Purpose of This PDQ Summary
Introduction

Natural History of Colorectal Cancer Molecular Events Associated With Colon Carcinogenesis Family History as a Risk Factor for Colorectal Cancer Inheritance of Colorectal Cancer Predisposition Difficulties in Identifying a Family History of Colorectal Cancer Risk Other Risk Factors for Colorectal Cancer Interventions         State of the evidence base         Rationale for screening         Identification of persons at high genetic risk of colorectal cancer Primary Prevention of Familial Colorectal Cancer         Chemoprevention         Modifying behavioral risk factors

Colon Cancer Genes

Major Genes Adenomatous Polyposis Coli (APC) Mut Y Homolog DNA Mismatch Repair Genes Peutz-Jeghers Gene(s) Juvenile Polyposis Gene Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)

Genetic Polymorphisms and Colorectal Cancer Risk

APC I1307K Genetic Variation in 8q24 and SMAD7

Major Genetic Syndromes

Introduction Familial Adenomatous Polyposis (FAP)         Density of colonic polyposis         Extracolonic tumors         Genetic testing for FAP         Interventions/FAP Attenuated FAP (AFAP) MYH-Associated Neoplasia Lynch Syndrome         Genetic/Molecular testing for Lynch syndrome         Interventions/Lynch syndrome         Screening for endometrial cancer in Lynch syndrome families         Risk-reducing surgery in Lynch syndrome Familial Colorectal Cancer (FCC)         Familial colorectal cancer Type X         Interventions/Family history of colorectal cancer Rare Colon Cancer Syndromes         Peutz-Jeghers syndrome         Juvenile polyposis syndrome         Hereditary mixed polyposis syndrome         CHEK2         Hyperplastic polyposis         Interventions/Rare colon cancer syndromes

Psychosocial Issues in Hereditary Colon Cancer Syndromes: Lynch Syndrome and Familial Adenomatous Polyposis

Introduction Interest in Genetic Counseling and Testing for Hereditary Colorectal Cancer in the General Population and High-Risk Families         Interest in genetic counseling and testing in the general population         Interest in genetic counseling and testing among colorectal cancer patients and their close relatives         Interest in genetic testing for children Participation in Genetic Counseling and Testing for Hereditary Colorectal Cancer         Lynch syndrome         Familial adenomatous polyposis Psychological Impact of Participating in Hereditary Colorectal Cancer Genetic Counseling and Testing         Lynch syndrome         Familial adenomatous polyposis Psychosocial Aspects of Screening and Risk Reduction Interventions for Lynch Syndrome and FAP         Endoscopic screening for Lynch syndrome         Gynecologic cancer screening in Lynch syndrome         Risk-reducing surgery for Lynch syndrome         Colorectal screening for FAP         Risk-reducing surgery for FAP         Chemoprevention         Family communication

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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of colorectal cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board ¹.

The following information is included in this summary:

• Family history and other risk factors for colorectal cancer.
• Primary prevention of familial colorectal cancer.
• Major genes and genetic polymorphisms associated with colorectal cancer risk.
• Genetic testing, screening, and risk modification for hereditary colorectal cancer.
• Psychosocial issues associated with hereditary colorectal cancer and genetic testing.

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview ².

This summary is intended to provide clinicians a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary colorectal cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Introduction

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms ³. 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 2008, an estimated 148,810 new cases will be diagnosed, and 49,960 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.[2-6] 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.

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 three 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.[10-12]

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 three 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,[14-18] 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, three 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.[21,22]

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[23-25] This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.[26,27] 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 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]).[25,28,29]

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 nine mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature.[30]

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),[24,31] and chromosome losses are associated with instability at the molecular and chromosomal level.[25] 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.[31] 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.

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%).[32] 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 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.[33-38]

Population-based studies have shown a familial association for close relatives of colon cancer patients to develop colorectal cancer and other cancers.[39] 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 ⁴).[40,41]

A systematic review and meta-analysis of familial colorectal cancer risk was reported.[41] Of 24 studies included in the analysis, all but one reported an increased risk of colorectal cancer if there was an affected first-degree relative. The relative risk (RR) for colorectal cancer 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 colorectal cancer risk. In studies reporting more than one first-degree relative with colorectal cancer, 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 colorectal cancer associated with adenoma in a first degree relative was analyzed. The pooled analysis demonstrated an RR for colorectal cancer of 1.99 (95% CI, 1.55–2.55) in individuals who had a first-degree relative with an adenoma.[41] Other studies have reported that age at diagnosis of the adenoma influences the colorectal cancer risk, with younger age at adenoma diagnosis associated with higher RR.[42,43] As with any meta-analysis, there could be potential biases which might affect the results of the analysis, including incomplete and non-random 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 colorectal cancer risk, age at diagnosis of both colorectal cancer and adenomas, and multiplicity of affected family members.

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 ⁶ 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.[44] 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.[45-47]

Several genes associated with colorectal cancer risk have been identified; these are described in detail in the Colon Cancer Genes ⁷ 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 ⁶ 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 colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).
   
   
   

Hereditary colorectal cancer has two well-described forms: familial adenomatous polyposis (FAP, including an attenuated form of polyposis [AFAP]), due to germline mutations in the APC gene,[48-55] and Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline mutations in DNA mismatch repair genes.[56-59] 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.[2]

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.[60] 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.[61] 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 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 [62-64] and meat (both red and white meat).[64-75]



• Some,[76-78] but not all,[79] 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.[80,81]



• Cigarette smoking is associated with an increased tendency to form adenomas that develop into colorectal cancer.[82,83]



• Colonoscopy with removal of adenomatous polyps may reduce the risk of colorectal cancer.[21]



• A sedentary lifestyle has been associated in some,[84-86] but not all,[87] studies with an increased risk of colorectal cancer.

(Refer to the PDQ Summary on Prevention of Colorectal Cancer ⁸ 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.[33] The increased cancer risk conferred by a family history of colorectal cancer appears to manifest itself primarily in people younger than 60 years.[33] 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 Lynch syndrome.[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, N-acetyl transferase and steroid 17-hydroxylase/17,20-lyase (CYP17), 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.[65,88-91]

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 increasing the likelihood of cure 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.

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 Lynch syndrome, 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).[92] 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 ⁹ 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 three randomized controlled trials.[93-95]



• Sigmoidoscopy screening is supported by four case-control studies.[22,96-98]



• Colonoscopy has been shown to be effective in reducing the incidence of colorectal cancer in two cohort studies of patients with adenomatous polyps.[21,99]



• 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 Lynch syndrome [100,101] and FAP [102] 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.

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.[103,104] Additional criteria (4 and 5) were added below.[105]

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 Lynch syndrome found earlier stage/local tumors in the screened individuals.[92]

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 ⁶ 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 Lynch syndrome-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 Lynch syndrome have been provided by several organizations representing various medical specialties and societies. These guidelines are readily available through the National Guideline Clearinghouse ¹⁰:

• American Cancer Society.[106]
• U.S. Multisociety (American Gastroenterological Association [AGA], American Society for Gastrointestinal Endoscopy [ASGE]) Task Force on Colorectal Cancer.[107]
• American Society of Colon and Rectal Surgeons (ASCRS).[108]
• National Comprehensive Cancer Network (NCCN).[109]
• Gene Reviews ¹¹.

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.

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.[110] (Refer to the PDQ summary on Prevention of Colorectal Cancer ⁸ 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.[111]

Randomized controlled trials have shown that NSAIDs (sulindac and celecoxib) induce regression of adenomas in patients with FAP.[112,113] 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.[114] These drugs may act by inhibiting cyclooxygenase II (COX-2), and therefore the production of prostaglandins, both of which are found in higher concentrations in colorectal cancers than in normal mucosa.[115] They may also act through COX-2–independent pathways that trigger programmed cell death.[116] 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.[117] 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.”[79] Other prospective studies showed a significant reduction in colorectal cancers in health care workers who regularly used aspirin.[118,119] 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.[78] 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.[120] Less is known about the effects of NSAIDs on polyp development in people with other kinds of familial cancer syndromes such as Lynch syndrome 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.[121]

The COX-2 inhibitors celecoxib and rofecoxib have each been shown to inhibit and cause regression of adenomas in FAP.[113,122,123] An effect of similar magnitude has been seen in trials with COX-2 inhibitors with respect to new adenoma formation in individuals with sporadic or nonfamilial adenomas.[124-128] These much larger trials, involving older subjects (older than 50 years), revealed a significant increase in drug-related serious adverse events, specifically heart attack and stroke.[127,128] These risks were duration and dose-dependent, but not clearly related to the presence of underlying cardiovascular risk factors. Publication of these findings led to termination of many cancer prevention trials and temporary suspension of COX-2 trials in FAP. Regulatory approval of celecoxib was withdrawn in some countries. There is some evidence that nonselective NSAIDs may carry cardiovascular risk as well, clouding the future for NSAIDs (with the possible exception of aspirin) in colon cancer chemoprevention.[129,130] Whether the greater risk of colorectal cancer in FAP, compared to the general population, will tilt the risk-benefit equation in FAP families in favor of COX-2 inhibitors and other NSAIDs remains to be seen.

