Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI]

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Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women.

Estimated new cases and deaths from CRC in 2015:[1]

  • New cases: 132,700.
  • Deaths: 49,700.

About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder. The remaining 25% of patients have a family history of CRC that suggests a hereditary contribution, common exposures among family members, or a combination of both. Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer–prone families; these mutations are estimated to account for only 5% to 6% of CRC cases overall. It is likely that other undiscovered genes and background genetic factors contribute to the development of familial CRC in conjunction with nongenetic risk factors.

(Refer to the PDQ summaries on Colorectal Cancer Screening; Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment for more information about sporadic CRC.)

Natural History of CRC

Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas).

Pathologists have classified the lesions into the following three groups:

  1. Nonneoplastic polyps (hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid polyps), which have not generally been thought of as precursors of cancer.
  2. Neoplastic polyps (adenomatous polyps, and adenomas).
  3. Cancers.

Research, however, suggests increased CRC risk in some families who have multiple members affected with juvenile polyposis, Peutz-Jeghers syndrome, and hyperplastic polyposis.[2,3,4]

Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[5]

Two complementary interpretations of this observation are as follows:

  1. The adenoma may reflect an innate or acquired tendency of the colon to form tumors.
  2. Adenomas are the primary precursor lesion of colon cancer.

More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that most CRCs arise from adenomas, adenocarcinomas are generally considered to arise from adenomas,[6,7,8,9,10] based upon the following important observations:

  1. Benign and malignant tissue occur within colorectal tumors.[11]
  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.[12]

The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[11]

  1. Larger size.
  2. Villous pathology.
  3. The degree of dysplasia within the adenoma.

In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[13,14] 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.[15,16] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[17]

Molecular Events Associated With Colon Carcinogenesis

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[18,19,20] This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.[21,22] At least five to seven major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least two major pathways by which these molecular events can lead to CRC. While the majority of CRCs are due to events that result in chromosomal instability (CIN), 20% to 30% of CRCs display characteristic patterns of gene hypermethylation, termed CpG island methylator phenotype (CIMP), of which a portion display microsatellite instability (15% of CRCs).[20,23,24,25,26,27]

The spectrum of somatic mutations contributing to the pathogenesis of CRC is likely to be far more extensive than previously appreciated. A comprehensive study that sequenced more than 13,000 genes in a series of CRCs found that tumors accumulate an average of approximately 90 mutant genes. Sixty-nine genes were highlighted as relevant to the pathogenesis of CRC, and individual CRCs harbored an average of nine mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature.[28]

Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and frequent detectable losses at the molecular level of portions of chromosome 5q, chromosome 18q, and chromosome 17p; and mutation of the KRAS oncogene. The important genes involved in these chromosome losses are APC (5q), DCC/MADH2/MADH4 (18q), and TP53 (17p),[19,29] and chromosome losses are associated with instability at the molecular and chromosomal level.[20] 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.[29] For example, the rate of adenoma-to-carcinoma progression appears to be faster in microsatellite-unstable tumors compared with microsatellite-stable tumors. Characteristic histologic changes such as increased mucin production can be seen in tumors that demonstrate microsatellite instability (MSI), suggesting that at least some molecular events contribute to the histologic features of the tumors.

The key characteristics of MSI cancers are that they are tumors with a largely intact chromosome complement and that, as a result of defects in the DNA mismatch repair (MMR) system, they more readily acquire mutations in important cancer-associated genes compared with cells that have an effective DNA MMR system. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as DNA microsatellites.

The knowledge derived from the study of inherited CRC syndromes has provided important clues regarding the molecular events that mediate tumor initiation and tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APC gene product, which appears to be consistent with its important role in predisposing persons with germline APC mutations to colorectal tumors.

Family History as a Risk Factor for CRC

Some of the earliest studies of family history of CRC were those of Utah families that reported a higher number of deaths from CRC (3.9%) among the first-degree relatives of patients who had died from CRC than among sex-matched and age-matched controls (1.2%).[30] This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.[31,32,33,34,35,36]

Population-based studies have shown a familial association for close relatives of colon cancer patients to develop CRC and other cancers.[37] Using data from a cancer family clinic patient population, the relative and absolute risk of CRC for different family history categories was estimated (see Table 1).[38,39]

A systematic review and meta-analysis of familial CRC risk was reported.[39] Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected first-degree relative. The relative risk (RR) for CRC in the pooled study was 2.25 (95% confidence interval [CI], 2.00–2.53) if there was an affected first-degree family member. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed a RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side).

The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one first-degree relative with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years, for family members of index cases diagnosed at ages 45 to 59 years, and for family members of index cases diagnosed at age 60 years or older, respectively (RR, 3.87; 95% CI, 2.40–6.22 vs. RR, 2.25; 95% CI, 1.85–2.72 vs. RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in a first-degree relative was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had a first-degree relative with an adenoma.[39] This finding has been corroborated.[40] Other studies have reported that age at diagnosis of the adenoma influences the CRC risk, with younger age at adenoma diagnosis associated with higher RR.[41,42] As with any meta-analysis, there could be potential biases that might affect the results of the analysis, including incomplete and nonrandom ascertainment of studies included; publication bias; and heterogeneity between studies relative to design, target populations, and control selection. This study is reinforcement that there are significant associations between familial CRC risk, age at diagnosis of both CRC and adenomas, and multiplicity of affected family members.

Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)
Family History Relative Risk of CRC[39] Absolute Risk (%) of CRC by Age 79 ya
CI = confidence interval.
a Data from the Surveillance, Epidemiology, and End Results database.
b The absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRC[39]and the absolute risk of CRC by age 79 yearsa.
No family history 1 4a
One first-degree relative with CRC 2.3 (95% CI, 2.0–2.5) 9b
More than one first-degree relative with CRC 4.3 (95% CI, 3.0–6.1) 16 b
One affected first-degree relative diagnosed with CRC before age 45 y 3.9 (95% CI, 2.4–6.2) 15b
One first-degree relative with colorectal adenoma 2.0 (95% CI, 1.6–2.6) 8b

When the family history includes two or more relatives with CRC, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history to determine the number of relatives affected, their relationship to each other, the age at which the CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Young subjects who report a positive family history of CRC are more likely to represent a high-risk pedigree than older individuals who report a positive family history.[43] Computer models are now available to estimate the probability of developing CRC. These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. At least three validated models are also available for predicting the probability of carrying a mutation in a MMR gene.[44,45,46]

Figure 1 shows the types of colon cancer cases that arise in various family risk settings.[47]

Pie chart showing the fractions of colon cancer cases that arise in various family risk settings. The majority of colon cancer cases diagnosed in these settings are sporadic. The remaining cancer cases are: cases with familial risk (10%–30%); Lynch syndrome (hereditary nonpolyposis colorectal cancer) (2%–3%); familial adenomatous polyposis (<1%); and hamartomatous polyposis syndrome (<0.1%).
Figure 1. The fractions of colon cancer cases that arise in various family risk settings. Reprinted from Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000), with permission from Elsevier.

Inheritance of CRC Predisposition

Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all gene mutations known to cause a predisposition to CRC are inherited in an autosomal dominant fashion.[48] To date, at least one example of autosomal recessive inheritance, MYH-associated polyposis (MAP), has been identified. (Refer to the MYH-Associated Polyposis [MAP] section of this summary for more information.) Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing mutation. These include the following:

  1. Vertical transmission of cancer predisposition in autosomal dominant conditions. (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 a hereditary predisposition typically occur at an earlier age than in sporadic (nongenetic) cases.
    • A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
    • In addition, two or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., two separate primary CRCs) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).
    • The presence of non-neoplastic extracolonic features may suggest a hereditary colon cancer predisposition syndrome (e.g., congenital hypertrophy of the retinal pigment epithelium and desmoids in familial adenomatous polyposis [FAP]).
    • An uncommon tumor (e.g., adrenocortical, sebaceous carcinoma, ampullary, and small bowel) may serve as a clue to the presence of a hereditary cancer syndrome, such as Li-Fraumeni or FAP.
    • The presence of multiple polyps may suggest a hereditary colon cancer predisposition syndrome. As susceptibility to oligopolyposis (as few as 10–15 polyps) has become apparent, clinicians, and GI endoscopists in particular, increasingly consider the possibility of inherited conditions, such as AFAP, MYH-associated polyposis, and POLD1/POLE, even when the family history appears entirely negative. Because oligopolyposis also involves diverse pathology (including hamartomas, sessile serrated polyps, and sessile serrated adenomas), careful attention to polyp count and polyp histologies helps to determine whether genetic testing and/or further clinical evaluation is appropriate.

Hereditary CRC has two well-described forms: FAP (including an attenuated form of polyposis [AFAP]), due to germline mutations in the APC gene,[49,50,51,52,53,54,55,56] and Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline mutations in DNA MMR genes.[57,58,59,60] (Figure 2 depicts a classic family with LS, highlighting some of the indicators of high CRC risk that are described above.) Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC.[48]

Pedigree showing some of the classic features of a family with Lynch syndrome across three generations, including transmission occurring through maternal and paternal lineages and the presence of both colon and endometrial cancers.
Figure 2. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.

