaining 15% are due to events that result in microsatellite instability (MSI or MIN, also known as replication error [RER]).^24,27,28

The spectrum of somatic mutations contributing to the pathogenesis of colorectal cancer is likely to be far more extensive than previously appreciated. A comprehensive study that sequenced more than 13,000 genes in a series of colorectal cancers found that tumors accumulate an average of approximately 90 mutant genes. Sixty-nine genes were highlighted as relevant to the pathogenesis of colorectal cancer, and individual colorectal cancers harbored an average of 9 mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature.^29,

Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and 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),^23,30 and chromosome losses are associated with instability at the molecular and chromosomal level.²⁴ 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.³⁰ 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 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 system, they more readily acquire mutations in important cancer-associated genes compared with cells that have an effective DNA mismatch repair 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. Mitotic instability of microsatellites is the hallmark of MSI cancers.

The knowledge derived from the study of inherited colorectal cancer 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. Acquired or inherited mutations of DNA damage-repair genes also play a role in predisposing colorectal epithelial cells to mutations.

Family History as a Risk Factor for Colorectal Cancer

Among the earliest studies of family history of colorectal cancer were those of Utah families that reported a higher number of deaths from colorectal cancer (3.9%) among the first-degree relatives of patients who had died from colorectal cancer, compared with sex-matched and age-matched controls (1.2%).³¹ This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a 2-fold to 3-fold increased risk of colorectal cancer. 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.^{32,33,34,35,36,37,}

Population-based studies have shown a familial association for close relatives of colon cancer patients to develop colorectal cancer and other cancers.³⁸ Using data from a cancer family clinic patient population, the relative and absolute risk of colorectal cancer for different family history categories was estimated (Table 1).^39,40

Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)

Family HistoryRelative Risk for CRC ^40,Absolute Risk of CRC by Age 79**Data from the Surveillance, Epidemiology, and End Results (SEER) database.†The absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRC ⁴⁰ and the absolute risk of CRC by age 79*.CI, confidence interval.No family history14%*One first-degree relative with colorectal cancer2.3 (95% CI, 2.0–2.5)9%†More than one first-degree relative with colorectal cancer4.3 (95% CI, 3.0–6.1)16%†One affected first-degree relative diagnosed with colorectal cancer before age 453.9 (95% CI, 2.4–6.2)15%†One first-degree relative with colorectal adenoma2.0 (95% CI, 1.6–2.6)8%†

When the family history includes two or more relatives with colorectal cancer, 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 colorectal cancer was diagnosed, the presence of multiple primary colorectal cancer, and the presence of any other cancers consistent with an inherited colorectal cancer syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Young subjects who report a positive family history of colorectal cancer are more likely to represent a high-risk pedigree than older individuals who report a positive family history.⁴¹ Computer models are now available to estimate the probability of developing colorectal cancer. These models can be helpful in providing genetic counseling to individuals at average risk as well as high risk of developing cancer. At least three validated models are also available for predicting the probability of carrying a mutation in a mismatch repair gene.^42,43,44,

Inheritance of Colorectal Cancer Predisposition

Several genes associated with colorectal cancer 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 colorectal cancer are inherited in an autosomal dominant fashion.² 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:

1. Vertical transmission of cancer predisposition. (Vertical transmission refers to the presence of a genetic predisposition in sequential generations.)
2. 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.
3. Other clinical characteristics also suggest inherited risk:
   • Cancers in people with an autosomal dominant predisposition typically occur at an earlier age than sporadic (nongenetic) cases.
   • An autosomal dominant predisposition to colorectal cancer may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
   • In addition, 2 or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., 2 separate primary colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).

Hereditary colorectal cancer has 2 well-described forms: familial adenomatous polyposis (FAP, including an attenuated form of polyposis [AFAP]), due to germline mutations in the APC gene,^{45,46,47,48,49,50,51,52} and hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by germline mutations in DNA mismatch repair genes.^53,54,55,56 Many other families exhibit aggregation of colorectal cancer and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial colorectal cancer (FCC).^2,

Difficulties in Identifying a Family History of Colorectal Cancer 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.⁵⁷ In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, some persons may carry a genetic predisposition to colorectal cancer but do not develop cancer, giving the impression of skipped generations in a family tree.

When family histories of colon cancer were checked in a research study, a sensitivity of 73% (95% CI, 54%–86%) was obtained.⁵⁸ In this study of Utah patients, the investigators compared self-reported family history of colon cancer with a computerized Utah Population Database, which was created by linking genealogical records with the state cancer registry. The kappa score, a measure of overall agreement between the reported family history and the database, was 0.56 (95% CI, 0.45–0.66), indicating moderately good agreement. Thus, what patients tell clinicians about their family histories is a reasonably good indicator of actual history.