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 (RR 0.25, 95% CI, 0.13–0.51).[69] 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.[68,131] 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).[68] 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.[80,132-134]

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 and nonfamilial adenomas: 1aii

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 ⁸ for more information.) These lifestyle factors may represent potential means of prevention.[110,134,135] 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.[136] 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.[137]

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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 (e.g., nonsense, 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.[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 Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary colorectal cancer, as noted below (see section on Lynch syndrome ¹⁴). 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.

Several reviews have been published describing the hereditary colon cancer genes.[3-5]

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 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.[6,7] AFAP is associated with truncating mutations primarily in the 5’ and 3’ ends of the gene and possibly missense mutations elsewhere.[8-11]

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.[8-10] 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]

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 two 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, the APC protein 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 patients with APC mutation-negative polyposis found two major germline mutations, 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.

Lynch syndrome is caused by mutation of one of several DNA mismatch repair genes.[17-23] The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in Lynch syndrome 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 Lynch syndrome families.[25,26]

A variety of Lynch syndrome-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.[26-29] 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 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 Lynch syndrome, 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 Lynch syndrome ³⁸ section of this summary.

Germline mutation analysis for hMSH2, hMLH1, hMSH6, and/or PMS2 may be recommended for suspected Lynch syndrome 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 a National Institutes of Health 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 Lynch syndrome 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 ³⁹, which set forth clinical indications for use of this assay (including Lynch syndrome) 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.[34,42-44]

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 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 ⁴⁰ section in the PDQ summary on the Genetics of Breast and Ovarian Cancer ⁴¹ for more information.)

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-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,[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-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.[60] Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with juvenile polyposis syndrome. It was also reported that two individuals had mutations in both PTEN and BMPR1A.[61] Rare juvenile polyposis syndrome families have demonstrated mutations in the ENG and PTEN genes but these have not been confirmed in other studies.[61,62]

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.[63]

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.[64] Individuals with mutations in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[65]

(Refer to the Cowden Syndrome ⁴² section in the PDQ summary on the Genetics of Breast and Ovarian Cancer ⁴¹ for more information.)

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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 ⁴. 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 BLM^Ash (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.[4-6]

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 twofold 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.

Genome-wide association studies of colorectal cancer have identified several new susceptibility loci that have been reproduced in multiple populations. Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with relative risks ranging from 1.17 to 1.27.[8-10] Although the relative risk 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.[11]

Other candidate alleles that have been identified on multiple (more than three) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.[12] None of these alleles, including the APC I1307K polymorphism, have 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.[13]

References

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
3. Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.  [PUBMED Abstract]
   
   
4. Gruber SB, Ellis NA, Scott KK, et al.: BLM heterozygosity and the risk of colorectal cancer. Science 297 (5589): 2013, 2002.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
8. Zanke 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.  [PUBMED Abstract]
   
   
9. Tomlinson 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.  [PUBMED Abstract]
   
   
10. Gruber SB, Moreno V, Rozek LS, et al.: Genetic Variation in 8q24 Associated with Risk of Colorectal Cancer. Cancer Biol Ther 6 (7): , 2007.  [PUBMED Abstract]
    
    
11. Broderick 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.  [PUBMED Abstract]
    
    
12. Hirschhorn JN, Lohmueller K, Byrne E, et al.: A comprehensive review of genetic association studies. Genet Med 4 (2): 45-61, 2002 Mar-Apr.  [PUBMED Abstract]
    
    
13. Zheng 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.  [PUBMED Abstract]
    
    

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 Lynch syndrome (also called 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 Lynch syndrome and FAP, and have been proposed for Peutz-Jeghers and juvenile polyposis families.

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 analysis [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.

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.

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 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.[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 ⁴⁵ 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 ⁷ 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.

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 ⁴⁶ 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.[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.[24,27-29] 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.[38-40] 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 seven 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 alpha 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 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 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 alpha 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 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.[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 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.[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.

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.[14,15,45-49] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[50,51]

The hyperplastic surface epithelium is, by definition, non-neoplastic. 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.[15,52] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs.[51] In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy (EGD), 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.[53]

Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs).[51,54] 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%.[55-58] 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.[59-62] 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

Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper gastrointestinal (GI) endoscopy,[63] 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.[45,46,64] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[11,61,65,66] 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.[14] 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.[67]

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.[68] 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.[65] 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.[69,70]

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.[14,66,71,72] 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.[72] According to this system, 36% of patients with the most advanced stage will develop carcinoma.[66] Individuals with dense polyposis, large adenomas, or histologically advanced adenomas are considered for endoscopic or surgical treatment of the polyps because approximately one-third of these patients will develop duodenal cancer.[66]

A baseline upper endoscopy should be performed between ages 25 and 30 years in FAP patients.[62] The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy. Endoscopy every 4 to 5 years has been recommended for patients with no duodenal adenomas and every 6 to 12 months for those with more advanced adenomas or with multiple larger adenomas.[61,62] In the absence of prospective randomized studies, the surveillance recommendations are based on expert opinion.

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;[69,70,73] 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.[74] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[74-77] 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. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.

Level of evidence: 3diii

The spectrum of tumors arising in FAP is summarized in Table 4 ⁴⁷.

Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP.[78] However, a recent study [79] 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.

Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma in an FAP patient.[80] In a study of 162 FAP patients who underwent abdominal computed tomography for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors.[81] 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.[81] 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.[82-91] Some series have also demonstrated LOH of APC in these tumors.[83,85,92] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[93]

The constellation of colorectal cancer 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 genes.[94]

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.

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 [18] and direct detection [95] 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.[96] The addition of MLPA and analysis of allelic mRNA expression with single nucleotide primer extension (SNuPE) improves the detection rate for APC mutations.[97]

These mutation search methods, however, can be difficult to perform in routine clinical laboratory settings. More widespread use of a simpler procedure that tests for the truncated protein product using in vitro transcription of the APC gene obtained from lymphocyte RNA is possible.[98] APC protein truncation testing considerably enhances the feasibility of testing at-risk individuals without requiring DNA from multiple affected family members (as linkage requires). In particular, it is useful for testing in small families or in patients with de novo, or spontaneous, mutations (the first occurrence of FAP in a kindred), which may account for as much as one-third of incident cases.[1,7,8] Only about 80% of APC mutations can be detected by this method. In addition, the protein truncation assay (PTT) does not characterize the precise location or character of the mutation. PTT is no longer used in the United States as a commercial test for APC mutations and has been largely replaced with direct end-to-end sequencing. This still carries approximately 80% sensitivity for the mutation. Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[99,100] 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.[101] MYH gene testing may be considered in APC mutation–negative affected individuals.[102] (Refer to the Colon Cancer Genes ⁷ 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 attenuated FAP (AFAP) and MYH-associated colorectal neoplasia (also reported as MYH polyposis or MYH-associated polyposis [MAP]).[103] AFAP can be diagnosed by testing for germline APC gene mutations. (Refer to the Attenuated FAP [AFAP] ⁴⁶ section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.[104]

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,[17] though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 years).[17,18] 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 polyps by flexible sigmoidoscopy or colonoscopy. The recommended age at which surveillance 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, colorectal cancer 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 should consist of either flexible sigmoidoscopy or colonoscopy every year.[105-107] If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Although many clinicians have suggested that surveillance can be stopped in midlife, this recommendation is based on experience with individuals who had a 50% risk of inheriting the mutation, thus including noncarriers. Colon surveillance should not be stopped in persons who are known to carry an APC mutation because polyps occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated FAP [AFAP] ⁴⁶ section of this summary for more information.) An interest in noninvasive methods of screening has led to the evaluation of new screening techniques, including virtual colonoscopy and the detection of DNA mutations in stool. These methods have not been adequately evaluated in high-risk populations such as FAP and Lynch syndrome. The stool DNA mutation tests detect somatic mutations derived from the tumor tissue and are not appropriate for germline mutation testing. (Refer to the PDQ summary on Colorectal Cancer Screening ⁹ 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.[105,108]

Table 5 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.

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.[114] 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.[115] 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.[116]

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 for 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, as well as case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy.[117-120] 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.[115] 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, the duration of follow-up after IRA, and the genotype of the patients.[121-127] 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.[126,117,127,128] 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.[129,130] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[131] 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.[132]

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.[133-135] 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 colorectal cancer 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.[136]

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.[135]

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.[137] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[138] 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).[137]

Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[139-142] it is unclear whether this class of agents will be safe for long-term use for patients with FAP, as well as the general population. Also, because of the short-term (6-month) 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, colorectal cancer incidence.[143]

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.[7,19] The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma.[66]

Attenuated FAP (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.[144] Adenomas in AFAP are believed to form in the midtwenties to late twenties.[52] Similar to classic FAP, the risk of colorectal cancer is higher in individuals with AFAP; the average age of diagnosis, however, is older than classic FAP at 56 years.[145-147] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper gastrointestinal polyps (fundic gland polyps, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoids.[52]

AFAP is associated with particular subsets of APC mutations, including missense changes. Three groups of site-specific APC mutations causing AFAP have been characterized:[145,146,148-150]

• 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 gastrointestinal 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.[108] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[108] The role for and timing of risk-reducing colectomy in AFAP is controversial.[151] If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.[99]

Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[152,153] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MYH-associated polyposis or MAP), Lynch syndrome, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or Lynch syndrome. Whether the family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue) [154-160] with or without magnification, or possibly newer imaging techniques, such as narrow band imaging,[161] may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper GI endoscopy may be informative if duodenal adenomas or FGPs with surface dysplasia are found. Such findings will increase the likelihood of mutation detection if APC or MYH testing is pursued.