Difficulties in Identifying a Family History of CRC Risk

The accuracy and completeness of family history data must be taken into account in using family history to assess individual risk in clinical practice, and in identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[61] In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, due to incomplete penetrance, some persons may carry a genetic predisposition to CRC but do not develop cancer, giving the impression of skipped generations in a family tree.

Accuracy of patient-reported family history of colon cancer has been shown to be good, but it is not optimal. Patient report should be verified by obtaining medical records whenever possible, especially for reproductive tract cancers that may be relevant in identifying risk of LS. (Refer to the Accuracy of the Family History section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Other Risk Factors for CRC

Other risk factors that may influence the development of adenomatous polyps and CRC risk include diet, use of nonsteroidal anti-inflammatory drugs (NSAIDs), cigarette smoking, colonoscopy with removal of adenomatous polyps, and physical activity. Even in LS, a hereditary form of colon cancer, cigarette smoking has been identified as a risk factor for the development of colorectal adenomas.[62] (Refer to the Lynch Syndrome [LS] section of this summary for more information).

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


In practical terms, knowing that a person is at an increased risk of CRC because of a germline abnormality is most useful if the knowledge can be used to prevent the development of cancer or cancer-related morbidity and mortality once it has developed. While one can also use the information for family planning, decisions about work and retirement, and other important life decisions, prevention is usually the central concern.

This section covers screening: testing in the absence of symptoms for CRC and its precursors (i.e., adenomatous polyps) to identify people with an increased probability of developing CRC. Those with abnormalities should undergo diagnostic testing to see whether they have an occult cancer, followed by treatment if cancer or a precursor is found. Taken together, this set of activities is aimed at either preventing the development of CRC by finding and removing its precursor, the adenomatous polyp, or increasing the likelihood of cure by early detection and treatment.

In the context of high-risk syndromes such as LS or FAP, surveillance implies examining patients in whom adenoma or cancer occurrence is highly probable, and the examination is done for early detection. It is not screening in the traditional sense. The meaning of the terms screening versus surveillance has evolved over time and their usage in this summary may not be consistent with other oncologic and epidemiologic contexts.

Primary prevention (eliminating the causes of CRC in people with genetically increased risk) is addressed later in this section.

State of the evidence base

Currently, there are no published randomized controlled trials of surveillance in people with a genetically increased risk of CRC and few controlled comparisons. While a randomized trial with a no-surveillance arm is not feasible, there is a need for well-designed studies comparing various surveillance methods or differing periods of time between procedures. An observational study that compared surveilled subjects with unsurveilled (by choice) controls evaluated a 15-year experience with 252 relatives at risk of LS, 119 of whom declined surveillance. Eight of 133 (6%) in the surveilled group developed CRC, compared with 19 in the unsurveilled group (16%, P = .014).[63] In general, however, people with genetic risk have been excluded from the trials of CRC screening that have been published thus far, so it is not possible to estimate effectiveness by subgroup analyses. Therefore, prevention in these patients cannot be based on strong evidence of effectiveness, as is ordinarily relied on by expert groups when suggesting screening or surveillance guidelines.

Given these considerations, clinical decisions are based on clinical judgment. These decisions take into account the biologic and clinical behavior of each kind of genetic condition, and possible parallels with patients at average risk, for whom screening is known to be effective.

The evidence base for the effectiveness of screening in average-risk people (those without apparent genetic risk) is the benchmark for considering an approach to people at increased risk. (Refer to the PDQ summary on Screening for Colorectal Cancer for more information.)

The fact that screening of average-risk persons reduces the risk of dying from CRC forms the basis for recommending surveillance in persons at a higher genetic risk of CRC. As logical as this approach seems, randomized trials of surveillance have not been performed in this special population, though observational studies performed on families with LS [64,65] and FAP [66] support the value of surveillance. These studies demonstrate a shift towards earlier stage at diagnosis and a corresponding reduction in CRC mortality among colonoscopy-detected cancers.

(Refer to the Major Genetic Syndromes section of this summary for more information about surveillance in high-risk populations.)

Rationale for screening

Widely accepted criteria (1–3 below) for appropriate screening apply as much to diseases with a strong genetic component (more than one affected first-degree relative or one first-degree relative diagnosed at younger than 60 years) as they do to other diseases.[67,68] Additional criteria (4 and 5) were added below.[69]

  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 the 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 CRC. The harms of screening (criterion 4), especially major complications of diagnostic colonoscopy (perforation and major bleeding), are also known. Evidence that early intervention results in better outcomes (criterion 3) is limited but suggests benefit. One study in the setting of LS found earlier stage/local tumors in the screened individuals.[63]

Identification of persons at high genetic risk of CRC

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

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

When such persons are identified, options tailored to the patient situation are considered. (Refer to the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)

At this time, the use of mutation testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of mutations in the APC tumor suppressor gene and LS-associated MMR genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost effective.

Rather detailed recommendations for surveillance in FAP and LS have been provided by several organizations representing various medical specialties and societies. The following guidelines are readily available through the National Guideline Clearinghouse:

  • American Cancer Society.[70]
  • United States Multisociety (American Gastroenterological Association and American Society for Gastrointestinal Endoscopy) Task Force on Colorectal Cancer.[71]
  • American Society of Colon and Rectal Surgeons.[72]
  • National Comprehensive Cancer Network.[73]
  • Gene Reviews.

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

Primary Prevention of Familial CRC


Observational studies of average-risk people have suggested that the use of some drugs and supplements (NSAIDs, estrogens, folic acid, and calcium) might prevent the development of CRC.[74] (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) None of the evidence is convincing enough to lead expert groups to recommend these drugs and supplements specifically to prevent CRC, and few studies specifically enrolled people with an inherited predisposition for CRC. Although antioxidants are hypothesized to prevent cancer, a randomized controlled trial of antioxidant vitamins (beta carotene, vitamin C, and vitamin E) has shown no effect on CRC incidence.[75]

(Refer to the Interventions for FAP section and the Chemoprevention in LS section in the Major Genetic Syndromes section of this summary for more information about chemoprevention.)

Modifying behavioral risk factors

Several components of diet and behavior have been suggested, with various levels of consistency, to be risk factors for CRC. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) These lifestyle factors may represent potential means of prevention.[74,76,77] Expert groups differ on the interpretation of the evidence for some of these components.

Little is known about whether these same factors are protective in people with a genetically increased risk of CRC. In one case-control study, low levels of physical activity, high caloric intake, and low vegetable intake were significantly related to cancer risk in people with no family history of CRC but showed no relationship in people with a family history, despite adequate statistical power to do so.[78]


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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, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic mutations in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[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 DNA repair 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 syndrome (JPS), among others. Germline mutations of oncogenes are not an important cause of inherited susceptibility to colorectal cancer (CRC), even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch syndrome [LS] section in the Major Genetic Syndromes section of this summary for more information). MYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.

Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer
Gene Syndrome Hereditary Pattern Predominant Cancer
FAP = familial adenomatous polyposis; JPS = juvenile polyposis syndrome; LS = Lynch syndrome; OMIM = Online Mendelian Inheritance in Man database; PJS = Peutz-Jeghers syndrome.
Tumor suppressor genes      
APC(OMIM) FAP Dominant Colon, intestine, etc.
TP53(p53) (OMIM) Li-Fraumeni Dominant Multiple (including colon)
STK11(LKB1) (OMIM) PJS Dominant Multiple (including intestine)
PTEN(OMIM) Cowden Dominant Multiple (including intestine)
BMPR1A(OMIM) JPS Dominant Gastrointestinal
SMAD4(MADH/DPC4) (OMIM) JPS Dominant Gastrointestinal
Repair/stability genes      
MLH1(OMIM),MSH2(OMIM),MSH6(OMIM),PMS2 (OMIM) LS Dominant Multiple (including colon, uterus, and others)
EPCAM (TACSTD1) (OMIM) LS Dominant Multiple (including colon, uterus, and others)
MYH(MUTYH) (OMIM) MYH-associated polyposis Recessive Colon
POLD1(OMIM),POLE(OMIM) Oligopolyposis Dominant Colon, endometrial

De Novo Mutation Rate

Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous mutation rate (de novo mutation rate) in these populations. Interestingly, FAP, JPS, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome are all thought to have high rates of spontaneous mutations, in the 25% to 30% range,[3,4,5] while estimates of de novo mutations in the MMR genes associated with LS are thought to be low, in the 0.9% to 5% range.[6,7,8] These estimates of spontaneous mutation rates in LS seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[9,10,11] making the de novo mutation rate for LS seem quite low in contrast to the relatively high rates in the other polyposis syndromes.

Genetic Polymorphisms and CRC 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.[12] 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.[13] The relative risk (RR) and absolute risk of CRC for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in first-degree relatives of individuals with colon adenomas.[14] The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by low-penetrance genes or gene combinations. Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.

Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in LS or FAP. However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide polymorphisms (SNPs).

Polymorphisms underlying polygenic susceptibility to CRC are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example those APC or MMR gene mutations leading to an autosomal dominant inheritance pattern in a family. The definition of a moderate risk of cancer is arbitrary, but it is usually considered to be in the range of an RR of 1.5 to 2.0. Because these types of sequence variants are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from the relatively rare syndromes such as FAP or LS. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (e.g., average age of CRC) in individuals with LS.

In general, low-penetrance variants have been identified in one of two manners. Earlier studies focused on candidates genes chosen because of biologic relevance to colon cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the Genome-wide searches section of this summary for more information.)