Other Risk Factors for Colorectal Cancer

Other risk factors that may influence the development of adenomatous polyps and colorectal cancer risk include diet, use of nonsteroidal anti-inflammatory drugs [NSAIDs], postmenopausal hormone use, cigarette smoking, colonoscopy with removal of adenomatous polyps, and physical activity.

• Dietary factors that appear to be associated with developing adenomatous polyps and an increased incidence of colorectal cancer risk include a diet high in total fat,^{59 60,61} and meat (both red and white meat).^{61,62,63,64,65,66,67,68,69,70,71,72,}
• Some ^73,74,75 but not all ⁷⁶ studies have reported an association between aspirin use and decreased adenomatous polyp development and colon cancer incidence. In addition, studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.^77,78,
• Cigarette smoking is associated with an increased tendency to form adenomas and develop into colorectal cancer.^79,80,
• Colonoscopy with removal of adenomatous polyps may reduce the risk of colorectal cancer.^81,
• A sedentary lifestyle has been associated in some,^82,83,84 but not all,⁸⁵ studies with an increased risk of colorectal cancer.

(Refer to the PDQ Summary on Prevention of Colorectal Cancer for more information.)

Genetic factors appear to influence the age at onset of colorectal cancer. People who have a first-degree relative with colorectal cancer are estimated to have an average onset of colorectal cancer about 10 years earlier than people with sporadic colorectal cancer.³² The increased cancer risk conferred by a family history of colorectal cancer appears to manifest itself primarily in people under age 60.³² Markedly early onset of cancer is seen in hereditary conditions conferring an increased risk of colorectal cancer with a mean age at diagnosis of colorectal cancer in the early 30s for FAP and in the 40s for HNPCC.^2,3,

For the most part, the effects of other nongenetic risk factors have not been evaluated in people who are genetically susceptible to colorectal cancer. Studies of carcinogen metabolic polymorphisms , such as glutathione-s transferase and N-acetyl transferase, suggest that there may be some influence on the risk of colorectal cancer through interactions with micronutrients or other environmental factors; however, these data are too preliminary to apply in a clinical setting.^62,86,87,88,

Interventions

In practical terms, knowing that a person is at an increased risk of colorectal cancer 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 colorectal cancer and its precursors (i.e., adenomatous polyps) to identify people with an increased probability of developing colorectal cancer. Those with abnormalities should undergo diagnostic testing to see if 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 colorectal cancer by finding and removing its precursor, the adenomatous polyp, or preventing complications by early detection and treatment.

Primary prevention, eliminating the causes of colorectal cancer 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 screening in people with a genetically increased risk of colorectal cancer and few controlled comparisons. While a randomized trial with a no-screening arm is not feasible, there is a need for well-designed studies comparing various screening methods or differing periods of time between screening procedures. A published observational study that compared screened with unscreened (by choice) controls evaluated a 15-year experience with 252 relatives at risk for HNPCC, 119 of whom declined screening. Eight of 133 (6%) in the screened group developed colorectal cancer, compared with 19 in the unscreened group (16%, P = .014).⁸⁹ In general, however, people with genetic risk have been excluded from the trials of colorectal cancer 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 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, as well as 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.) In average-risk people, screening programs based on several different kinds of tests have been shown, with various degrees of persuasiveness, to prevent death from colorectal cancer:^20,

• Fecal occult blood testing (FOBT) is supported by 3 randomized controlled trials.^90,91,92,
• Sigmoidoscopy screening is supported by 4 case-control studies.^21,93,94,95,
• Colonoscopy has been shown to be effective in reducing the incidence of colorectal cancer in 2 cohort studies of patients with adenomatous polyps.^81,96,
• Double-contrast barium enema may be effective, considering that it allows examination of the entire bowel, but it has low sensitivity for large polyps and cancers.^20,

The fact that screening of average-risk persons reduces the risk of dying from colorectal cancer forms the basis for recommending screening in persons at a higher genetic risk of colorectal cancer. As logical as this approach seems, it is important to note that randomized trials of screening have not been performed in this special population, though observational studies performed on families with HNPCC ^97,98 and FAP ⁹⁹ support the value of screening. These studies suggest a stage shift towards earlier stages and a probable reduction in colorectal cancer mortality among screen-detected cancers.