Homozygous mutations in the MYH gene have been associated with a phenotype of multiple colorectal adenomas with or without cancer. This accounts for a proportion of FAP patients without a pathogenic APC mutation. The syndrome has been referred to as MYH polyposis or MYH-associated polyposis (MAP).[102,162] The original report described three APC mutation–negative affected siblings, two of whom had approximately 50 adenomas at the ages of 55 years and 59 years, and one with colorectal cancer and an unknown number of adenomas at 46 years. Each sibling was found to carry the same biallelic mutations in the MYH gene.[104]

This finding led other investigators to estimate the proportion of APC mutation–negative patients accounted for by germline biallelic MYH mutations. On the basis of studies from multiple FAP registries, approximately 7% to 17% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.[102,104,162,163] In these individuals, the burden of adenomas ranges from very few to hundreds. MYH-associated neoplasia has been reported to have an autosomal recessive pattern of inheritance. In one study of 64 at-risk siblings of 25 index patients with identifiable biallelic MYH mutations, ten siblings were affected with colon polyposis alone, and seven had polyposis and colorectal cancer. Five of the 17 were tested for MYH mutations and shown to have similar biallelic mutations as their respective index case.[162] Neither MYH testing nor the colorectal phenotype, however, was reported in the other 47 siblings in this study.

Several studies have examined the frequency of MYH mutations in apparently sporadic colorectal cancer patients and in subjects undergoing colonoscopy screening.[164-167] Mutation detection was limited to the two major variants (Y165C and/or G382D) in most of these studies.[165,167] A Finnish population-based study of 1,042 patients with colorectal cancer found four patients (0.4%) with biallelic MYH mutations.[165] In addition to the colorectal cancer, these four patients had between 5 and 100 adenomas,[165] while no biallelic mutations were found in 400 cancer-free control subjects. In a hospital-based series of 400 individuals undergoing screening colonoscopy who had up to three adenomas, 444 patients with colorectal cancer, and 140 patients referred for genetic testing for possible FAP but with negative APC gene testing, 18 of the total individuals (2%) had biallelic MYH mutations. None of the screening patients, 16 (11%) of the APC mutation–negative patients, and two patients with colorectal cancer had biallelic MYH mutations.[167] A similar detection rate of 1% biallelic MYH mutations was found in a population-based study of 1,238 cases from Ontario with colorectal cancer and 1,255 healthy, randomly selected controls.[168] In a multiregister study of 358 unrelated colorectal cancer patients in the United Kingdom diagnosed at age 56 years or younger, the whole coding sequence of the MYH gene was examined.[164] Only two patients (0.6%) had biallelic MYH mutations, one with four adenomas and one with ten adenomas.[164] These studies identified several individuals with monoallelic MYH mutations. The relative risk (RR) of monoallelic mutations has been estimated at 1.27 (95% confidence interval [CI], 1.01–1.61). The RR in biallelic carriers is very high (RR 117, 95% CI, 74–184).[169] These data support the hypothesis that monoallelic mutations are a low penetrance risk factor for colorectal cancer.[168,170]

In Lynch syndrome,[171-173] unlike FAP, most patients do not have an unusual number of polyps. Lynch syndrome accounts for about 3% to 5% of all colorectal cancer. Other designations include HNPCC and cancer family syndrome. Lynch syndrome is an autosomal dominant condition caused by the mutation of one of several DNA mismatch repair (MMR) genes. (Refer to the DNA Mismatch Repair Genes ⁴⁹ section of this summary for more information.) The average age of colorectal cancer diagnosis in Lynch syndrome mutation carriers is 44 years, compared with 64 years in sporadic colorectal cancer. Individuals with mutations in hMSH6 have been reported to have a mean age at colorectal cancer diagnosis of 55 to 57 years.[174] Lynch syndrome mutation carriers also have an increased risk of developing colon adenomas (hazard ratio = 3.4), and the onset of adenomas appears to occur at a younger age than that seen in nonmutation carriers.[175] Individuals with a Lynch syndrome gene mutation have an estimated 80% lifetime risk of developing colon or rectal cancer.[3] Unlike sporadic cancers, which develop most often in the left side of the colon, Lynch syndrome cancers are most likely to develop in the right side, defined as proximal to the splenic flexure.

Newer data from a combined set of Lynch syndrome families showed that the average age at diagnosis of colorectal cancer is 61 years among gene carriers when a more rigorous statistical approach is utilized in which all gene carriers (both affected and unaffected) are considered.[174,176] A meta-analysis of population-based or ascertainment-adjusted published results showing that the cumulative lifetime risks of colorectal and endometrial cancer are lower than previously reported, and these estimates have been incorporated into a computer prediction model (MMRPro) for calculating lifetime risk.[177] This meta-analysis suggests the lifetime risk of colorectal cancer is higher in males (60%) than females (30%) among all MLH1 or MSH2 gene mutation carriers, and the risk of colorectal cancer is lower in carriers of MSH6 mutations (30% for men and women) than those who carry mutations in either MLH1 or MSH2.[177] Other computer models predict the probability of a MMR gene mutation. PREMM and the MMRPro models are easy to use and have been validated.[178,179] These models incorporate immunohistochemistry (IHC) for MMR protein expression as well as microsatellite instability (MSI) testing as predictive variables. All three computer prediction models take family history of endometrial cancer into account.

Patients with Lynch syndrome can have synchronous and metachronous colorectal cancers as well as other primary extracolonic malignancies. In addition to colorectal cancer, patients and their relatives are at risk for a wide variety of other cancers. The most common is endometrial adenocarcinoma, which affects at least one female member in about 50% of Lynch syndrome pedigrees. Lynch syndrome-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 Lynch syndrome.[180] Patients with Lynch syndrome are also at risk for cancers of the stomach, small intestine, liver and biliary tract, brain, and ovary, as well as transitional cell carcinoma of the ureters and renal pelvis.[181-184] The risk of endometrial cancer in hMSH2 and hMLH1 mutation carriers is 61% and 42%, respectively, but the difference is not statistically significant in this small study.[3] A more recent study of 281 families in Germany did not identify any significant differences in the cumulative probability or mean age at onset of endometrial cancers when comparing hMSH2 versus hMLH1 mutation carriers.[185] A cohort study of 146 hMSH6 mutation carriers identified a cumulative risk for colorectal cancer of 69% for men and 30% for women. The cumulative risk for endometrial cancer in women was 71% at age 70 years.[174]

Muir-Torre syndrome is considered a variant of Lynch syndrome, and includes a phenotype of multiple cutaneous adnexal neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas) and tumors in the small and large bowel, stomach, endometrium, kidney, and ovaries. The skin lesions and colorectal cancer define the phenotype,[186,187] and clinical variability is common. Some families with Muir-Torre syndrome have been found to have mutations in the hMSH2 and hMLH1 genes.[188-190]

The research criteria for defining Lynch syndrome families were established by the International Collaborative Group (ICG) meeting in Amsterdam in 1990, and are known as the ICG or Amsterdam criteria.[191]

Amsterdam criteria:

1. One member diagnosed with colorectal cancer before age 50 years.
2. Two affected generations.
3. Three affected relatives, one of them a first-degree relative of the other two.
4. FAP should be excluded.
5. Tumors should be verified by pathological examination.

These criteria provide a general approach to identifying Lynch syndrome families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline mismatch repair gene mutations, have been reported.[192,193]

To address these issues and to improve the diagnosis of Lynch syndrome clinically, the ICG developed revised criteria in 1999; these are known as Amsterdam criteria II.[194]

Amsterdam criteria II:

1. There should be at least three relatives with a Lynch syndrome-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis).
2. One should be a first-degree relative of the other two.
3. At least two successive generations should be affected.
4. At least one should be diagnosed before age 50 years.
5. Familial adenomatous polyposis should be excluded in the colorectal cancer cases.
6. Tumors should be verified by pathological examination.

A third set of clinical criteria that can be used to identify Lynch syndrome families is the revised Bethesda guidelines.[195] These criteria are the least stringent for identifying families with germline mutations in one of the MMR genes.

Revised Bethesda Guidelines for Testing of Colorectal Tumors for Microsatellite Instability (MSI)

1. Colorectal cancer diagnosed in an individual younger than 50 years.



2. Presence of synchronous, metachronous colorectal, or other Lynch syndrome-associated tumors (i.e., endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas; and carcinoma of the small bowel), in an individual regardless of age.



3. Colorectal cancer with MSI-high pathologic associated features diagnosed in an individual younger than 60 years.  [Note: Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.]



4. Colorectal cancer or Lynch syndrome-associated tumor* diagnosed in at least one first-degree relative younger than 50 years.



5. Colorectal cancer or Lynch syndrome-associated tumor* diagnosed at any age in two first-degree or second-degree relatives.

*Lynch syndrome-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.[195,196]

Research has included colorectal cancer families who do not meet Amsterdam criteria for Lynch syndrome and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations, both truncating and missense, in hMSH6.[197-201] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in hMSH6 may predispose to late-onset familial colorectal cancers that do not meet Amsterdam criteria for Lynch syndrome.