Polymorphism-modifying risk in average-risk populations

Low-penetrance candidate genes

Several candidate genes have been identified and their potential use for clinical genetic testing is being determined. Candidate alleles that have been shown to associate with modest increased frequencies of colon cancer include heterozygous BLMAsh (the allele that is a founder mutation in Ashkenazi Jewish individuals with Bloom syndrome), the GH1 1663 T?A polymorphism (a polymorphism of the growth hormone gene associated with low levels of growth hormone and IGF-1), and the APC I1307K polymorphism.[15,16,17]

Of these, the variant that has been most extensively studied is APC I1307K. Yet, neither it nor any of the other variants mentioned above are routinely used in clinical practice. (Refer to the APC I1307K section of this summary for more information.)

Genome-wide searches

Although the major genes for polyposis and nonpolyposis inherited CRC syndromes have been identified, between 20% and 50% of cases from any given series of suspected FAP or LS cases fail to have a mutation detected by currently available technologies. It is estimated that heredity is responsible for approximately one-third of the susceptibility to CRC,[18] and causative germline mutations account for less than 6% of all CRC cases.[19] This has led to suspicions that there may be other major genes that, when mutated, predispose to CRC with or without polyposis. A few such genes have been detected (e.g., MYH, EPCAM) but the probability for discovery of other such genes is fairly low. More recent measures for new gene discovery have taken a genome-wide approach. Several GWAS have been conducted with relatively large, unselected series of CRC patients that have been evaluated for patterns of polymorphisms in candidate and anonymous genes spread throughout the genome. These SNPs are chosen to capture a large portion of common variation within the genome, based on the International HapMap Project.[20,21] The goal is to identify alleles that, while not pathologically mutated, may confer an increase (or potential decrease) in CRC risk. Identification of yet unknown aberrant CRC alleles would permit further stratification of at-risk individuals on a genetic basis. Such risk stratification would potentially enhance CRC screening. The use of genome-wide scans has led to the discovery of multiple common low-risk CRC susceptibility alleles. (Refer to Table 3 for more information.)

A large GWAS was performed using tagSNPs in a total of 10,731 CRC cases and 10,961 controls from eight centers to identify and enrich for CRC susceptibility alleles.[22] In addition to the previously reported 8q24, 15q13, and 18q21 CRC risk loci, two previously unreported associations at 10p14 (P = 2.5 × 10-13) and 8q23.3 (P = 3.3 × 10-8) were identified. The 8q23.3 locus tags a plausible causative gene, EIF3H (OMIM). The authors of this study estimated that the loci identified account for approximately 3% to 4% of the excess familial CRC risk but that a high proportion of the population would be carriers of at-risk genotypes. They estimated that 3% of individuals may carry seven or more deleterious alleles. The authors concluded that their data are compatible with a polygenic model in which individual alleles, each exerting a small effect, combine either additively or multiplicatively to produce much larger risks in carriers of multiple risk alleles.

A GWAS using 555,510 SNPs in 14,500 cases of CRC and 13,294 controls from seven different centers revealed a previously unreported association on 11q23 (odds ratio [OR], 1.1; P = 5.8 × 10-10) and replicated susceptibility loci at 8q24 (OR, 1.19; P = 8.6 × 10-26) and 18q21 (OR, 1.2; P = 7.8 × 10-28).[23] Furthermore, the authors were unable to identify causative coding sequence variants in any of the candidate genes at 8q24 (POU5F1P1, HsG57825, and DQ515897) or 18q21 (SMAD7). The variants identified are common in the general population, with risk-allele frequencies in populations of European ancestry of 0.29, 0.37, and 0.52, respectively. Carrying all six possible risk alleles yielded an estimated OR of 2.6 (95% confidence interval [CI], 1.75–3.89) for CRC.

A meta-analysis of GWAS data obtained from the two studies above (the combined dataset analyzed contained 38,710 polymorphic SNPs in 2,024 cases and 2,092 controls) revealed four additional susceptibility loci.[24] In addition to six loci identified in previous GWAS (8q23, 8q24, 10p14, 11q23, 15q13, and18q21), the following four new loci were identified:

  • Two SNPs linked to a 38 kilobase (kb) region on 20p12.3 [two SNPs: (i) combined OR, 1.12; 95% CI, 1.08–1.16; P = 2.0 × 10-10 and (ii) combined OR, 1.12; 95% CI, 1.08–1.17; P = 2.1 × 10-10] lacking genes or predicted protein-encoding transcripts;
  • 14q22.2 (combined OR, 1.11; 95% CI, 1.08–1.15; P = 8.1 × 10-10) in a region 9.4kb from the transcription start site of the BMP4 gene;
  • 19q13.1 [two SNPs: (i) combined OR, 0.87; 95% CI, 0.83–0.91; P = 4.6 × 10-9 and (ii) combined OR, 0.89; 95% CI, 0.85–0.93; P = 2.2 , 10-7], which lies within the Rho GTPase binding protein 2 (RHPN2) gene; and
  • 16q22.1 (combined OR, 0.91; 95% CI, 0.89–0.94; P = 1.2 × 10-8), which lies within intron 1 of the E-cadherin (CDH1) gene.

No interactions between the loci were associated with an increased risk of CRC and the loci identified were estimated to collectively account for approximately 6% of the excess familial risk of CRC. The data analyses led the authors to conclude the following:

  • The loci readily detectable through current GWAS are associated with modest effects (genotypic risks of approximately 1.2).
  • The number of common variants explaining more than 1% of inherited risk is very low.
  • Only a small proportion of heritability of any cancer can be explained by the currently identified loci.
  • Of the common risk loci identified thus far, no significant epistatic effects were observed.

Because few of the observed associations seem to result from a correlation with common coding variants and many of the loci map to regions lacking genes of protein-coding transcripts, much of the common variation in cancer risk is likely mediated through sequence changes influencing gene expression.

A genome-wide linkage analysis was performed in 30 Swedish non-FAP/non-LS families with a strong family history of CRC.[25] Several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected by parametric and nonparametric analysis.

A GWAS of affected, unaffected, and discordant sibling pairs in 194 kindreds utilized clinical information (histopathology, size and number of polyps, and other primary cancers) in conjunction with age at onset and family history to define five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancers) before analysis.[26] 1p31.1 strongly linked to the multiple-cancer subgroup (P < .00007). 15q14-q22 linked to the full-sample (P < .018), oligopolyposis (P < .003), and young (P < .0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome in families of Ashkenazi descent. BRCA2 linked with the colon/breast phenotypic subgroup. Linkage to 17p13.3 in the breast/colon subgroup identified HIC1 (hypermethylated in colon cancer 1) as a candidate gene.

Nonparametric analysis revealed three loci at 3q29 (logarithm of the odds [LOD] score = 2.61; P = .0003), 4q31.3 (LOD = 2.13; P = .0009), and 7q31.31 (LOD = 3.08; P = .00008) in a GWAS performed in 70 kindreds with at least two siblings affected with colorectal adenocarcinoma or colorectal polyps with high-grade dysplasia.[27] Linkage to 8q24, 9q22, and 11q23 was not obtained in these kindreds. Minor linkage to 3q21-q24 was present in this study population.

Table 3. Colorectal Cancer Susceptibility Loci Identified Through Genome-Wide Association Studies
Chromosome Logarithm of the Odds (LOD) Score/Odds Ratio (OR) P Value Single Nucleotide Polymorphism (SNP) Marker
ORhet = odds ratio among heterozygotes; ORhom = odds ratio among homozygotes.
a Identified in a breast/colon cohort.
3q29 LOD = 2.61[27] .0003   D3S240
4q31.3 LOD = 2.13[27] .0009   D4S2999
7q31.31 LOD = 3.08[27] .00008   D7S643
8q23.3 Combined OR = 1.29[24] 1.1 × 10-10 rs11986063  
8q23.3 ORallelic = 1.25, ORhet = 1.27, ORhom = 1.43[22] 3.3 × 10-18 rs16892766  
Combined OR = 1.32[24] 1.1 × 10-10
8q24 ORallelic = 1.24, ORhet = 1.35, ORhom = 1.57[22] 7.0 × 10-11 rs6983267  
Combined OR = 0.83[24] 2.1 × 10-14
8q24 OR = 1.19[23] 8.6 × 10-26 rs7014346  
Combined OR = 1.21[24] 3.0 × 10-13
8q24 Combined OR = 1.17[24] 1.2 × 10-10 rs7837328  
8q24 Combined OR = 1.14[24] 1.5 × 10-7 rs10808555  
10p14 ORallelic = 0.89, ORhet = 0.87, ORhom = 0.80[22] 2.5 × 10-13 rs10795668  
Combined OR = 0.91[24] 3.1 × 10-4
11q23 OR = 1.11[23] 5.8 × 10-10 rs3802842  
Combined OR = 1.21[24] 5.2 × 10-13
14q22.2 Combined OR = 1.11[24] 8.1 × 10-10 rs4444235  
15q13 ORallelic = 1.23, ORhet = 1.17, ORhom = 1.70[22] 4.7 × 10-7 rs4779584  
Combined OR = 1.19[24] 1.7 × 10-8
16q22.1 Combined OR = 0.91[24] 1.2 × 10-8 rs9929218  
17p13.3a Not available[26] .0364   D17S1308
18q21 ORallelic = 0.85, ORhet = 0.84, ORhom = 0.73[22] 1.7 × 10-6 rs4939827  
OR = 1.20[23] 7.8 × 10-28
Combined OR = 0.85[24] 2.2 × 10-11
19q13.1 Combined OR = 0.89[24] 2.2 × 10-7 rs7259371  
19q13.1 Combined OR = 0.87[24] 4.6 × 10-9 rs10411210  
20p12.3 Combined OR = 1.12[24] 2.0 × 10-10 rs355527  
20p12.3 Combined OR = 1.12[24] 2.1 10-10 rs961253  

Limitations of the tagged SNP approach in GWAS in identifying SNPs with minor allele frequencies of 5% to 10%, low-frequency variants with potentially stronger effects, and copy number variants are noted. It is yet unclear how the identification of these new susceptibility alleles in individuals will apply to CRC screening and how comprehensive panels of low-penetrance cancer associated alleles may be applied in the clinical setting.