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.^100,101 Additional criteria (4 and 5) were added below.^102,

1. A high burden of suffering, in terms of morbidity, mortality, and loss of function.
2. A screening test that is sufficiently sensitive, specific, safe, convenient, and inexpensive.
3. 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.
4. Evidence on the extent to which screening test and treatment do harm.
5. The value judgment that the screening test does more good than harm.

Of these criteria, the first and second are satisfied in genetically determined colorectal cancer. 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 HNPCC found earlier stage/local tumors in the screened individuals.^89,

Identification of persons at high genetic risk of colorectal cancer

Clinical criteria may be used to identify persons who are candidates for genetic testing to determine whether an inherited susceptibility to colorectal cancer is present. These criteria include:

• A strong family history of colorectal cancer and/or polyps.
• Multiple primary cancers in a patient with colorectal cancer.
• Existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of colorectal cancer, such as endometrial cancer.
• Early age at diagnosis of colorectal cancer.

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 colorectal cancer is not recommended as a screening measure in the general population. The rarity of mutations in the APC- and HNPCC-associated mismatch repair 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 HNPCC have been provided by several organizations representing various medical specialties and societies. These guidelines are readily available through the National Guideline Clearinghouse:

• American Cancer Society ^103,
• US Multisociety (American Gastroenterological Association [AGA], American Society for Gastrointestinal Endoscopy [ASGE]) Task Force on Colorectal Cancer ^104,
• American Society of Colon and Rectal Surgeons (ASCRS) ^105,
• National Comprehensive Cancer Network (NCCN) ^106,
• Gene Reviews

The evidence bases for recommendations are generally included within the statements of guidelines. In many instances, these guidelines reflect expert opinion resting on studies that are rarely randomized prospective trials.

Primary Prevention of Familial Colorectal Cancer

Chemoprevention

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 colorectal cancer.¹⁰⁷ (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 colorectal cancer, and few studies specifically enrolled people with an inherited predisposition for colorectal cancer. 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 colorectal cancer incidence.^108,

Randomized controlled trials have shown that NSAIDs (sulindac and celecoxib) induce regression of adenomas in patients with FAP.^109,110 However, in a small study of pediatric patients who were APC gene mutation carriers and who had not yet developed adenomas, sulindac did not yield a significant reduction in adenoma incidence.¹¹¹ These drugs may act by inhibiting cyclo-oxygenase II (COX-2), and therefore the production of prostaglandins, both of which are found in higher concentrations in colorectal cancers than in normal mucosa.¹¹² They may also act through COX-2–independent pathways that trigger programmed cell death.¹¹³ The NSAID effect apparently stops when the drugs are stopped. The results of these trials are consistent with observational studies showing that aspirin is a protective factor for colorectal cancer.¹¹⁴ No randomized trial has shown that NSAIDs prevent deaths from colorectal cancer, however, and at least one prospective study showed no association between aspirin use and the incidence of colorectal cancer. The authors concluded “the low dose of aspirin used and the short treatment period may account for the null findings.”⁷⁶ Other prospective studies showed a significant reduction in colorectal cancers in health care workers who regularly used aspirin.^115,116 A randomized, double-blind, placebo-controlled trial in patients who had a personal history of colon adenomas showed a modest but statistically significant reduction in the incidence of colonic adenomas with daily aspirin use.⁷⁵ In a double-blind placebo study, daily aspirin use was also associated with reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer.¹¹⁷ Less is known about the effects of NSAIDs on polyp development in people with other kinds of familial cancer syndromes such as HNPCC and familial aggregation. Polymorphisms in drug-metabolizing genes may contribute to variation in response to NSAIDs. For example, flavin monooxygenase 3 (FMO3) may reduce the catabolism of sulindac, resulting in an increased efficacy in the prevention of polyps in FAP.^118,

Use of folic acid supplements for more than 15 years has been shown in one observational study to be associated with a 75% lower colorectal cancer rate (relative risk [RR] 0.25, 95% CI, 0.13–0.51).⁶⁶ It is hypothesized that since folate is required for DNA synthesis, suboptimal amounts might cause abnormalities in DNA synthesis or repair. Randomized controlled trials are under way to test the hypothesis that folic acid supplements prevent cardiovascular disease (through their effect on homocysteine). When completed, the trials may have enough statistical power, singly or together, to provide stronger evidence on the effect of folic acid supplements on colorectal cancer.