Genetic risk assessment of Lynch syndrome generally considers the cancer family history and age at diagnosis of colorectal cancer in the patient. Studies of gene testing using DNA sequencing in suspected Lynch syndrome probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative hMSH2 or hMLH1 mutation. This means that genetically informed management strategies could be developed for the family.[202,203] An attractive, cost-effective strategy is to first perform an MSI assay on the affected family member’s colorectal tumor, if available.[204,205] Colonoscopy surveillance is often recommended empirically for subjects with strong family histories but no prior genetic or tumor testing. In this instance, only an adenoma may be found. This raises the question of whether using adenomas for MSI and IHC testing is informative. One study found 8 of 12 adenomas to have both MSI and IHC protein loss.[206] All of the patients had prior colorectal cancer and known MMR mutations; however, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude Lynch syndrome.

If a colorectal tumor (adenocarcinoma or adenoma) is found to exhibit MSI, then the patient or family may consider germline testing of an affected patient for the three MMR genes, hMSH2, hMLH1, and hMSH6, for which commercial genetic tests are available. A complementary approach is to test the tumor by IHC for protein expression of hMSH2, hMLH1, and hMSH6. If protein expression is absent, then proceed directly to genetic testing. Meta-analysis suggests that, while combinations of clinical criteria (such as the Bethesda guidelines) and MSI/IHC are imperfect, use of MSI does improve detection sensitivity and specificity.[207] The loss of expression of hMSH2, hMLH1, or hMSH6 suggests the possibility of germline mutations in those genes and indicates individuals who could be considered for MMR gene mutation analysis.[208]

Although regional practice patterns vary, it is reasonable to begin a molecular diagnostic evaluation of suspected Lynch syndrome with both MSI and IHC testing. Using these tests together increases the sensitivity of the initial screen and, through the information provided by the IHC testing, provides information regarding the gene most likely to harbor a germline mutation.[209-212] MSI and IHC results indicative of a MMR defect both lead to further germline testing. Because of the generally concordant results, this combination of testing provides reassurance. Although most laboratories assess both MSI and IHC initially, 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.[213] Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories.[209]

Consistent with the Bethesda guidelines, certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. Together these features have been combined into computational scores that have high predictive value in identifying MSI colorectal cancers.[214,215]

Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals who have germline mutations in one of the MMR genes are BRAF mutations and hMLH1 promoter methylation. Aberrant methylation of hMLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers.[216] It has also been detected in Lynch syndrome colon cancers in individuals with germline mutations in either hMLH1 or hMSH2, less frequently ranging from 10% to 50% of cancers.[216-218] Thus, detection of aberrantly methylated hMLH1 in the colon cancer is more suggestive of a sporadic MSI tumor.

BRAF mutations have been detected predominantly in sporadic MSI tumors.[219-222] These BRAF mutations are likely important in the serrated adenoma pathway which may include those cases that appear to have hyperplastic polyposis syndrome ⁵⁰. This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing; however, there are limitations to the current studies that preclude this conclusion at this time. None of the studies clearly define the clinical criteria used to diagnose the families with Lynch syndrome, limiting the general application of the results to patients seen in the clinic setting. Furthermore, at least one person with a germline mutation in hMLH1 (mutation not described) had a colon cancer with a BRAF mutation. Recommendations on the use of somatic BRAF mutations for stratifying individuals for germline mutation testing can be made once a study is performed using a population of individuals who meet borderline clinical criteria for Lynch syndrome and who have had subsequent germline mutation testing. Correlation of BRAF mutation testing with the germline mutation testing in this population will define the test characteristics in the appropriate patient population to which such a test would be applied.

If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members. If no mutation is identified in the affected family member, then testing would be considered uninformative for the 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 hMSH2 or hMLH1 gene. The current sensitivity of testing is between 50% and 95%, depending on the methodology used. Clinically available tests may not detect large genomic rearrangements in hMSH2 or hMLH1 that may be present in a significant number of Lynch syndrome probands.[223-225] An assessment of 365 probands with suspected Lynch syndrome showed 153 probands with germline mutations in hMLH1 or hMSH2, 12 of 67 (17.9%) and 39 of 86 (45.3%) of which were large genomic alterations in hMLH1 and hMSH2, respectively.[226] In this group of patients, other techniques such as Southern blotting or MLPA [227,228] may be necessary to rule out a disease-causing mutation in these genes. Recent studies have also shown that a subset of Lynch syndrome families who do not have detectable hMLH1, hMSH2, or hMSH6 germline mutations will have mutations in PMS2. The incidence of PMS2 germline mutations has been underappreciated.[229-231] One study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected Lynch syndrome.[232] In this same study, patients with PMS2 mutations presented with colorectal cancer 7 to 8 years later than those with hMLH1 and hMSH2 mutations. These families were small and did not fulfill Amsterdam criteria.[232]

Alternatively, the family could have a mutation in one of the other Lynch syndrome-associated genes for which clinical testing is not currently available, or the pedigree may have a mutation in a yet-unidentified gene that causes Lynch syndrome or a predisposition to colon cancer. For example, deleterious mutations in the hMSH6 gene have been reported in fewer than 5% of patients suspected of Lynch syndrome.[201,233] 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. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk in spite of 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 colorectal cancer by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions/Lynch syndrome ⁵¹ section of this summary for more information.)

There is overlap in the phenotype of families with Lynch syndrome and attenuated FAP as both syndromes can present with multiple colonic adenomas and extracolonic cancers.[234] (Refer to the Attenuated FAP ⁴⁶ section of this summary for more information.) A clinical finding that would suggest AFAP over Lynch syndrome is fundic gland polyposis of the stomach. The presence of uterine, gastric, urinary, and/or ovarian cancers within a family would favor the diagnosis of Lynch syndrome. Genetic counseling for the affected individual is suggested to determine the best options for genetic testing.[72]

An interest in noninvasive methods of screening has led to evaluation of new screening techniques, including computed tomography (CT) colography (also known as virtual colonoscopy or CT colonography) and detection of DNA mutations in stool. One study of 78 individuals with Lynch syndrome, all of whom underwent CT colography and colonoscopy, showed that CT colography had good sensitivity for large polyps but poor sensitivity for small polyps.[235] Therefore, CT colography was not recommended as a primary tool for Lynch syndrome surveillance. These findings are of particular importance in Lynch syndrome screening, since neoplasms in this setting begin as subtle flat lesions. The stool DNA mutation tests detect somatic mutations derived from the tumor tissue and cannot replace germline mutation testing. This method has not been adequately evaluated in high risk populations such as patients with FAP or Lynch syndrome. (Refer to the PDQ summary on Colorectal Cancer Screening ⁹ for more information on these methods.)

Several aspects of the biologic behavior of Lynch syndrome suggest how the approach to surveillance should differ from that for average-risk people:

1. Colorectal cancers in Lynch syndrome occur earlier in life than do sporadic cancers. For hMLH1 and hMSH2 mutation carriers, the estimated risks for colorectal cancer at age 40 years are 31% and 32% for females and males, respectively, and at age 50 years , the estimated risks are 52% and 57%, respectively.[3] This suggests that screening should begin earlier in life.



2. A larger proportion of Lynch syndrome colorectal cancers (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.



3. The progression from normal mucosa to adenoma to cancer is accelerated,[236,237] suggesting that screening should be done at shorter intervals (every 1–2 years) and with colonoscopy.[237,238] Because patients with Lynch syndrome 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.[175] 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).[175]



4. Incidence of colorectal cancer through life is substantially higher, suggesting that the most sensitive test available should be used.



5. Patients with Lynch syndrome 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.[183] There is some evidence that the rate of individual cancers varies from kindred to kindred.[182,239,240] Expert consensus suggests consideration of endometrial cancer screening by age 25 years.[241]

Evidence-based reviews of surveillance colonoscopy in Lynch syndrome have been reported.[242,243] There is only one controlled trial of colorectal cancer screening in Lynch syndrome.[237,238] In a study from Finland, 252 at-risk members of 22 families with Lynch syndrome 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 colorectal cancer deaths (10 vs. 26, P = .003). All of the colorectal cancers detected in the screened population were local and caused no deaths, compared with nine deaths from colorectal cancer 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.[244] 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 recently updated.[245] Over the course of the study (early 1980s to present) the approach to colonoscopy surveillance has evolved. Colonoscopy is now limited to MMR mutation carriers when this information is obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years. The current 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 colorectal cancer 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 6 ⁵² of this summary for more information.)

In other series, the risk of developing adenomas in a MMR gene mutation carrier has been reported to be 3.6 times higher than the risk in noncarriers.[175] 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.[175] 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.[155,246]

Although screening the intact colon is usually recommended for at-risk Lynch syndrome family members, some patients, faced with the high risk of colorectal cancer and the fallibility of screening, elect to undergo risk-reducing colectomy. However, there is a risk of developing cancer in the remaining rectum.[247]

Level of evidence: 3a

Table 6 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance for Lynch syndrome.

Note: A separate PDQ summary on Endometrial Cancer Screening ⁵⁴ in the general population is also available.

Cancer of the endometrium is the second most common cancer observed in Lynch syndrome families with initial estimates of cumulative risk in Lynch syndrome carriers of 30% to 39% by age 70 years.[182,184] In a large Finnish study of 293 putative Lynch syndrome gene carriers, the cumulative lifetime risk for 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 for endometrial cancer in Lynch syndrome 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 Lynch syndrome.[249]

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 Lynch syndrome differs from the general population.