Genetic Variation in 8q24 andSMAD7

Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with RR ranging from 1.17 to 1.27.[28,29,30] Although the RR is modest for the risk alleles in 8q24, the prevalence (and population-attributable fraction) of these risk alleles is high. The genes responsible for this association have not yet been identified. In addition, common alleles of SMAD7 have also been shown to be associated with an approximately 35% increase in risk of colon cancer.[31]

Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1null allele and the NAT2 G/G allele.[32] None of these alleles has been characterized enough to currently support its routine use in a clinical setting. Family history remains the most valuable tool for establishing risk of colon cancer in these families. Similar to what has been reported in prostate cancer, a combination of susceptibility loci may yet hold promise in profiling individual risk.[33,34]

Variants of Uncertain Significance in Major Cancer Susceptibility Genes


Polymorphisms in APC are the most extensively studied polymorphisms with regard to cancer association. The APC I1307K polymorphism is associated with an increased risk of colon cancer but does not cause colonic polyposis. The I1307K polymorphism occurs almost exclusively in people of Ashkenazi Jewish descent and results in a twofold increased risk of colonic adenomas and adenocarcinomas compared with the general population.[17,35] 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.[17] Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated colon cancer risk is not high enough to support routine use. On the basis of currently available data, it is not yet known whether the I1307K carrier state should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.

Clinical implications of low-penetrance alleles

Although the statistical evidence for an association between genetic variation at these loci and CRC risk is convincing, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with ORs for developing CRC in heterozygous carriers usually from 1.1 to 1.3. More risk variants will likely be identified. Risks in this range do not appear to confer enough increase in age-specific risk as to warrant modification of otherwise clinically prudent screening. Until their collective influence is prospectively evaluated, their use cannot be recommended in clinical practice.


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  26. Daley D, Lewis S, Platzer P, et al.: Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study. Am J Hum Genet 82 (3): 723-36, 2008.
  27. Neklason DW, Kerber RA, Nilson DB, et al.: Common familial colorectal cancer linked to chromosome 7q31: a genome-wide analysis. Cancer Res 68 (21): 8993-7, 2008.
  28. 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.
  29. 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.
  30. Gruber SB, Moreno V, Rozek LS, et al.: Genetic variation in 8q24 associated with risk of colorectal cancer. Cancer Biol Ther 6 (7): 1143-7, 2007.
  31. 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.
  32. Hirschhorn JN, Lohmueller K, Byrne E, et al.: A comprehensive review of genetic association studies. Genet Med 4 (2): 45-61, 2002 Mar-Apr.
  33. 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.
  34. Slattery ML, Herrick J, Curtin K, et al.: Increased risk of colon cancer associated with a genetic polymorphism of SMAD7. Cancer Res 70 (4): 1479-85, 2010.
  35. 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.

Major Genetic Syndromes


Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient and family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch I and II syndromes, Peutz-Jeghers syndrome [PJS], Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first five, while hamartomas were found to be characteristic in the last three.

With the development of the Human Genome Project and the identification in 1990 of the adenomatous polyposis coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by mutations in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations as having FAP mutation on the 3' and 5' ends of the gene. Turcot syndrome families were shown to be genetically part of FAP with medulloblastomas and Lynch syndrome (LS) with glioblastomas. Muir-Torre and LS were shown to have genetic similarities. MYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the mutations were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for mutation carriers (see Table 4).

Table 4. Absolute Risks of Colorectal Cancer for Mutation Carriers in Hereditary Colorectal Cancer Syndromes
Syndrome Absolute Risk in Mutation Carriers
FAP = familial adenomatous polyposis; JPS = juvenile polyposis syndrome; LS = Lynch syndrome; PJS = Peutz-Jeghers syndrome.
a Cancer risk estimates quoted here predate the widespread use of surveillance and prophylactic surgery.
b Refer to the Lynch syndrome (LS)section of this summary for a full discussion of risk.
FAPa 90% by age 45 y[1]
Attenuated FAP 69% by age 80 y[2]
LS 40% to 80% by age 75 yb[3,4]
MYH-associated polyposis 35% to 53%[5]
PJS 39% by age 70 y[6]
JPS 17% to 68% by age 60 y[7,8]

With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for mutations in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron -exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic mutations from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance that cannot be used for predictive purposes.

Familial Adenomatous Polyposis (FAP)

FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,9,10] 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.[11] 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 (GI) tract, extraintestinal manifestations such as congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignant changes such as thyroid tumors, small bowel cancer, hepatoblastoma, and brain tumors, particularly medulloblastoma (see Table 5).

Table 5. Extracolonic Tumor Risks in Familial Adenomatous Polyposis
Malignancy Relative Risk Absolute Lifetime Risk (%)
Adapted from Giardiello et al.,[12]Jagelman et al.,[13]Sturt et al.,[14]Lynch et al.,[15]Bülow et al.,[16]Burt et al.,[17]and Galiatsatos et al.[18]
a The Leeds Castle Polyposis Group.
Desmoid 852.0 15.0
Duodenum 330.8 5.0–12.0
Thyroid 7.6 2.0
Brain 7.0 2.0
Ampullary 123.7 1.7
Pancreas 4.5 1.7
Hepatoblastoma 847.0 1.6
Gastric 0.6a

FAP is also known as familial polyposis coli, adenomatous polyposis coli (APC), or Gardner syndrome (colorectal polyposis, osteomas, and soft tissue tumors). Gardner syndrome has sometimes been used to designate FAP patients who manifest these extracolonic features. However, Gardner syndrome has been shown molecularly to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.[19]

Most cases of FAP result from 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%.[1,9,10] 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.[1,9,10,20,21] Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life.[1,9,10] 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.[22,23]

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.[24] Some proponents feel that the genetic testing of children for FAP presents an example in which possible medical benefit justifies genetic testing of minors, especially for the anticipated 50% of children who will be found not to be mutation carriers and who can thus be spared the necessity of unpleasant and costly annual sigmoidoscopy. The psychological impact of such testing is currently under investigation and is addressed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary.

A number of different APC mutations have been described in a series of FAP patients. 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.

Adenomatous polyposis coli (APC)

The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with FAP and 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.[25,26] AFAP is associated with truncating mutations primarily in the 5' and 3' ends of the gene and possibly missense mutations elsewhere.[27,28,29,30]

More than 300 different disease-associated mutations of the APC gene have been reported.[26] 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.[31]

Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[27,28,29] There has been much interest in correlating the location of the mutation within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with mutations that occur in or before exon 4 and in the latter two-thirds of exon 15,[28] and that retinal lesions are rarely associated with mutations that occur before exon 9.[29,32] Exon 9 mutations have also been associated with attenuated polyposis. Additionally, individuals with exon 9 mutations tend not to have duodenal adenomas.[33]

Density of colonic polyposis

Researchers have found that dense carpeting of colonic polyps, a feature of classic FAP, is seen in most patients with APC mutations, particularly those mutations that occur between codons 169 and 1393. At the other end of the spectrum, sparse polyps are features of patients with mutations occurring at the extreme ends of the APC gene or in exon 9. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.)