It has been suggested that calcium, by binding bile acids in the bowel lumen, might inhibit their carcinogenic effects.^65,119 A randomized controlled trial of calcium supplementation, with a daily intake of 1,200 mg of elemental calcium for 4 years, reduced the risk of recurrent adenomas in presumably average-risk people with adenomas by 19% (adjusted risk ratio 0.81, 95% CI, 0.67–0.99).⁶⁵ It is uncertain whether this finding applies to people with genetically increased risk of colorectal cancer. Similarly, the observational evidence that estrogens are associated with a lower incidence of colorectal cancer does not include information specifically about people with a genetically increased risk of colorectal cancer.^{77,120,121,122,}

There may be other reasons for taking drugs such as aspirin and folic acid to prevent cardiovascular disease or taking calcium and estrogens to prevent osteoporosis. But if these substances are taken solely to prevent colorectal cancer, users should understand that the current evidence is not strong. In the case of NSAIDs, there is a small risk of bleeding complications such as stroke and upper gastrointestinal ulceration and bleeding to balance against the possibility of benefit.

Level of evidence for NSAIDs in FAP: 3a

Level of evidence for other risk groups and interventions: 6

Modifying behavioral risk factors

Several components of diet and behavior have been suggested, with various levels of consistency, to be risk factors for colorectal cancer. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) These lifestyle factors may represent potential means of prevention.^107,122,123 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 colorectal cancer. In one case-control study, physical activity, high energy, and low vegetable intake were significantly related to cancer risk in people with no family history of colorectal cancer but showed no relationship in people with a family history, despite adequate statistical power to do so.¹²⁴ One observational study has shown that the use of multivitamins and folate in women with a family history of colorectal cancer was associated with a decreased relative risk of colon cancer.^125,

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⁸³ Slattery ML, Schumacher MC, Smith KR, et al.: Physical activity, diet, and risk of colon cancer in Utah. Am J Epidemiol 128 (5): 989-99, 1988.

⁸⁴ Friedenreich CM: Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev 10 (4): 287-301, 2001.

⁸⁵ Kune GA, Kune S, Watson LF: Body weight and physical activity as predictors of colorectal cancer risk. Nutr Cancer 13 (1-2): 9-17, 1990.

⁸⁶ Lin HJ, Probst-Hensch NM, Louie AD, et al.: Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 7 (8): 647-52, 1998.

⁸⁷ Chen J, Stampfer MJ, Hough HL, et al.: A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer. Cancer Res 58 (15): 3307-11, 1998.

⁸⁸ Shaheen NJ, Silverman LM, Keku T, et al.: Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 95 (2): 154-9, 2003.

⁸⁹ Järvinen 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.

⁹⁰ Mandel JS, Bond JH, Church TR, et al.: Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 328 (19): 1365-71, 1993.

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⁹² Winawer SJ, St John J, Bond J, et al.: Screening of average-risk individuals for colorectal cancer. WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68 (4): 505-13, 1990.

⁹³ Selby JV, Friedman GD, Quesenberry CP Jr, et al.: A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 326 (10): 653-7, 1992.

⁹⁴ Newcomb PA, Norfleet RG, Storer BE, et al.: Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 84 (20): 1572-5, 1992.

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¹⁰⁰ U.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.

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¹⁰⁴ Winawer 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.

¹⁰⁵ Church 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.

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¹⁰⁸ Greenberg 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.

¹⁰⁹ Hawk E, Lubet R, Limburg P: Chemoprevention in hereditary colorectal cancer syndromes. Cancer 86 (11 Suppl): 2551-63, 1999.

¹¹⁰ Steinbach 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.

¹¹¹ Giardiello FM, Yang VW, Hylind LM, et al.: Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 346 (14): 1054-9, 2002.

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¹¹⁴ Greenberg ER, Baron JA, Freeman DH Jr, et al.: Reduced risk of large-bowel adenomas among aspirin users. The Polyp Prevention Study Group. J Natl Cancer Inst 85 (11): 912-6, 1993.

¹¹⁵ Giovannucci E, Rimm EB, Stampfer MJ, et al.: Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121 (4): 241-6, 1994.

¹¹⁶ Giovannucci E, Egan KM, Hunter DJ, et al.: Aspirin and the risk of colorectal cancer in women. N Engl J Med 333 (10): 609-14, 1995.

¹¹⁷ Sandler RS, Halabi S, Baron JA, et al.: A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348 (10): 883-90, 2003.

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Colon Cancer Genes

Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (nonsense, frameshift , etc.) 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.¹ 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 stability genes.² 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, even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair genes responsible for hereditary nonpolyposis colorectal cancer (HNPCC), account for a substantial fraction of hereditary colorectal cancer, as noted below (see section on Hereditary Nonpolyposis Colorectal Cancer [HNPCC]). MYH is another important example of a stability gene that confers risk of colorectal cancer on the basis of defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of colorectal cancer, with their corresponding diseases.