Given their substantial increased risk for endometrial cancer, endometrial screening for women with Lynch syndrome 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.[250,251] Two studies have examined the use of TVUS in endometrial screening for women with Lynch syndrome.[252,253] In one study of 292 women from Lynch syndrome or Lynch syndrome-like families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women.[252] In a second study, 41 women with Lynch syndrome 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.[253] Both of these studies concluded that TVUS is neither sensitive or specific. A study of 175 women with Lynch syndrome that 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.[254] 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 Lynch syndrome. 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 Lynch syndrome 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 Lynch syndrome families. Some studies suggest that women with a clinical or genetic diagnosis of Lynch syndrome do not universally adopt intensive gynecologic screening.[255,256] (Refer to the Gynecologic cancer screening in Lynch Syndrome ⁵⁵ 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.[243,248]

Level of evidence: 5

There have been no controlled studies of the benefit of risk-reducing surgery in at-risk Lynch syndrome mutation carriers. Recommendations based upon expert opinion, however, have been formulated by a panel convened by an NIH research consortium.[241] The expert panel recommended consideration of risk-reducing subtotal colectomy as an option for persons with Lynch syndrome 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 Lynch syndrome 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 an option for women with Lynch syndrome, and that counseling include thoughtful discussion of childbearing plans, psychosocial effects of risk-reducing surgery, and long term effects of prolonged estrogen replacement therapy, as well as 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 Lynch syndrome reported no occurrences of endometrial, ovarian, or primary peritoneal cancers in women who underwent RRH with or without RRSO as compared with women who had no risk-reducing surgery.[257] 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 Lynch syndrome.[257] 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 Lynch syndrome must be individualized.[258] Management of these patients can be subdivided into patients with newly diagnosed colorectal cancer, those with colorectal cancer treated with segmental resection, and those who are at risk of developing colorectal cancer 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 Lynch syndrome 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 colorectal cancers 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 colorectal cancer.[184,259] 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.[260] 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.[260]

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.[247] 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 Lynch syndrome patients who have undergone a partial surgical resection of the colon, endoscopic surveillance should be the mainstay of follow-up.

An estimated 7% to 10% of people have a first-degree relative with colorectal cancer,[261,262] and approximately twice that many have either a first-degree or a second-degree relative with colorectal cancer.[262,263] A simple family history of colorectal cancer (defined as one or more close relatives with colorectal cancer 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 colorectal cancer 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.[261,264] A positive family history of colorectal cancer appears to increase the risk of colorectal cancer 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.[261] 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 colorectal cancer 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 [265] and increases the risk of colorectal cancer in relatives.[266] The RR of colorectal cancer, adjusted for the year of birth and sex, was 1.78 for the parents and siblings of the patients with adenomas as compared with the spouse controls (95% CI, 1.18–2.67). The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% Cl, 1.46–4.58), as 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, as well as a parental history of colorectal cancer.

While familial clusters of colorectal cancers account for approximately 20% of all colorectal cancer cases in developed countries,[267] the rare and highly penetrant Mendelian colorectal cancer 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 colorectal cancers.

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.[268] 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 for colorectal cancer. For colorectal cancer, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that though nonshared environmental factors constitute the major risk for familial colorectal cancer, heredity plays a larger-than-expected role.

The second study utilized the Swedish Family-Cancer Database, which contained 6,773 and 31,100 colorectal cancers in offspring and their parents, respectively, from 1991 to 2000.[269] 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 standardized incidence ratio (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 colorectal cancer conferred between spouses, the authors concluded that heredity plays a significant role in familial colorectal cancers; however, controls for shared environmental effects among siblings were absent in this study.

Ten percent to 15% of persons with colorectal cancer and/or colorectal adenomas have other affected family members,[261,262,264-266,270-275] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for Lynch syndrome. Such families are categorized as having FCC, which is currently a diagnosis of exclusion (of known hereditary colorectal cancer disorders). The presence of colorectal cancer 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 FCC remains a research challenge.

Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in FCC families,[276] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[275] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[277] A more recent study has linked three potential loci in FCC families on chromosomes 11, 14, and 22.[278]

Families meeting Amsterdam-I criteria for Lynch syndrome 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 Lynch syndrome and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCC Type X,[279-283] and it has been suggested that these families be classified as a distinct group.

Clinically, the age of onset of colorectal cancer in FCC Type X is older than in Lynch syndrome (55 years vs. 41 years), and the lifetime risk of cancer is substantially lower. The SIR for colorectal cancer 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 mismatch repair (Lynch syndrome families).[279] The risk of extracolonic tumors was also not found to be elevated for the Type X families, suggesting that enhanced surveillance for colorectal cancer 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 Lynch syndrome.[281]

There are no controlled comparisons of screening in people with a mild or modest family history of colorectal cancer. 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.[106]

A common but unproven clinical practice is to initiate colorectal cancer screening 10 years before the age of the youngest colorectal cancer 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 colorectal cancer.

These issues were weighed by a panel of experts convened by the American Gastroenterological Association (AGA) before publishing clinical guidelines for colorectal cancer screening, including those for persons with a positive family history of colorectal cancer.[241] These guidelines have been endorsed by a number of other organizations.

The American Cancer Society (ACS) and the U.S. Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[106,284] The recommendations ¹⁰ for screening average-risk persons (asymptomatic, older than 50 years, with no other risk factors) include the following options:

• Fecal occult blood screening each year (Level of evidence: 1) and/or screening flexible sigmoidoscopy every 5 years (Level of evidence: 2), followed by colonoscopy if adenomatous polyps or blood in the stool is found;
• Double contrast barium enema every 5 to 10 years (Level of evidence: 5); or
• Colonoscopy every 10 years (Level of evidence: 3).

Individuals with a first-degree relative diagnosed before age 60 years with colorectal cancer or adenoma should be offered full-colon screening beginning at age 60 years or 10 years prior to the earliest diagnosis in the family (Level of evidence: 5).

Peutz-Jeghers syndrome (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.[285-287] Germline mutations in the STK11 gene at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[288] have been identified in approximately half of PJS families.[289-292] A study of 419 individuals with PJS (297 of whom had a documented STK11/LKB1 mutation) reported that 85% of individuals developed cancer by age 70. In comparison, the highest cumulative risk of developing noncutaneous cancer by age 70 was for breast cancer (45%), colorectal cancer (39%); uterine, ovarian, cervical and other gynecologic cancers (18%); and pancreatic cancer (11%). No statistical difference in cancer risk was found in individuals according to their mutation status.[4]

Juvenile polyposis syndrome (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.[293,294] 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 [295] 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.[296,297] The lifetime colorectal cancer risk in JPS has been reported to be 39%.[298]

Hereditary mixed polyposis syndrome (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, as well as colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[299,300] 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.[301-303] 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 colorectal cancer; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR] = 1.5; 95% Cl 1.2–3.0) of colorectal cancer.[304]

Isolated and multiple hyperplastic polyps (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 hyperplastic polyps (HP) occurring proximal to the sigmoid colon (of which at least two are >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.[305]

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 colorectal cancer.[306,307] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for HPPS is 50% or more.[308-312]

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.[306] 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 colorectal cancer. 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).[313] 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 colorectal cancer 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 Apc^min/+ mice, tumor progression was accelerated suggesting that Ephb2 is a tumor suppressor whose loss of expression in the colon enhances adenoma progression.[314]

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 (V599E) was found in polyp tissue.[315] Fifty percent (20 of 40) of HPs from these patients demonstrated the V599E 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.[309]  [Note: The V559E mutation has also been published as V600E due to differences in counting bases.]

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.[316] BRAF mutations are more commonly associated with the right colon and methylation of p16^INK and MINT31.[315]

There are no data upon which to base recommendations for monitoring individuals for extracolonic cancers in these rare disorders. One must employ one's best clinical judgment in the context of the pattern of disease displayed in each family.

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290. 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.  [PUBMED Abstract]
     
     
291. Boudeau 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.  [PUBMED Abstract]
     
     
292. Lim 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.  [PUBMED Abstract]
     
     
293. Veale AM, McColl I, Bussey HJ, et al.: Juvenile polyposis coli. J Med Genet 3 (1): 5-16, 1966.  [PUBMED Abstract]
     
     
294. Chow E, Macrae F: A review of juvenile polyposis syndrome. J Gastroenterol Hepatol 20 (11): 1634-40, 2005.  [PUBMED Abstract]
     
     
295. Howe JR, Roth S, Ringold JC, et al.: Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280 (5366): 1086-8, 1998.  [PUBMED Abstract]
     
     
296. 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.  [PUBMED Abstract]
     
     
297. Zhou 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.  [PUBMED Abstract]
     
     
298. Brosens LA, van Hattem A, Hylind LM, et al.: Risk of colorectal cancer in juvenile polyposis. Gut 56 (7): 965-7, 2007.  [PUBMED Abstract]
     
     
299. Jaeger 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.  [PUBMED Abstract]
     
     
300. Thomas 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.  [PUBMED Abstract]
     
     
301. Meijers-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.  [PUBMED Abstract]
     
     
302. Cybulski C, Górski B, Huzarski T, et al.: CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75 (6): 1131-5, 2004.  [PUBMED Abstract]
     
     
303. de Jong MM, Nolte IM, Te Meerman GJ, et al.: Colorectal cancer and the CHEK2 1100delC mutation. Genes Chromosomes Cancer 43 (4): 377-82, 2005.  [PUBMED Abstract]
     
     
304. Cybulski 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.  [PUBMED Abstract]
     
     
305. Jass 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. 
     
     
306. Chow 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.  [PUBMED Abstract]
     
     
307. Lage 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.  [PUBMED Abstract]
     
     
308. Leggett BA, Devereaux B, Biden K, et al.: Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 25 (2): 177-84, 2001.  [PUBMED Abstract]
     
     
309. Rashid A, Houlihan PS, Booker S, et al.: Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119 (2): 323-32, 2000.  [PUBMED Abstract]
     
     
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Psychosocial Issues in Hereditary Colon Cancer Syndromes: Lynch Syndrome and Familial Adenomatous Polyposis

Introduction

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 summary will focus on psychosocial aspects of genetic counseling and testing for Lynch syndrome ¹⁴, familial adenomatous polyposis (FAP) ⁵⁸, and familial colorectal cancer, including those issues surrounding medical screening, risk-reducing surgery, and chemoprevention for those syndromes. Other hereditary colorectal cancer (CRC) syndromes such as Turcot, Muir-Torre and Peutz-Jeghers syndromes are not specifically addressed in this summary because they are very rare, and psychosocial research regarding these syndromes is lacking.