Extracolonic tumors

Desmoid tumors

Desmoid tumors are proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening.[34] Desmoids may occur sporadically, as part of classical FAP, or in a hereditary manner without the colon findings of FAP.[15,35] Desmoids have been associated with hereditary APC gene mutations even when not associated with typical adenomatous polyposis of the colon.[35,36]

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.[35,37,38]APC mutations occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[32,36,39,40] 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.[35]

A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors.[41] The desmoid risk factor scale was based on gender, presence or absence of extracolonic manifestations, family history of desmoids, and genotype, if available. By utilizing this scale, it was possible to stratify FAP patients into low-, medium-, and high-risk groups for developing desmoid tumors. The authors concluded that the desmoid risk factor scale could be used for surgical planning. Validation of the risk factors comprising this scale were recently supported by a large, multiregistry, retrospective study from Europe.[42]

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 before surgery and progress to mesenteric fibromatosis after surgical trauma, ultimately giving rise to desmoid tumors.[43] It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly.[44] 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.[45,46]

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.[38] In some series, desmoids are the second most common cause of death after CRC in FAP patients.[47,48] A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity.[49] 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.[49]

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 after any surgery, including risk-reducing colectomy and surgical surveillance procedures such as laparoscopy.[37,44,50]

The management of desmoids in FAP can be challenging and can complicate prevention efforts. Currently, there is no accepted standard treatment for desmoid tumors. Multiple medical treatments have generally been unsuccessful in the management of desmoids. Treatments have included antiestrogens, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy, and radiation therapy, among others. Studies have evaluated the use of raloxifene alone, tamoxifen or raloxifene combined with sulindac, and pirfenidone alone.[51,52,53] There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed.[54] 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.[55]

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.[51] Six of the patients had been on tamoxifen or sulindac before treatment with raloxifene, and seven patients were previously untreated. All 13 patients with intra-abdominal desmoid disease had either a partial or a complete response 7 months to 35 months after starting treatment, and most desmoids decreased in size at 4.7 ± 1.8 months after treatment. Response occurred in patients with desmoid plaques and with distinct lesions. Study limitations include small sample size, and the clinical evaluation of response was not consistent in all patients. Several questions remain concerning patients with desmoid tumors not expressing estrogen alpha receptors who have received raloxifene and their outcome and which patients may benefit from this potential treatment.

A second study of 13 patients with FAP-associated desmoids, who were treated with tamoxifen 120 mg/day or raloxifene 120 mg/day in combination with sulindac 300 mg/day, reported that ten patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that three patients had stable disease for more than 30 months.[52] 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.[53] 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.[56] A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.[56,57] Issues of subject selection are critical in evaluating surgical outcome data.[57] Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.

Stomach tumors

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.[16,18,58,59,60,61,62] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[63,64]

The hyperplastic surface epithelium is, by definition, nonneoplastic. Accordingly, FGPs have not been considered precancerous; in Western FAP patients the risk of stomach cancer is minimally increased, if at all. However, case reports of stomach cancer appearing to arise from FGPs have led to a reexamination of this issue.[18,65] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs.[64] In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, FGPs were detected in 88% of the patients. Low-grade dysplasia was detected in 38% of these patients, whereas high-grade dysplasia was detected in 3% of these patients. In the author's view, if a polyp with high-grade dysplasia is identified, polypectomy can be considered with repeat endoscopic surveillance in 3 to 6 months. Consideration for treatment with daily proton-pump inhibitors (PPIs) also may be given.[66]

Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming PPIs.[64,67] 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%.[68,69,70,71] 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.[72,73,74,75] The recommended management for gastric adenomas is endoscopic polypectomy. The management of adenomas in the stomach is usually individualized based on the size of the adenoma and the degree of dysplasia.

Level of evidence: None assigned

Duodenum/small bowel tumors

Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper GI endoscopy,[76] 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.[58,59,77] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[13,74,78,79] 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.[16] 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.[80,81,82] One study of computed tomography (CT) duodenography found that larger adenoma size could be accurately measured but smaller, flatter adenomas could not be accurately counted.[83]

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.[84] 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.[78] 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.[85,86]

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.[16,79,87,88] 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 to attempt to identify those individuals with FAP at highest risk of developing duodenal adenocarcinoma.[88] According to this system, known as the Spigelman Classification (see Table 6), 36% of patients with the most advanced stage will develop carcinoma.[79]

Table 6. Spigelman Classification
Points Polyp Number Polyp Size (mm) Histology Dysplasia
Stage I, 1–4 points; Stage II, 5–6 points; Stage III, 7–8 points; Stage IV, 9–12 points[88]
1 1–4 1–4 Tubular Mild
2 5–20 4–10 Tubulovillous Moderate
3 >20 >10 Villous Severe

A baseline upper endoscopy, including side-viewing duodenoscopy, should be performed between ages 25 and 30 years in FAP patients.[75] The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy, often, based on Spigelman stage. Recommended intervals are based on expert opinion although the relatively liberal intervals for stage 0-II disease are based in part on the natural history data generated by the Dutch/Scandinavian duodenal surveillance trial (see Table 7).[16]

The main advantages of the Spigelman Classification are its long-standing familiarity to and usage by those in the field, which allows reasonable standardization of outcome comparisons across studies.[71,89] However, there are several limitations on attempted application of the Spigelman Classification:

  • Most pathologists do not currently employ the term moderate dysplasia, preferring a simpler low- versus high-grade dysplasia system.
  • Because of the villous nature of normal duodenal epithelium, pathologists commonly disagree over the classification of "tubular," "tubulovillous," and "villous."
  • Spigelman staging requires biopsy, which is not always essential when only a few small plaques are present; conversely, for larger adenomas, sampling variation leads to understaging.[90,91]
Table 7. Recommended Screening Intervals by Spigelman Stage
Spigelman Stage NCCN (2014)[92] Groves et al. (2002)[79]
CP = chemoprevention; ET = endoscopic therapy; GA = general anesthetic; NCCN = National Comprehensive Cancer Network.
Refer to the Interventions for FAPsection in the Major Genetic Syndromessection of this summary for more information about chemoprevention.
See belowfor additional information about the use of surgical resection in Spigelman stage IV disease.
0 (no polyps) Endoscopy every 4 y Endoscopy every 5 y
I Endoscopy every 2–3 y Endoscopy every 5 y
II Endoscopy every 1–3 y Endoscopy every 3 y
III Endoscopy every 6–12 mo Endoscopy every 1–2 y
CP + ET (+/- GA)
IV Surgical referral Surgical resection
Complete mucosectomy or duodenectomy or Whipple procedure if duodenal papilla is involved
Expert endoscopic surveillance every 3–6 mo Endoscopy every 1–2 y
CP + ET (+/- GA)

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;[85,86,93] however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum.[90] 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.[94] In a series of 47 patients with FAP and Spigelman stage III or stage IV disease who underwent definitive radical surgery, the local recurrence rate was reported to be 9% at a mean follow-up of 44 months. This local recurrence rate is dramatically lower than any local endoscopic or surgical approach from the same study.[90] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[91,94,95,96] 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 (IPAA). As noted in a Northern European study,[16] and others,[97,98] the vast majority of patients with duodenal adenomas will not develop cancer and can be followed with endoscopy. However, individuals with advanced adenomas (Spigelman stage III or stage IV disease) generally require endoscopic or surgical treatment of the polyps. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.

The endoscopic approach to larger and/or flatter adenomas of the duodenum depends on whether the ampulla is involved. Endoscopic mucosal resection (EMR) after submucosal injection of saline, with or without epinephrine and/or dye, such as indigo carmine, can be employed for nonampullary lesions. Ampullary lesions require even greater care including endoscopic ultrasound evaluation for evidence of bile or pancreatic duct involvement. Stenting of the pancreatic duct is commonly performed to prevent stricturing and pancreatitis. The stents require endoscopic removal at an interval of 1 to 4 weeks. Because the ampulla is tethered at the ductal orifices, it typically does not uniformly "lift" with injection, so injection is commonly not used. Any consideration of EMR or ampullectomy requires great experience and judgment, with careful consideration of the natural history of untreated lesions and an appreciation of the high rate of adenoma recurrence despite aggressive endoscopic intervention.[86,90,91,95,99,100,101,102] The literature uniformly supports duodenectomy for Spigelman stage IV disease. For Spigelman stage II and III disease, there is a role for endoscopic treatment invariably focusing on the one or two worst lesions that are present.

Reluctance to consider surgical resection has to do with short-term morbidity and mortality and long-term complications related to surgery. Although these concerns are likely overstated,[90,91,96,99,103,104,105,106,107,108,109] fear of surgical intervention can lead to aggressive and somewhat ill-advised endoscopic interventions. In some circumstances, endoscopic resection of ampullary and/or other duodenal adenomas cannot be accomplished completely or safely by endoscopic means, and duodenectomy cannot be accomplished without risking a short-gut syndrome or cannot be done at all because of mesenteric fibrosis. In such cases, surgical transduodenal ampullectomy/polypectomy can be performed. This is, however, associated with a high risk of local recurrence similar to that of endoscopic treatment.

Level of evidence: 3diii

Other tumors

The spectrum of tumors arising in FAP is summarized in Table 5.

Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP.[110] However, a recent study [111] of papillary thyroid cancers in six females with FAP failed to demonstrate loss of heterozygosity (LOH) or mutations of the wild-type allele in codons 545 and 1061 to 1678 of the six tumors. In addition, four out of five of these patients had detectable somatic RET/PTC chimeric genes. This mutation is generally restricted to sporadic papillary thyroid carcinomas, suggesting the involvement of genetic factors other than APC mutations. Further studies are needed to show whether other genetic factors such as the RET/PTC chimeric gene are independently responsible for or cooperative with APC mutations in causing papillary thyroid cancers in FAP patients. Although level 1 evidence is lacking, a consensus opinion recommends annual thyroid examinations beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP. The same panel suggests clinicians could consider the addition of annual thyroid ultrasounds to this screening routine.[92,112,113]

Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma in an FAP patient.[114] In a study of 162 FAP patients who underwent abdominal CT for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors.[115] 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.[115] 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.[116,117,118,119,120,121,122,123,124,125] Some series have also demonstrated LOH of APC in these tumors.[117,119,126] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[127] Although lacking level 1 evidence, a consensus panel has recommended abdominal examination, abdominal ultrasound, and measurement of serum alpha fetoprotein every 3 to 6 months for the first 5 years of life in children with a predisposition to FAP.[92,128]

The constellation of CRC and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with mutations in APC, while colon cancer and glioblastoma are associated with mutations in mismatch repair (MMR) genes.[129]

There are several reports of other extracolonic tumors associated with FAP, but whether these are simply coincidence or actually share a common molecular genetic origin with the colonic tumors is not always evident. Some of these reports have demonstrated LOH or a mutation of the wild-type APC allele in extracolonic tumors in FAP patients, which strengthens the argument for their inclusion in the FAP syndrome.