Table 2: Major Genes Associated with Risk of Colorectal Cancer

Gene Syndrome Hereditary Pattern Predominant Cancer Adapted from Vogelstein et al.^2,Tumor suppressor genes APCFAPDominantColon, intestine, etc.AXIN2Attenuated PolyposisDominantColonTP53 (p53)Li-FraumeniDominantMultiple (including colon)STK11Peutz-JeghersDominantMultiple (including intestine)PTENCowdenDominantMultiple (including intestine)BMPR1AJuvenile PolyposisDominantGastrointestinalSMAD4 (DPC4)Juvenile PolyposisDominantGastrointestinalRepair/Stability genes hMLH1, hMSH2, hMSH6, PMS2HNPCCDominantMultiple (including colon, uterus, and others)MYH (MutYH)Attenuated PolyposisRecessiveColonBLMBloomRecessiveMultiple (including colon)Oncogenes KITFamilial GI Stromal TumorGI stromal tumorsPDGFRAFamilial GI Stromal TumorGI stromal tumors

Several reviews have been published describing the hereditary colon cancer genes.^3,4,5,

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 (CIN) colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (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.^6,7 AFAP is associated with truncating mutations primarily in the 5’ and 3’ ends of the gene and possibly missense mutations elsewhere.^8,9,10,11

More than 300 different disease-associated mutations of the APC gene have been reported.⁷ 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.^12,

Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype .^8,9,10 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 the latter two thirds of exon 15,⁹ and that retinal lesions are rarely associated with mutations that occur before exon 9.^10,13

Mut Y Homolog

The Mut Y homolog (MYH) gene, located on chromosome 1p, has been implicated in individuals with multiple adenomas and colorectal cancer. MYH is one of several base excision-repair genes that corrects oxidative DNA damage. Failure to correct this damage can lead to the formation of 8-oxoG, causing an increase in G:C→T:A transversions. MYH was suspected as a susceptibility gene after researchers examined somatic mutations in the APC gene from a kindred without a germline APC mutation consisting of 2 siblings with multiple (about 50) adenomas and one sibling with colorectal cancer and adenomas. Somatic G:C→T:A transversions were identified in the APC gene in adenomas and colorectal cancer from these siblings, suggesting the possibility of underlying germline mutations in the MYH gene.¹⁴ Thus, APC is a major downstream target of MYH mutations.¹⁵ Notably, the occurrence of multiple adenomas was primarily found in patients with mutations in both alleles (i.e., biallelic mutations), suggesting an autosomal recessive mode of inheritance. A study of 152 patients with multiple adenomas and 107 APC mutation-negative polyposis patients found 2 major germline mutations, called Y165C and G382D, in addition to other variants.¹⁶ Understanding the significance of these additional variants will require further research in comprehensive analysis of the MYH gene in larger study populations.

DNA Mismatch Repair Genes

HNPCC is caused by mutation of one of several DNA mismatch repair genes.^{17,18,19,20,21,22,23} The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in HNPCC include hMSH2 (human mutS homolog 2) on chromosome 2p16;^20,21 hMLH1 (human mutL homolog 1) on chromosome 3p21;¹⁹ PMS2 (postmeiotic segregation 2) on chromosome 7p22;^23,24 and hMSH6 on chromosome 2p16. The genes hMSH2 and hMLH1 are thought to account for most mutations of the mismatch repair genes found in HNPCC families.^25,26,

A variety of HNPCC-associated mutations in hMSH2 and hMLH1 have been identified and catalogued, including founder mutations in the Ashkenazi Jewish (hMSH2 1906G-->C), Finnish (hMLH1 Fin 1 mutation), and German-American (hMSH2 exons 1–6 deletion) populations.^26,27,28,29 The wide distribution of the mutations in the 2 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 hMSH2 and hMLH1. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for hMSH2 and hMLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in HNPCC, methods such as Southern blot or multiplex ligation-dependent probe amplification (MLPA),³⁰ for detection of large deletions, are being used.³¹ Issues to be considered in testing for these mutations are reviewed in the Genetic/Molecular Testing for HNPCC section of this summary.