Interest in genetic counseling and testing for hereditary colorectal cancer has been highest in studies involving general population samples (Table 7A ⁵⁹, 7B ⁶⁰, 7C ⁶¹). Initial random-digit-dial surveys that addressed this topic [1-3] showed that more than 80% of respondents indicated at least some interest in having a genetic test for hereditary colorectal cancer, and 40% to 47% indicated that they would be very interested. One study [3] 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 colorectal cancer–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.[4] Perceived risk of developing colorectal cancer 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 colorectal cancer, the most common concerns included the lack of availability of preventive options, increased anxiety, and worry about cancer risks in family members, especially children.[2] 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 colorectal cancer 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.[2] 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.[5,6]

Studies of colorectal cancer patients and their unaffected relatives showed varying levels of interest in or intention to undergo hereditary colorectal cancer genetic testing (Table 7A ⁵⁹, 7B ⁶⁰, 7C ⁶¹). Participants in these studies were recruited through tumor registries or familial colon cancer registries,[7-10] oncology treatment centers,[11-14] and the community.[9,12-14] 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 colorectal cancer 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 Lynch syndrome (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.

In several studies, higher perceived risk and worry of developing colorectal cancer were correlated with interest in or intention to have testing.[7,8,11] 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.[7,8,11-14] 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.

A key difference between genetic testing for Lynch syndrome 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.[18] 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.[18]

Studies conducted before the clinical availability of APC testing showed that most parents favored testing for FAP in early childhood.[19] 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.[17] 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.

There are an increasing number of studies examining the actual uptake of Lynch syndrome genetic counseling and testing (Table 8 ⁶⁵). 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.[10,20-26] 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.

Participation in both pretest genetic counseling and posttest counseling for disclosure of results ranged from 14% to 59% across studies (Table 8 ⁶⁵). 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%.[10,20-22,24-26] 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 Lynch syndrome 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 Lynch syndrome decide to undergo or decline genetic counseling and testing. Participation in Lynch syndrome genetic counseling was associated with having children, having a greater number of relatives affected by colorectal cancer, and greater social support.[25] A study of colorectal cancer 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 Lynch syndrome-predisposing gene mutation, believed that testing would help family members, and more strongly endorsed the benefits and importance of having testing.[23] Factors associated with both counseling and testing uptake included having: children, a greater number of affected relatives, a greater perceived risk of developing colorectal cancer, and more frequent thoughts about colorectal cancer.[20-22,24-26]

Less is known about the characteristics of persons who decide to not undergo Lynch syndrome genetic counseling and testing. Studies have found that persons who declined counseling and testing reported to have a lower perceived risk for colorectal cancer,[20] to have fewer first-degree relatives affected with cancer,[26] to be less likely to have had a previous colonoscopy,[20] to have a college education,[21] to have previously participated in cancer genetics research,[21] or to be employed.[24] 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,[20] and were more likely to report having depressive symptoms.[21] 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.[26]

In contrast to the Lynch syndrome 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 Lynch syndrome underwent genetic testing and counseling for disclosure of test results.[24] 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.[24]

The uptake for genetic testing for FAP may be higher than testing for Lynch syndrome. A study of asymptomatic individuals in the United States at risk for FAP who were enrolled in a colorectal cancer registry and were offered genetic counseling found that 82% of adults and 95% of minors underwent genetic testing.[28] Uptake rates close to 100% have been reported in the United Kingdom.[17] A possible explanation for the greater uptake of APC genetic testing is that it may be more cost-effective than annual endoscopic screening [29] 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;[30] 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.[28] 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.[28]

Studies have examined the psychological status of individuals before, during, and after genetic counseling and testing for Lynch syndrome. Some studies have included only persons with no personal history of any Lynch syndrome-associated cancers,[31-34] and others have included both colorectal cancer patients as well as cancer-unaffected persons who are at risk for having a Lynch syndrome mutation.[35-39] Cross-sectional evaluations of the psychosocial characteristics of individuals undergoing Lynch syndrome genetic counseling and testing have indicated that mean pretest scores of psychological functioning for most participants are within normal limits.[35-37]

Several longitudinal studies have evaluated psychological outcomes before genetic counseling and testing for Lynch syndrome and at multiple time periods in the year following disclosure of test results. In general, findings from these studies suggested that mismatch repair mutation carriers may experience increased general distress,[33,38] cancer-specific distress,[31,32] or cancer worries [38] relative to their pretest measurements, within the period of time immediately following disclosure of their mutation status (e.g., 2 weeks to 1 month). Carriers often experienced significantly higher distress following disclosure of test results compared to individuals who do not carry a mutation previously identified in the family (noncarrier).[31-33,38] However, in most cases, carriers’ distress levels subsided during the course of the year after disclosure [33,38] and did not differ from pretest distress levels at 1 year postdisclosure.[31,32] Findings from these studies also indicated that noncarriers experienced a reduction or no change in distress up to a year following results disclosure.[31-33,38] A study that included unaffected individuals and colorectal cancer 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.[39]

Less is known about the long-term psychological impact of Lynch syndrome 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.[31] 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 Lynch syndrome 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.[40]

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.[35-39,41] A study of colorectal cancer patients who had donated blood for Lynch syndrome testing found that higher levels of depressive symptoms and/or anxiety were found among women, younger persons, and nonwhites, as well as those with less formal education and fewer and less satisfactory sources of social support.[35] 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 Lynch syndrome mutation carriers and being able to cope with learning their test results.[36] In a follow-up report that evaluated psychological outcomes following disclosure of test results among both colorectal cancer patients as well as relatives at risk of having a Lynch syndrome 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.[38] 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.[39,41] While further research is needed in this area, case studies indicate that it is important to identify persons who may be at risk for experiencing psychiatric distress and to provide psychological support and follow-up throughout the genetic counseling and genetic testing process.[42]

Studies also have examined the effect of Lynch syndrome genetic counseling and testing on cancer risk comprehension. One study reported that nearly all mutation carriers as well as noncarriers could accurately recall the test result 1 year after disclosure. More noncarriers than carriers correctly identified their risk of developing colorectal cancer at both 1 month and 1 year following result disclosure. Mutation carriers who incorrectly identified their colorectal cancer risk were more likely to have had lower levels of pretest subjective risk perception compared with those who correctly identified their level of risk.[33] Another study reported that accuracy of estimating colorectal and endometrial cancer risk improved following disclosure of mutation status in both carriers and noncarriers.[34]

Studies evaluating psychological outcomes following genetic testing for FAP suggest that some individuals, particularly mutation carriers, may be at risk for 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.[43] Lower optimism and lower self-esteem were associated with higher anxiety in this study,[43] and FAP-related distress, perceived seriousness of FAP, and belief in the accuracy of genetic testing were associated with more state anxiety among carriers.[44] In an earlier study, however, 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 compared with the other syndromes.[30]

In a cross-sectional Australian study focusing on younger adults diagnosed with FAP (n = 88), aged 18 to 35 years, 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.[45] Seventy-five percent indicated that they would consider prenatal testing for FAP, 61% would consider pre-implantation genetic diagnosis 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.

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.[46] 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.[47] 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.[43] Mutation-negative children in this study experienced less anxiety and improved self-esteem over this same time period.

Recommendations for Lynch syndrome screening in persons at risk include colonoscopy every 1 to 2 years by age 20 to 25 years or 10 years earlier than the youngest age at diagnosis in the family, and annual endometrial cancer screening consisting of transvaginal ultrasound with endometrial sampling in women aged 30 to 35 years or starting 10 years earlier than the youngest age at diagnosis in the family.[48] These recommendations apply to persons who carry a Lynch syndrome-predisposing gene mutation, or who have a family history that is suggestive of Lynch syndrome in the absence of testing or the identification of a known mutation. Benefits of genetic counseling and testing for Lynch syndrome 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 for Lynch syndrome may have had some CRC screening before genetic counseling and testing, but most are not likely to adhere to Lynch syndrome screening recommendations. Among persons aged 18 years or older who did not have a personal history of colorectal cancer and who participated in U.S.-based research protocols offering genetic counseling and testing for Lynch syndrome, between 52% and 62% reported ever having had a colonoscopy before genetic testing.[20,22,49,50] 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.[34,51] Factors associated with ever having a colonoscopy before genetic testing included higher income and older age,[49] higher perceived risk of developing CRC,[51] higher education level, and being informed of increased risk for CRC.[50]

In a study of cancer-affected and cancer-unaffected persons who fulfilled clinical criteria for Lynch syndrome, 92% reported having had a colonoscopy and/or flexible sigmoidoscopy at least once before genetic testing.[52] Another study of unaffected individuals presenting for genetic risk assessment and possible consideration of Lynch syndrome, FAP, or APCI1307K genetic testing reported that 77% had undergone at least one screening exam (either colonoscopy, flexible sigmoidoscopy, or barium enema).