Genetic testing for FAP

APC gene testing is now commercially available and has led to changes in management guidelines, particularly for those whose tests indicate they are not mutation carriers. Presymptomatic genetic diagnosis of FAP in at-risk individuals has been feasible with linkage [21] and direct detection [130] 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.[131]

Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[132,133] 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.[134]MYH gene testing may be considered in APC mutation–negative affected individuals.[135] (Refer to the Adenomatous polyposis coli [APC] section of this summary for more information.)

Patients who develop fewer than 100 colorectal adenomatous polyps are a diagnostic challenge. The differential diagnosis should include AFAP and MYH-associated colorectal neoplasia (also reported as MYH-associated polyposis or MAP).[136] AFAP can be diagnosed by testing for germline APC gene mutations. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section in the Major Genetic Syndromes section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.[137]

Presymptomatic genetic testing removes the necessity of annual screening of at-risk individuals who do not have the familial 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,[20] though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 years).[20,21] 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 and are too numerous or histologically advanced to monitor safely using endoscopic resection.

Interventions for FAP

Individuals at risk of FAP, because of a known APC mutation in either the family or themselves, are evaluated for onset of polyposis by flexible sigmoidoscopy or colonoscopy. Once an FAP family member is found to manifest polyps, the only effective management to prevent CRC is eventual colectomy. In patients with classic FAP identified very early in their course, the surgeon, endoscopist, and family may choose to delay surgery for several years in the interest of achieving social milestones. In addition, in carefully selected patients with AFAP (those with minimal polyp burden and advanced age), deferring a decision about colectomy may be reasonable with surgery performed only in the face of advancing polyp burden or dysplasia.

The recommended age at which surveillance for polyposis should begin involves a trade-off. On the one hand, someone who waits until the late teens to begin surveillance faces a remote possibility that a cancer will have developed at an earlier age. Although it is rare, CRC can develop in a teenager who carries an APC mutation. On the other hand, it is preferable to allow people at risk to develop emotionally before they are faced with a major surgical decision regarding the timing of colectomy. Therefore, surveillance is usually begun in the early teenage years (age 10–15 years). Surveillance has consisted of either flexible sigmoidoscopy or colonoscopy every year.[92,138,139] If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Historically, sigmoidoscopy may have been a reasonable approach at the time in identifying early adenomas in a majority of the patients. However, colonoscopy must be considered the tool of choice in light of (a) improved instrumentation for full colonoscopy, (b) safer and deeper sedation (Propofol), (c) recognition of AFAP, in which the disease is typically most manifest in the right colon, and (d) the growing tendency to defer surgery for a number of years. Individuals who have tested negative for an otherwise known family mutation do not need FAP-oriented surveillance at all. They are recommended to undergo average-risk population screening. In the case of families in which no family mutation has been identified in an affected person, then clinical surveillance is warranted. Colon surveillance should not be stopped in persons who are known to carry an APC mutation but who do not yet manifest polyps, since adenomas occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.) (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)

In some circumstances, full colonoscopy may be preferred over the more limited sigmoidoscopy. Among pediatric gastroenterologists, tolerability of endoscopic procedures in general has been regarded as improved with the use of deeper intravenous sedation.

Table 8 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP)
Organization APCGene Test Recommended Age Screening Initiated Frequency Method Comment
C = colonoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; NA = not addressed; NCCN = National Comprehensive Cancer Network.
a GI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.
American Society of Colon and Rectal Surgeons (2001, 2003)[140,141,142] Yes NA NA NA  
American Cancer Society (2002)[143] NA Puberty NA Endoscopy Referral to a center specializing in FAP screening suggested.
GI Societies (2003)a[138] Yes 10–12 y Annual FS  
NCCN (2014)[92] Yes 10–15 y Annual FS or C ConsiderMYHmutation testing ifAPCtesting is negative and family history is compatible with recessive inheritance; in families in which no mutation is found, offspring of those affected are screened as if they were carriers.

Once an FAP family member is found to manifest polyposis, colectomy is the only effective management. Patient and doctor should enter into an individualized discussion to decide when surgery should be performed. It is useful to incorporate into the discussion the risk of developing desmoid tumors after surgery. Timing of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology.[144] 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.[145] 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.[146]

Surgical options include restorative proctocolectomy with 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. There is no risk of developing rectal cancer after TPC because the whole mucosa at risk is removed. Whether a colectomy and an IRA or a restorative proctocolectomy is performed, most experts suggest that periodic and lifelong surveillance of the rectum or the ileal pouch be performed to remove or ablate any polyps. This is necessitated by case series of rectal cancers arising in the rectum of FAP patients who had subtotal colectomies with an IRA in which there was an approximately 25% cumulative risk of rectal adenocarcinoma 20 years after IRA and by case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy.[147,148,149,150] 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.[145] Other factors that have been reported to increase the rectal cancer risk after IRA include the presence of colon cancer at the time of IRA, the length of the rectal stump, and the duration of follow-up after IRA.[151,152,153,154,155,156,157] An abdominal colectomy with IRA as the primary surgery for FAP does not preclude later conversion to an IPAA for uncontrolled rectal polyps and/or rectal cancer. In the Danish Polyposis Registry, the morbidity and functional results of a secondary IPAA (after a previous IRA) in 24 patients were reported to be similar to those of 59 patients who underwent primary IPAA.[158]

In most cases, the clinical polyp burden in the rectum at the time of surgery dictates the type of surgical intervention, namely restorative proctocolectomy with IPAA versus IRA. Patients with a mild phenotype (<1,000 colonic adenomas) and fewer than 20 rectal polyps may be candidates for IRA at the time of prophylactic surgery.[159] In some cases, however, the polyp burden is equivocal, and in such cases, investigators have considered the role of genotype in predicting subsequent outcomes with respect to the rectum.[160] 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.[156,147,157,161] 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.[162,163] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[164] A meta-analysis of quality of life after 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.[165]

Celecoxib, a specific cyclooxygenase II (COX-2) inhibitor, and 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.[166,167] Although celecoxib had been approved by the U.S. Food and Drug Administration (FDA), its license was voluntarily withdrawn by the manufacturer. Currently, there are no FDA-approved drugs for chemoprevention in FAP. Nevertheless, agents such as celecoxib and sulindac are in sufficiently widespread use that chemopreventive clinical trials typically utilize one of these agents as the control arm.

A small, randomized, placebo-controlled, dose-escalation trial of celecoxib in a pediatric population (aged 10–14 years) demonstrated the safety of celecoxib at all dosing levels when administered over a 3-month period.[168] This study found a dose-dependent reduction in adenomatous polyp burden. At a dose of 16 mg/kg/day, which approximates the approved dose of 400 mg twice daily in adults, the reduction in polyp burden paralleled that demonstrated with celecoxib in adults.

Omega-3-polyunsaturated fatty acid eicosapentaenoic acid in the free fatty acid form has been shown to reduce rectal polyp number and size in a small study of patients with FAP post subtotal colectomy.[169] Although not directly compared in a randomized trial, the effect appeared to be similar in magnitude to that previously observed with celecoxib.

It is unclear at present how to incorporate COX-2 inhibitors into the management of FAP patients who have not yet undergone risk-reducing surgery. A double-blind, placebo-controlled trial in 41 APC mutation carrier children and young adults who had not yet manifested polyposis demonstrated that sulindac may not be effective as a primary treatment in FAP. There were no statistically significant differences between the sulindac and placebo groups over 4 years of treatment in incidence, number, or size of polyps.[167]

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.[170] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[171] The same issues surrounding the use of COX-2 inhibitors for the treatment of colonic polyps apply to 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).[170]

Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[172,173,174,175] it is unclear whether this class of agents will be safe for long-term use for patients with FAP and in the general population. Also, because of the short-term (6 months) nature of these trials, there is currently no clinical information about cardiac events in FAP patients taking COX-2 inhibitors on a long-term basis.

Level of evidence (celecoxib): 1

One cohort study has demonstrated regression of colonic and rectal adenomas with sulindac (an NSAID) treatment in FAP. The reported outcome of this trial was the number and size of polyps, a surrogate for the clinical outcome of main interest, CRC incidence.[176]

Level of evidence (sulindac): 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.[9,22] The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma.[79] (Refer to the Duodenum/small bowel tumors section and the Other tumors section in the Major Genetic Syndromes section of this summary for more information about screening for extracolonic malignancies in patients with FAP.)

Attenuated Familial Adenomatous Polyposis (AFAP)

AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. It was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, though they ranged in number from a few to hundreds.[177] Adenomas in AFAP are believed to form in the mid-twenties to late twenties.[65] Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years.[27,28,178] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (FGPs, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoids.[65]

AFAP is associated with particular subsets of APC mutations, including missense changes. Three groups of site-specific APC mutations causing AFAP have been characterized:[27,28,29,30,179,180]

  • 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 GI polyps.
  • Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
  • 3' region mutations in which patients have very few adenomas (<50).