Germline mutation analysis for hMSH2, hMLH1, hMSH6, and/or PMS2 may be recommended for suspected HNPCC patients after screening the tumors for microsatellite instability (MSI) and/or the absence of protein expression. Microsatellites are short, repetitive sequences of mononucleotides, dinucleotides, and trinucleotides located throughout the genome, primarily in intronic sequences.³² Tumor DNA that shows alterations in microsatellite regions indicates probable defects in mismatch repair genes, which may be due to somatic or germline mutations in mismatch repair genes.³³ Similarly, absence of hMSH2, hMLH1, and hMSH6 protein expression has been shown to have a high predictive value to detect germline mutations. However, loss of protein expression may not be seen in all MSI-high (MSI-H) tumors.^34,35,

At a molecular level, the mismatch repair genes encode proteins that are responsible for correcting mispairing of DNA nucleotide bases and the small insertions or deletions that frequently occur during normal DNA replication. Thus, the mismatch repair system maintains the fidelity of genomic DNA.^36,37 While haploinsufficient cells have normal or nearly normal repair activity, cells in which both alleles of the mismatch repair gene are nonfunctional lack the ability to repair DNA replication mismatches. Evidence for this hypermutable state within the cell is seen by the insertion or deletion of mononucleotide, dinucleotide, or trinucleotide base pair repeats in the microsatellite tracts in the genomic DNA taken from tumor cells.³⁸ When these repetitive elements are replicated incorrectly and not repaired by the mismatch repair proteins, MSI ensues. The resulting genomic instability is thought to be responsible for the rapid accumulation of somatic mutations in oncogenes and tumor suppressor genes in the cell’s genome that have crucial roles in the initiation and progression of tumors.^39,

Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma as 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 an NIH Consensus conference.³⁸ If a tumor shows more than 30% to 40% of markers are unstable, it is scored as MSI-H; if fewer than 30% to 40% of markers are unstable, the tumor is designated MSI-low. If no loci are unstable, the tumor is designated microsatellite stable (MSS). Most tumors arising in the setting of HNPCC will be MSI-H.³⁸ One important distinction is that people with germline mutations in hMSH6 do not necessarily manifest the MSI-H phenotype.

The role of MSI analysis has led to the development of the Revised Bethesda Guidelines, which set forth clinical indications for use of this assay (including HNPCC) and standardization of tumor analysis.^38,40,41 Even simpler assays to screen tumors are being evaluated. One method that has been reported is immunohistochemistry, using monoclonal antibodies to the hMLH1 and hMSH2 proteins. Loss of expression of either protein appears to correlate with the presence of MSI and may suggest which specific mismatch repair gene is altered in a particular patient.^34,42,43,44,

Peutz-Jeghers Gene(s)

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.^45,46 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.^47,48 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.⁴⁹ Subsequently, the cancers that develop in STK11 +/- mice do show LOH;⁵⁰ indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.^51,

Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, as well as splice-site variants.⁵² Large deletions appear to be uncommon.⁵³ 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.⁵²

Only one gene (STK11) has been unequivocally demonstrated to cause PJS, but there is some evidence of locus heterogeneity that suggests the involvement of at least one other gene.^54,55 Mutations in STK11 can be identified in approximately 70% of patients,⁵³ and some families without identifiable mutations show linkage to 19q13.4. In addition, a novel chromosomal translocation involving 19q13.4 was identified in a PJS polyp from a 6-day-old infant, providing further evidence of the existence of a second PJS gene in this region. Recent data suggest that the combination of direct sequencing and multiplex ligation-dependent probe amplification (MLPA) enable detection of STK11 mutations in up to 94% of patients meeting clinical criteria for PJS.⁵⁶ Given the results of this study, it is unlikely that other major genes cause PJS.

(Refer to the Peutz-Jeghers Syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)

Juvenile Polyposis Gene

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%.^57,58,

SMAD4 encodes a protein that is a mediator of the TGF-β 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,⁵⁹ 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-β 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.^60,

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 (PHTS). Approximately 85% of patients diagnosed with Cowden syndrome and approximately 60% of patients with BRRS have an identifiable mutation of PTEN.^61,

PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine as well as 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.⁶² Individuals with mutations in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.^63,

(Refer to the Cowden Syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)

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² Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 10 (8): 789-99, 2004.

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⁴ Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348 (10): 919-32, 2003.

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⁹ Brensinger 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.

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¹⁵ Halford SE, Rowan AJ, Lipton L, et al.: Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Am J Pathol 162 (5): 1545-8, 2003.

¹⁶ Sieber 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.

¹⁷ Peltomäki P, Aaltonen LA, Sistonen P, et al.: Genetic mapping of a locus predisposing to human colorectal cancer. Science 260 (5109): 810-2, 1993.

¹⁸ Lindblom 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.

¹⁹ Bronner 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.

²⁰ Fishel 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.

²¹ Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75 (6): 1215-25, 1993.

²² Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994.

²³ Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994.

²⁴ Worthley 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.