A few studies determined whether cancer-unaffected persons adhered to Lynch syndrome colonoscopy screening recommendations before genetic testing, and reported adherence rates of 10%,[34] 28%,[50] and 47%.[52]

Several longitudinal studies examined the use of screening colonoscopy by cancer-unaffected persons after undergoing testing for a known Lynch syndrome mutation.[34,49-51] These studies compared colonoscopy use before Lynch syndrome genetic testing to colonoscopy use within 1 year after disclosure of test results. One study reported that Lynch syndrome mutation carriers were more likely to have a colonoscopy compared with 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.[50] 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,[49,51] though noncarriers’ colonoscopy rates decreased in the same time period. Factors associated with colonoscopy use at 1 year after results disclosure included carrying a Lynch syndrome-predisposing mutation,[49-51] older age,[49] 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.

Two studies examined the level of adherence to published screening guidelines after Lynch syndrome genetic testing, based on mutation status. One study reported a colonoscopy adherence rate of 100% among mutation carriers.[34] Another study found that 35% of mutation carriers and 13% of noncarriers did not adhere to published guidelines for appropriate colorectal cancer screening;[49] in both groups, about one-half screened more frequently than published guidelines recommend, and one-half screened less frequently. There are no data available regarding variables that influence compliance with screening guidelines.

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.[31] 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.[34] 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 Lynch syndrome during a time that ranged from 2 years to 18 years after risk assessment and counseling.[53] Eighty-six percent of Lynch syndrome mutation carriers, 68% of those who did not test or who had an uninformative Lynch syndrome genetic test result, and 73% of those with a clinical Lynch syndrome 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 Lynch syndrome 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 Lynch syndrome genetic testing, and 88% reported that they had undergone colonoscopy since their genetic diagnosis (P < .001).[40]

A few studies have examined the use of screening for endometrial and ovarian cancers associated with Lynch syndrome. These studies have included relatively small numbers of women and suggest that screening rates for Lynch syndrome-associated gynecologic cancers are low before genetic counseling and testing. Two U.S. studies [22,52] reported that 14% of women with a family history of Lynch syndrome 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.[52]

Some studies suggest that women with a clinical or genetic diagnosis of Lynch syndrome do not universally adopt intensive gynecologic screening.[31,54] In a Belgian study, 85% of female mutation carriers and 27% of noncarriers underwent TVUS within the year following disclosure of genetic test results.[34] One Australian longitudinal study examined gynecologic screening behaviors before testing, as well as 1 year after disclosure of results. They found that 30% of women had undergone TVUS and 7% had undergone an endometrial biopsy before testing.[51] 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 Lynch syndrome 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).[40] However, the screening interval and specific gynecologic tests were not described.

There is no consensus regarding the use of risk-reducing colectomy for Lynch syndrome, and little is known about decision-making and psychological sequelae surrounding risk-reducing colectomy for Lynch syndrome.

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.[22] This study also indicated that consideration of risk-reducing surgery for Lynch syndrome 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 Lynch syndrome genetic counseling and testing, 5% of cancer-unaffected individuals at risk for a mismatch repair mutation in a longitudinal study reported that they would consider colectomy, and 5% of women indicated that they would have an RRH and a RRSO, if they were found to be mutation-positive. At 3 years following disclosure of results, no participants had undergone risk-reducing colectomy.[31,51] Two women who had undergone a RRH before genetic testing underwent RRSO within 1 year after testing,[51] however, no other female mutation carriers in the study reported having either procedure at 3 years following test result disclosure.[31]

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.[52] 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 for FAP, had undergone recommended endoscopic screening.[55] Among persons who had or were at risk for 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 for colorectal cancer. Only 42% of the study population had ever undergone genetic counseling. A small percentage of participants (14% to 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 has improved tolerance for screening procedures.

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 colorectal cancer. 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 post-operative period, decreasing to three stools per day by 1 year post-surgery.[56]

With regards to behavioral or psychosocial outcomes, 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.[57,58] However in one study, 29% who had undergone subtotal colectomy reported that increased stool frequency adversely affected their activities and 14% reported occasional liquid soiling.[56] Another study showed that 20% of those with good bowel function nonetheless reported fears about incontinence that affected their quality of life.[59]

Chemoprevention trials are currently under way to evaluate the effectiveness of various therapies for persons at risk of Lynch syndrome and FAP.[60,61] 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.[62] 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 colorectal cancer 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 Lynch syndrome genetic counseling and testing. Studies have focused on whether individuals disclosed information about Lynch syndrome 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 Lynch syndrome predisposition and have comprised relatively small samples.

Research findings indicated that persons generally are willing to share information about the presence of a Lynch syndrome-predisposing mutation within their families.[63-65] Motivations for sharing genetic risk information include a desire to increase family awareness about health promotion options and predictive genetic testing, as well as a perceived moral obligation and responsibility to help others in the family.[64,65] Findings across studies suggested that most believed that Lynch syndrome genetic risk information was shared openly within families; however, such communication was more likely to occur with first-degree relatives (e.g., siblings, children) rather than with more distant relatives.[63-65] In regard to informing more distant relatives, individuals tended to favor a cascade approach: for example, it was assumed that once a relative was given information about the family’s risk for Lynch syndrome, he or she would then be responsible for informing his or her first-degree relatives.[63-65] This cascade approach to communication was distinctly preferred in regard to informing relatives’ offspring, particularly those of minor age, and the consensus suggested 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.[63-66]

While communication about genetic risk was generally viewed as an open process, some barriers to doing so 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. Disclosure seemed less likely if at-risk individuals were considered too young to receive the information (i.e., children), or if information about the hereditary cancer risk had previously created conflict in the family,[65] or if it was assumed that relatives would be uninterested in information about testing.[64] Prior existence of conflict seemed to inhibit discussions about hereditary cancer risk, particularly if such discussions involved disclosure of bad news.[65]

For most participants in these studies, the news that the pattern of cancers in their families was attributable to a Lynch syndrome-predisposing mutation did not come as a surprise,[63,64] as individuals had suspected a hereditary cause for the familial cancers or had prior family discussions about cancer. Identification of a Lynch syndrome-predisposing mutation in the family was considered a private matter but not necessarily a secret,[63] and many individuals had discussed the family’s mutation status with someone outside of the family. Knowledge about the detection of a Lynch syndrome-predisposing mutation in the family was not viewed as stigmatizing, though individuals expressed concern about the potential impact of this information on insurance discrimination.[63] 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.[66] In a few cases, individuals reported that their relatives expressed anger, shock, or other negative emotional reactions after receiving news about the family’s Lynch syndrome risk;[65] however, most indicated little to no difficulty in informing their relatives.[64] 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.[65]

In some cases, probands reported feeling particularly obliged to inform family members about a hereditary cancer risk [65] and were often the strongest advocates for encouraging their family members to undergo genetic counseling and testing for the family mutation.[63] 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.[64] Another study suggested that mothers may be particularly influential members of the family network in regard to communicating health risk information.[67] 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.[63]

Various modes of communication (e.g., in-person, telephone, or written contact) may typically be used to disclose genetic risk information within families.[63-65] In one study, communication aids such as a genetic counseling summary letter or Lynch syndrome booklet were viewed as helpful adjuncts to the communication process but were not considered central or necessary to its success.[64] Studies have suggested that recommendations by health care providers to inform relatives about hereditary cancer risk may encourage communication about Lynch syndrome [65] and that support by health care professionals may be helpful in overcoming barriers to communicating such information to family members.[66]

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Changes to This Summary (12/19/2008)

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.

Colon Cancer Genes ⁷

Added text ⁷⁰ to state that patients with juvenile polyposis syndrome have been reported to have large genomic deletions in BMPR1A and SMAD4, and rarely, mutations in both of the PTEN and BMPR1A genes, or both of the PTEN and ENG genes (cited van Hattem et al. and Sweet et al. as references 61 and 62, respectively).

Major Genetic Syndromes ⁶

Added text ⁷¹ to describe genetic testing techniques.

Added text ⁷² to state that in a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, fundic gland polyps 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 (cited Bianchi et al. as reference 53).

Added South et al. as reference 190 ⁷³.

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Glossary Terms

One of two major ancestral groups of Jewish individuals, comprised of those whose ancestors lived in Eastern Europe (Germany, Poland, Russia). The other group is designated Sephardic Jews and includes those whose ancestors lived in North Africa, the Middle East, and Spain. Most Jews living in the United States are Ashkenazi Jews. Also called Eastern European Jews.

Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).

Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).

Two nitrogen-containing bases pair together between double-stranded DNA; only specific combinations of these bases (e.g., adenine with thymine; guanine with cytosine) are possible, a fact which facilitates accurate DNA replication; when quantified (e.g., 8 base pairs, or bp), this term refers to the actual number of base pairs in a sequence of nucleotides.