APC gene testing is an important component of the evaluation of patients suspected of having AFAP.[181] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[181] The role for and timing of risk-reducing colectomy in AFAP is controversial.[182] If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.[132]

Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[183,184] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), LS, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or LS.

Table 9 summarizes the clinical practice guidelines from different professional societies regarding surveillance of AFAP.

Table 9. Clinical Practice Guidelines for Colon Surveillance of Attenuated Familial Adenomatous Polyposis (AFAP)
Organization Condition Screening Method Screening Frequency Age Screening Initiated Comment
IPPA = ileal pouch–anal anastomosis; IRA = ileorectal anastomosis; NCCN = National Comprehensive Cancer Network.
a Fewer than 20 adenomas that are each <1 cm in diameter and without advanced histology so that colonoscopy with polypectomy can be used to effectively eliminate the polyps.
Europe Mallorca Group (2008)[185] AFAP Colonoscopy Every 2 y; every 1 y if adenomas are detected 18–20 y  
NCCN (2014)[92] Personal history of AFAP with small adenoma burdena Colonoscopy Every 1–2 y   If patient had colectomy with IRA due to significant polyposis not manageable with polypectomy, endoscopic evaluation every 6–12 mo depending on polyp burden.
Colectomy and IRA may be considered in patients aged ?21 y
NCCN (2014)[92] Personal history of AFAP with significant polyposis Not applicable Not applicable Not applicable Colectomy with IRA preferred. Consider proctocolectomy with IPAA if dense rectal polyposis.
NCCN (2014)[92] Unaffected, at-risk family member; family mutation unknown;APCmutation status unknown or positive Colonoscopy Every 2–3 y Late teens  

MYH-Associated Polyposis (MAP)

MAP is an autosomal recessive inherited polyposis syndrome. The MYH gene was first identified in 2002 in three siblings with multiple colonic adenomas and CRC but no APC mutation.[137] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and LS.[186] MAP patients tend to develop fewer adenomas at a later age than patients with APC mutations [135,187] and also carry a high risk of CRC (35%–63%).[5,188] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MYH mutations of 4% (95% confidence interval [CI], 3%–5%) among those with 10 to 19 adenomas, 7% (95% CI, 6%–8%) among those with 20 to 99 adenomas, and 7% (95% CI, 6%–8%) among those with 100 to 999 adenomas.[189] This broad clinical presentation results from the MYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.[5,135,190,191]

Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients. The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[192] Clinical management guidelines for biallelic MAP range between once a year to every 3 years for colonoscopic surveillance beginning at age 18 to 30 years,[92,185,188] with upper endoscopic surveillance beginning at age 25 to 30 years.[185] (Refer to Table 10 for more information about available clinical practice guidelines for colon surveillance in biallelic MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria.[185] Total colectomy with ileorectal anastomosis or subtotal colectomy may be appropriate for patients with MYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.[188,193]

Table 10 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.

Table 10. Clinical Practice Guidelines for Colon Surveillance of BiallelicMYH-Associated Polyposis (MAP)
Organization Condition Screening Method Screening Frequency Age Screening Initiated Comment
IPAA = ileal pouch–anal anastomosis; IRA = ileorectal anastomosis; NCCN = National Comprehensive Cancer Network.
a Fewer than 20 adenomas that are each <1 cm in diameter and without advanced histology so that colonoscopy with polypectomy can be used to effectively eliminate the polyps.
Europe Mallorca Group (2008)[185] BiallelicMYHmutation carrier Colonoscopy Every 2 y 18–20 y  
Nieuwenhuis et al. (2012)[188] BiallelicMYHmutation carrier Colonoscopy Every 1–2 y    
NCCN (2014)[92] Personal history of MAP, small adenoma burdena Colonoscopy Every 1–2 y   If patient had colectomy with IRA due to significant polyposis not manageable with polypectomy, endoscopic evaluation every 6–12 mo depending on polyp burden.
Colectomy and IRA may be considered in patients aged ?21 y
NCCN (2014)[92] Personal history of MAP with significant polyposis Not applicable Not applicable Not applicable Colectomy with IRA preferred. Consider proctocolectomy with IPAA if dense rectal polyposis. If patient had colectomy with IRA, then endoscopic evaluation of rectum every 6–12 mo depending on polyp burden.
NCCN (2014)[92] Unaffected, at-risk family member; family mutation unknown;MYHmutation status unknown or positive (biallelic) Colonoscopy Every 2–3 y 25–30 y If positive for a singleMYHmutation, follow average-risk colorectal screening.

Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, and thyroid and skin cancers including melanoma, squamous epithelial, and basal cell carcinomas.[194,195] Additionally, extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[135,195,196,197] Female MAP patients have an increased risk of breast cancer.[198] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or LS.[199,200]

Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying a biallelic MYH mutation and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.

The clinical phenotype of monoallelic MYH mutations is less well characterized with respect to incidence and associated clinical phenotypes, and its role in pathogenesis of polyposis coli and colorectal carcinoma remains in dispute. Approximately 1% to 2% of the general population carry a deleterious mutation in MYH.[5,135,137] A 2011 meta-analysis found that monoallelic MYH mutation carriers are at modest increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98–1.36); however, given the rarity of monoallelic mutation carriers, they account for only a trivial proportion of all CRC cases.[201] Although some studies have suggested screening these individuals on the basis of this modest increase in risk,[187,202] others have suggested following screening recommendations for the general population.[92]

MMR genes may interact with MYH and increase the risk of CRC. An association between MYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 mutations in monoallelic MYH mutation carriers with CRC compared to noncarriers (11.5% vs. 0%; P = .037).[203]

Mut Y Homolog

The Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1.[192] The protein encoded by MYH is a base excision repair glycosylase. It repairs one of the most common forms of oxidative damage. Over 100 unique sequence variants of MYH have been reported (Leiden Open Variation Database). A founder mutation with ethnic differentiation is assumed for MYH mutations. In Caucasian populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations.[204] Other causative variants that have been found include P405L (formerly known as P391L) (Netherlands),[205,206] E480X (India),[190] Y104X (Pakistan),[207] 1395delGGA (Italy),[196] 1186-1187insGG (Portugal),[208] and p.A359V (Japan, Korea).[209,210,211] Biallelic MYH mutations are associated with a 93-fold excess risk of CRC, with near complete penetrance by age 60 years.[212]


Oligopolyposis is a popular term used to describe the clinical presentation of a polyp count or burden that is greater than anticipated in the course of screening in average-risk patients but that falls short of the requirement for a diagnosis of FAP. Thus, oligo-, Greek for few, can mean different things to different observers. While conceding a lack of consensus on the matter, the National Comprehensive Cancer Network (NCCN) committee on CRC screening suggests an AFAP diagnosis is worth considering when 10 to 100 adenomas are present.[92] It will be used here to describe the circumstance in which the polyp count (generally adenoma) is large enough, with or without any attendant family history, to raise in the mind of the endoscopist the possibility of an inherited susceptibility.

In the setting of known or suspected LS, the detection of one to ten adenomas is still in keeping with the diagnosis. A similar adenoma count in a young patient undergoing colonoscopy for symptoms or in a screening patient over age 50 years could raise the question of LS. In the appropriate clinical setting—early onset and positive family history—the detection of any number of adenomas may support the testing and diagnosis of a patient for underlying LS mutations, consistent with guidelines such as those offered by the NCCN. Some controversy exists over the utility of testing adenoma tissue for microsatellite instability (MSI), as the yield is lower than in invasive cancer.[213] In general, and subject to the above caveats, LS is not routinely considered in a discussion of oligopolyposis.

One study considered a series of polyps (37 adenomas) from 21 patients with known MMR mutations, performing MSI and immunohistochemistry (IHC) for MMR protein expression.[214] Overall, MSI-high (MSI-H) was seen in 41% and in 100% of adenomas larger than 1 cm. Adenomas measuring smaller than 1 cm yielded MSI about 30% of the time. Correlation between MSI and loss of staining on IHC was fairly high, although the discordance rate (17%) was higher than in other series that evaluated invasive cancers from known MMR mutation carriers. A higher MSI likelihood was observed in subjects older than 50 years. IHC staining in relation to mutation showed 8 of 12 MLH1 adenomas to have lost protein expression, with 10 of 20 adenomas from MSH2 patients to have loss of expression. In contrast, none (0 of 6) of the adenomas from MSH6 mutation carriers had loss of associated protein expression. The authors concluded that while normal MSI/IHC was simply not informative, abnormal MSI/IHC was as likely in larger (>8 mm) polyps as in cancers and thus a reasonable test to consider.