²⁵ Marra G, Boland CR: Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87 (15): 1114-25, 1995.

²⁶ Peltomäki 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.

²⁷ Mitchell 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.

²⁸ Foulkes 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.

²⁹ Wagner 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.

³⁰ Ainsworth 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.

³¹ Gruber SB: New developments in Lynch syndrome (hereditary nonpolyposis colorectal cancer) and mismatch repair gene testing. Gastroenterology 130 (2): 577-87, 2006.

³² Weber 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.

³³ Aaltonen LA, Peltomäki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 260 (5109): 812-6, 1993.

³⁴ Lindor NM, Burgart LJ, Leontovich O, et al.: Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20 (4): 1043-8, 2002.

³⁵ Rigau V, Sebbagh N, Olschwang S, et al.: Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med 127 (6): 694-700, 2003.

³⁶ Rhyu MS: Molecular mechanisms underlying hereditary nonpolyposis colorectal carcinoma. J Natl Cancer Inst 88 (5): 240-51, 1996.

³⁷ Chung DC, Rustgi AK: DNA mismatch repair and cancer. Gastroenterology 109 (5): 1685-99, 1995.

³⁸ Boland 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.

³⁹ Lazar V, Grandjouan S, Bognel C, et al.: Accumulation of multiple mutations in tumour suppressor genes during colorectal tumorigenesis in HNPCC patients. Hum Mol Genet 3 (12): 2257-60, 1994.

⁴⁰ Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al.: A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89 (23): 1758-62, 1997.

⁴¹ Umar 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.

⁴² Thibodeau 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.

⁴³ Cawkwell 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.

⁴⁴ de La Chapelle A: Microsatellite instability phenotype of tumors: genotyping or immunohistochemistry? The jury is still out. J Clin Oncol 20 (4): 897-9, 2002.

⁴⁵ Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998.

⁴⁶ Jenne 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.

⁴⁷ Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998.

⁴⁸ Wang 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.

⁴⁹ Miyoshi H, Nakau M, Ishikawa TO, et al.: Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 62 (8): 2261-6, 2002.

⁵⁰ Nakau 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.

⁵¹ Takeda 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.

⁵² Hearle 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.

⁵³ Amos CI, Keitheri-Cheteri MB, Sabripour M, et al.: Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 41 (5): 327-33, 2004.

⁵⁴ Olschwang S, Markie D, Seal S, et al.: Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J Med Genet 35 (1): 42-4, 1998.

⁵⁵ Mehenni H, Gehrig C, Nezu J, et al.: Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet 63 (6): 1641-50, 1998.

⁵⁶ Aretz 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.

⁵⁷ Sayed 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.

⁵⁸ Howe 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.

⁵⁹ Howe JR, Roth S, Ringold JC, et al.: Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280 (5366): 1086-8, 1998.

⁶⁰ Howe 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.

⁶¹ Zhou 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.

⁶² Eng C: PTEN: one gene, many syndromes. Hum Mutat 22 (3): 183-98, 2003.

⁶³ Marsh 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.

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.¹ 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.² The relative and absolute risk of colorectal cancer 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.³ 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.

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 a 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.^4,5,6,

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 two-fold increased risk of colonic adenomas and adenocarcinomas compared with the general population.^6,7 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.⁶ Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated colon cancer risk may not be 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.

Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.⁸ None of these alleles, including the APC I1307K polymorphism, have been characterized enough to currently support its routine use in a clinical setting. At the present time, the family history remains the most valuable tool for establishing risk of colon cancer in these families.

¹ Burt 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.

² Butterworth 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.

³ Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.

⁴ Gruber SB, Ellis NA, Scott KK, et al.: BLM heterozygosity and the risk of colorectal cancer. Science 297 (5589): 2013, 2002.

⁵ Le 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.

⁶ Laken 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.

⁷ Lothe 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.

⁸ Hirschhorn JN, Lohmueller K, Byrne E, et al.: A comprehensive review of genetic association studies. Genet Med 4 (2): 45-61, 2002 Mar-Apr.

Major Genetic Syndromes

Introduction

A number of familial syndromes are associated with a high risk of colorectal adenocarcinoma and are summarized in Table 3. The absolute lifetime risk of colorectal adenocarcinoma is highest in familial adenomatous polyposis (FAP), where the large intestines of affected patients are studded with hundreds to thousands of adenomatous polyps. The absolute risks are lower in Peutz-Jeghers syndrome and juvenile polyposis syndrome than in hereditary nonpolyposis colorectal cancer (HNPCC) or FAP, and these syndromes differ in that the intestinal polyps are hamartomatous although the transformation to adenocarcinoma may be preceded by adenomatous change. Colorectal cancer screening and surveillance recommendations are established for HNPCC and FAP, and have been proposed for Peutz-Jeghers and juvenile polyposis families.