Clinical testing designed to identify the presence of a specific cancer in an asymptomatic individual or population thought to be at risk of that specific cancer. The intent is to find cancers at the earliest possible stage in their development, in order to improve the chances for disease cure.

In classical genetics, an individual who carries one deleterious allele for an autosomal recessive disorder. In clinical discussions, may refer to an individual who carries a deleterious allele that predisposes to disease.

Discrete physical structures inside a cell nucleus that consist of proteins and DNA organized into genes.

An identical copy of a DNA sequence or entire gene; one or more cells derived from and identical to a single ancestor cell OR to isolate a gene or specific sequence of DNA.

In DNA or RNA, a sequence of 3 consecutive nucleotides that codes for a specific amino acid or signals the termination of gene translation (stop or termination codon).

An alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents, or a mutation that arises in the fertilized egg itself during early embryogenesis. Also called new mutation.

A mutation that is documented to be associated with risk of disease.

Presence of necrotic cellular debris within the lumen of the neoplastic glands in the colorectal mucosa.

The molecular basis of heredity; encodes the genetic information responsible for the development and function of an organism and allows for transmission of that genetic information from one generation to the next. The DNA molecule is structured as a double-stranded helix held together by weak hydrogen bonds between purine-pyrimidine nucleotide base pairs: adenine (A) paired with thymine (T), and guanine (G) paired with cytosine (C). Also called deoxyribonucleic acid.

Coding sequence of DNA present in mature messenger RNA. Most genes have multiple exons.

A phenotype or trait that occurs with greater frequency in a given family than in the general population; familial traits may have a genetic and/or nongenetic etiology.

The genetic relationships within a family combined with the medical history of individual family members. When represented in diagram form using standardized symbols and terminology, it is usually referred to as a pedigree or family tree.

The parents, siblings, or children of an individual. Also called FDR.

An insertion or deletion involving a number of base pairs that is not a multiple of three, which consequently disrupts the triplet reading frame of a DNA sequence. Such mutations usually lead to the creation of a premature termination (stop) codon, and result in a truncated (shorter-than-normal) protein product.

The basic unit of heredity that occupies a specific location on a chromosome. Each consists of nucleotides arranged in a linear manner. Most genes code for a specific protein or segment of protein leading to a particular characteristic or function.

A communication process that seeks to assist affected or at-risk individuals and families in understanding the natural history, disease risks, and mode of transmission of a genetic disorder; to facilitate informed consent for genetic testing when appropriate; to discuss options for risk management and family planning; and to provide for or refer individuals for psychosocial support as needed. The National Society of Genetic Counselors Task Force has also defined the term genetic counseling.

An identifiable segment of DNA (e.g., Single Nucleotide Polymorphism [SNP], Restriction Fragment Length Polymorphism [RFLP], Variable Number of Tandem Repeats [VNTR], microsatellite) with enough variation between individuals that its inheritance and co-inheritance with alleles of a given gene can be traced; used in linkage analysis.

Increased likelihood or chance of developing a particular disease due to the presence of one or more gene mutations and/or a family history that indicates an increased risk of the disease. Also called genetic susceptibility.

Genetic testing designed to identify individuals in a given population who are at higher risk of having or developing a particular disorder, or carrying a gene for a particular disorder.

Increased likelihood or chance of developing a particular disease due to the presence of one or more gene mutations and/or a family history that indicates an increased risk of the disease. Also called genetic predisposition.

Randomized, controlled clinical trial with incidence as an endpoint. See the Cancer Genetics Overview for more information.

Randomized controlled clinical trial. See the Cancer Genetics Overview for more information.

Nonrandomized controlled clinical trial. See the Cancer Genetics Overview for more information.

Cohort or case-control analytic studies, preferably from more than one center or research group. See the Cancer Genetics Overview for more information.

Opinion of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. See the Cancer Genetics Overview for more information.

Randomized controlled clinical trial. See the Cancer Genetics Overview for more information.

Cohort or case-control analytic studies with total mortality (or overall survival from a defined time) as an endpoint. See the Cancer Genetics Overview for more information.

Cohort or case-control analytic studies with disease-free survival as an indirect surrogate endpoint. See the Cancer Genetics Overview for more information.

Cohort or case-control analytic studies with tumor response rate as an indirect surrogate endpoint. See the Cancer Genetics Overview for more information.

Ecologic, natural history, or descriptive studies. See the Cancer Genetics Overview for more information.

Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. See the Cancer Genetics Overview for more information.

The cells from which eggs or sperm (i.e., gametes) are derived.

Occurs when the two alleles at a particular gene locus are different. A heterozygous genotype may include one normal allele and one mutation, or two different mutations. The latter is called a compound heterozygote.

Occurs when both alleles at a particular gene locus are the same. A person may be homozygous for the normal allele or for a mutation.

A clinically affected individual through whom attention is first drawn to a genetic disorder in a family.

In genetic testing, a test result that reveals definitively the presence or absence of the germline genetic alteration associated with the hereditary disorder being assessed. In linkage analysis, the ability to distinguish between maternally inherited and paternally inherited DNA markers (polymorphisms) within or near a given gene of interest.

A process of information exchange between a clinician and an individual or their legal proxy designed to facilitate autonomous, informed decision making. The informed consent process for genetic testing should include an explanation of the medical and psychosocial risks, benefits, limitations, and potential implications of genetic analysis, a discussion of privacy, confidentiality, the documentation and handling of genetic test results, as well as options for managing the hereditary disease risk.

Describes the clinical manifestations associated with a mutation conferring cancer susceptibility.

An extended family.

The state in which a genetic trait is expressed later in life or is expressed at no fixed time in a life history.

A gene-hunting technique that traces patterns of disease in high-risk families. It attempts to locate a disease-causing gene by identifying genetic markers of known chromosomal location that are co-inherited with the trait of interest.

The physical site or location of a specific gene on a chromosome.

Repetitive segments of DNA scattered throughout the genome in noncoding regions between genes or within genes (introns). They are often used as markers for linkage analysis because of their naturally occurring high variability in repeat number between individuals. These regions are inherently genetically unstable and susceptible to mutations.

A single base pair substitution that alters the genetic code in a way that produces an amino acid that is different from the normal amino acid at that position.

A change in the usual DNA sequence at a particular gene locus. Mutations (including polymorphisms) can be harmful, beneficial, or neutral in their effect on cell function.

Germline genetic testing method targeted to detect a specific mutation (such as a deleterious MSH2 mutation previously identified in a family), panel of mutations (such as the 3 BRCA mutations comprising the founder mutation panel for individuals of Ashkenazi Jewish ancestry) or type of mutation (such as a large deletions or insertions in the BRCA1 gene). This type of testing is distinct from complete gene sequencing or mutation scanning. The latter are designed to detect most mutations in the region being tested. Current usage also applies this term to any genetic test.

The likelihood that an individual with a negative test result is truly unaffected and/or does not have the particular gene mutation in question. Also called NPV.

An individual who does not carry a mutation previously identified in his or her family.

A graphic illustration of family history.

A characteristic of a genotype; it refers to the likelihood that a clinical condition will occur when a particular genotype is present.

The observable characteristics in an individual resulting from the expression of genes; the clinical presentation of an individual with a particular genotype.

A common mutation. “Common” is typically defined as an allele frequency of at least 1%. All genes occur in pairs, except when x and y chromosomes are paired in males; thus a polymorphism with an allele frequency of 1% would be found in about 2% of the population, with most carriers having one copy of the polymorphism and one copy of the normal allele.

The individual through whom a family with a genetic disorder is ascertained. In males this is called a propositus, and in females it is called a proposita.

The quantitative or qualitative assessment of an individual’s risk of carrying a certain gene mutation, or developing a particular disorder, or of having a child with a certain disorder; sometimes done by using mathematical or statistical models incorporating such factors as personal health history, family medical history and ethnic background.

The aunts, uncles, grandparents, grandchildren, nieces, nephews, or half-siblings of an individual. Also called SDR.

The frequency with which a test yields a true positive result among individuals who actually have the disease or the gene mutation in question. A test with high sensitivity has a low false-negative rate and thus does a good job of correctly identifying affected individuals.

Electrophoresis-based technique used in genetic testing to detect large deletions in DNA that can be missed by PCR-based genetic testing methods.

This term has two meanings. It is sometimes used to differentiate cancers occurring in people who do not have a germline mutation that confers increased susceptibility to cancer from cancers occurring in people who are known to carry a mutation. Cancer developing in people who do not carry a high-risk mutation is referred to as sporadic cancer. The distinction is not absolute, because genetic background may influence the likelihood of cancer even in the absence of a specific predisposing mutation. Alternatively, sporadic is also sometimes used to describe cancer occurring in individuals without a family history of cancer.

A germline mutation that increases an individual’s susceptibility or predisposition to a certain disease or disorder. When such a mutation is inherited, development of symptoms is more likely, but not certain. Also called predisposing mutation.

The process of synthesizing messenger RNA (mRNA) from DNA.

A negative test result in an individual where a clearly deleterious mutation has not been found in any family members. The genetic risk status of such an individual must be interpreted in the context of his or her personal and family history. Also called inconclusive and indeterminate.

A variation in a genetic sequence whose association with disease risk is unknown. Also called unclassified variant, variant of uncertain significance, and VUS.