Table 3. Absolute Risks of Colorectal Cancer for Mutation Carriers in Hereditary Colorectal Cancer Syndromes

SyndromeAbsolute Risk in Mutation Carriers *See text on Hereditary Nonpolyposis Colorectal Cancer (HNPCC) for a full discussion of risk.Familial Adenomatous Polyposis (FAP)90% by age 45 ^1,Attenuated FAP69% by age 80 ² Hereditary Nonpolyposis Colorectal Cancer80% by age 75* ^3,MYH-Associated NeoplasiaNot establishedPeutz-Jeghers39% by age 70 ^4,Juvenile Polyposis17% to 68% by age 60 ^5,6,

Familial Adenomatous Polyposis (FAP)

FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.^1,7,8 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.⁹ 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 (CHRPE), 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. For additional information, refer to Table 4.

Table 4. Extracolonic Tumor Risks in FAP

Malignancy Relative Risk Absolute Lifetime Risk (%) Adapted from Giardiello et al.,¹⁰ Jagelman et al.,¹¹ Sturt et al.,¹² Lynch et al.,¹³ Bülow et al.,¹⁴ and Galiatsatos et al.^15,*The Leeds Castle Polyposis GroupDesmoid852.015.0Duodenum330.83.0–5.0Thyroid7.62.0Brain7.02.0Ampullary123.71.7Pancreas4.51.7Hepatoblastoma847.01.6Gastric—0.6*

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.^16,

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%.^1,7,8 The age at onset of adenomas in the colon is variable: By age 10, only 15% of FAP gene carriers manifest adenomas; by age 20, the probability rises to 75%; and by age 30, 90% will have presented with FAP.^1,7,8,17,18 Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life.^1,7,8 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.^19,20

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 .²¹ 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: Hereditary Nonpolyposis Colon Cancer and Familial Adenomatous Polyposis 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 FAP section of this summary for more information.)

Extracolonic tumors

Desmoid Tumors

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.²² Desmoids may occur sporadically , as part of classical FAP, as part of the clinical variant Gardner syndrome, or in a hereditary manner without the colon findings of FAP.^13,23 Desmoids have been associated with hereditary APC gene mutations even when not associated with typical adenomatous polyposis of the colon.^23,24

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.^23,25,26 APC mutations occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.^24,27,28,29 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.^23,

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.³⁰ It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly.³¹ 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.^32,33

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.²⁶ In some series, desmoids are the second most common cause of death after colorectal cancer in FAP patients.^34,35 A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity.³⁶ 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.^36,

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.^25,31,37

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 anti-estrogens, 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.^38,39,40 There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed.⁴¹ Significant desmoid tumor regression was reported in 7 patients who had symptomatic, unresectable, intra-abdominal desmoid tumors and failed hormonal therapy when treated with chemotherapy (doxorubicin and dacarbazine) followed by meloxicam.^42,

Thirteen patients with intra-abdominal desmoids and/or unfavorable response to other medical treatments, who had expression of estrogen α receptors in their desmoid tissues, were included in a prospective study of raloxifene, given in doses of 120 mg daily.³⁸ Six of the patients had been on tamoxifen or sulindac before treatment with raloxifene, and 7 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 as well as 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 α receptors who have received raloxifene and their outcome, as well as 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 10 patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that 3 patients had stable disease for more than 30 months.³⁹ 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.⁴⁰ In this study, some patients had regression, some patients had progression, and some patients had stable disease.

These 3 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.

The use of these agents in clinical practice is based on anecdotal experience only, as no randomized clinical trials have been performed.

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.⁴³ A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.^43,44 Issues of subject selection are critical in evaluating surgical outcome data.⁴⁴ Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.

Stomach Tumors

The most common gastric polyps in FAP are fundic gland polyps (FGP). The incidence of FGP has been estimated to be as high as 60% in individuals with FAP, compared with 0.8% to 1.9% in the general population.^{14,15,45,46,47,48,49} These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.⁵⁰ FGP has been considered to be benign, but there have been case reports of gastric adenocarcinoma (lifetime risk of 0.6%) associated with FAP.^15,51

Gastric adenomas do 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%.^52,53,54,55 These adenomas can progress to carcinoma. FAP patients in Korea and Japan have been reported to have an increased risk of gastric cancer 3 to 4 times that of the general population; this increased risk has not been found in Western populations.^56,57,58,59 The recommended management for gastric adenomas is