AFAP is found at the other end of the oligopolyposis spectrum. Most cases will have more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC mutation are clearly variant cases of FAP, as the term AFAP implies.[215] However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC mutation. The lower the polyp count the lower the probability of APC mutation. Some of these cases are now known to carry biallelic MYH mutations, although even here, the lower the adenoma count the lower the mutation likelihood.[216]

Another study evaluated 152 patients with 3 to 100 adenomas and another 107 APC mutation–negative patients with a "classic" FAP polyp burden for evidence of MYH mutations.[135] Six patients with multiple adenomas and eight with a classic FAP burden had biallelic MYH mutations. The authors concluded that a cut-point of about 15 adenomas was a threshold above which MYH testing was reasonable, and many insurance companies in the United States have adopted a policy based on this cumulative adenoma count. Similar mutation rates for MYH biallelic mutations were found by others using 20 adenomas as the threshold for considering testing.[216]

Mutations in related DNA polymerase genes POLE and POLD1 have been described in families with oligopolyposis and endometrial cancer.[217,218] An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative with CRC. All had negative APC, MYH, and MMR gene mutation test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic mutations in tumors were generally consistent with the otherwise typical chromosome instability (CIN) pathway, as opposed to MSI or CIMP. No extracolonic manifestations were seen. A similar approach, whole-genome testing for shared variants, with further "filtering" by linkage analysis identified a variant in the POLD1 gene, p.Ser478Asn alteration, c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to mutations related to base substitution.

The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternatives mutation testing is uninformative and surveillance akin to that afforded patients with LS or MAP.[217,218]POLE and POLD1 mutation testing is being incorporated into the new multigene CRC susceptibility panels offered commercially.

A majority of patients with oligopolyposis involving adenomas are currently not found to have an underlying predisposition when evaluated for mutations in known predisposition genes. Such cases are generally managed as if they are at an increased risk of recurrent adenomas even when the colon can be "cleared" of polyps endoscopically.

Oligopolyposis caused by juvenile polyposis syndrome (JPS) or PJS can readily be distinguished from adenomatous polyposis on simple endoscopic and histologic grounds. Serrated polyposis can present in highly variable fashion. The World Health Organization (WHO) criteria for serrated polyposis (?5 serrated polyps proximal to sigmoid with 2 ?1 cm, or any number of polyps proximal to sigmoid if there is a relative with serrated polyposis, or >20 serrated polyps anywhere in the colon) have never been validated. Furthermore, no genetic basis has been established, even in the uncommon familial cases. But cases of oligopolyposis of the serrated variety can initially be challenging to distinguish from oligoadenomatosis, particularly when there is an admixture of adenomas. Consequently, such patients are increasingly being referred for genetic counseling and for consideration of genetic testing. Occasional cases of MYH biallelic mutations have been found in patients with at least some features of serrated polyposis and serrated polyps can be seen in LS. Generally though, the genetic workup of serrated polyposis is unrewarding.[219,220,221,222,223]

Lynch Syndrome (LS)

Between 1900 and 1990, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset; high risk of second primary tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as Lynch 1 (families with CRC only), Lynch 2 (families with CRC and extracolonic tumors), cancer family syndrome, and later, hereditary nonpolyposis colorectal cancer (HNPCC), were commonly employed.

By 1990, the need for enhanced surveillance (colonoscopy at an early age and repeated frequently) was recognized. However, the need to limit this aggressive regimen to families most likely to have an inherited susceptibility or "true" HNPCC led to development of the so-called Amsterdam criteria: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50 years, and no evidence of FAP.

At about this same time, a chromosomal abnormality on 5q led to detecting genetic linkage between FAP and this genomic region, from which the APC gene was eventually cloned. This led to searches for similar linkage in HNPCC. The APC gene was one of several genes (along with DCC and MCC) evaluated and to which no HNPCC linkage was found. An extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large HNPCC families in 1993. Once MSH2, the first HNPCC gene, was sequenced, it was evident (from the somatic mutation patterns in the tumors) that the mismatch repair (MMR) family of genes was likely involved. Shortly thereafter, additional MMR genes were identified, including MLH1, MSH6, and PMS2. These MMR genes were formerly referred to as hMSH2, hMLH1, hMSH6, and hPMS2, with the "h" designating them as human homologs; for simplicity, the "h" was dropped.

Concurrent with the linkage studies, somatic genetic studies of HNPCC tumors showed evidence of characteristic mutations in microsatellite regions of numerous genes, which appeared to be a molecular marker of MMR deficiency. This was characterized with synonyms such as ubiquitous somatic mutations, replication errors, and eventually, the currently employed term microsatellite instability (MSI). In HNPCC-related tumors showing MSI, there is typically loss of immunohistochemical expression for one or more of the proteins associated with the MMR genes. Since IHC is relatively easy to perform, it can serve to complement or even supplant MSI screening of suspected HNPCC cases. Although MSI characterizes nearly all HNPCC tumors, it can also occur sporadically in about 12% of CRCs. These cases clearly do not have the inherited disorder HNPCC, since further studies have shown that the MSI is caused by somatic inactivation of the MLH1 protein by hypermethylation of the MLH1 promoter. In most instances, the sporadic nature of these cases can be confirmed by concurrent detection of somatic BRAF mutations in CRC tumor tissue.

Mutational testing for germline alterations has been somewhat disappointing, as no more than half of suspected HNPCC cases have detectable pathologic mutations. Because of this, and the lack of sufficiently specific clinical features, various genetic screening strategies have emerged to improve the yield of genetic testing. A sufficiently compelling family history, ideally complemented by the presence of MSI, warrants mutational testing, and most clinical practice guidelines provide for such an approach. The Bethesda guidelines are a combination of clinical, pathologic, and family history features that are sufficiently predictive to warrant MSI/IHC screening. Computer risk-assessment profiles have been developed to do this same work more quantifiably and can estimate mutation risk likelihood with or without the intermediate step of using MSI/IHC.

Against this background of potential clinical selection criteria for mutation testing, population studies have emerged that can estimate HNPCC frequency (1%–3%) and determine the performance characteristics of these same selection tools when implemented in otherwise unselected cases.

The combination of genetic counseling/testing strategies with clinical screening/treatment measures has led to the development of consensus clinical practice guidelines. These guidelines can be used by providers and patients alike to better understand the available options and key decision-points that exist. (Refer to Table 11 for more information about practice guidelines for diagnosis and colon surveillance in LS.)

Terminology related to familial CRC has certainly evolved. Most in the field use the term Lynch syndrome (LS) as a preferred synonym over HNPCC, since HNPCC is both excessively wordy and misleading—many patients have polyps and many have tumors other than CRC. In addition, entities such as Muir-Torre syndrome are now recognized as phenotypic variants of LS. Even Turcot syndrome, which was initially thought to only be an FAP variant, is now known to be an LS variant when it presents with glioblastomas and an FAP variant when it presents with medulloblastomas. It has been suggested that the term LS be applied to cases in which the genetic basis can be confidently linked to a germline mutation in a DNA MMR gene (either a germline mutation is present or can be confidently inferred based on the clinical presentation combined with MSI/IHC).[224]

The term "familial colorectal cancer type X" or "FCCX" was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities.[225] Some refer to FCCX as "Lynch-like syndrome." Complicating the terminology further, the term "Lynch-like" has also been used in cases with MSI-H tumors and presumed underlying MMR germline mutation, but in which no such mutation is detected.

In LS,[226,227,228] unlike FAP, most patients do not have an unusual number of polyps. LS accounts for about 1% to 3% of all CRCs.[229] LS is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors. LS is caused by mutations in the DNA MMR genes, namely MLH1, MSH2, MSH6, and PMS2. Mutations of the EPCAM gene that result in hypermethylation and silencing of MSH2 have also been described. (Refer to the MSI section in the Major Genetic Syndromes section of this summary for more information.) The average age of CRC diagnosis in LS mutation carriers is 44 to 52 years [229,230,231] and 71 years in sporadic CRC.[232] In mutation-positive families when probands were excluded and both affected and nonaffected relatives were ascertained, the average age at diagnosis of CRC was reported to be 61 years,[233] suggesting ascertainment bias in early reports.

The lifetime risk of CRC in MLH1 and MSH2 mutation carriers was 68.7% in males and 52% in females.[233] However, in a meta-analysis of three population-based studies and one clinic-based study, the lifetime risk of CRC in MLH1 and MSH2 mutation carriers was reported to be 53% in males and 33% in females.[234,235] In a study of 113 families with MSH6 mutation carriers, the estimated cumulative risk of CRC in males was 22% and 10% in females.[236]PMS2 lifetime CRC risk to age 70 years has been reported to be 20% in males and 15% in females.[237] A large registry-based study from France estimated CRC risk at age 70 years to be 41% for MLH1 mutation carriers, 48% for MSH2 mutation carriers, and 12% for MSH6 mutation carriers.[238]

These data have been largely retrospective and potentially include some biases for that reason. Some prospective data exist, however. The Colon Cancer Family Registry program followed 446 carriers prospectively and found a 10-year risk of CRC of 8%.[239]

Patients with LS can have synchronous and metachronous colorectal neoplasms and other primary extracolonic malignancies. LS mutation carriers have an increased risk of developing colon adenomas (hazard ratio [HR], 3.4), and the onset of adenomas appears to occur at a younger age than in nonmutation carriers from the same families.[240] Unlike patients with sporadic cancers, whose cancer develops most often in the left side of the colon, approximately two-thirds of LS cancers develop in the right side of the colon, defined as proximal to the splenic flexure.

The most common extracolonic malignancy in LS is endometrial adenocarcinoma, which affects at least one female member in about 50% of LS pedigrees. Fifty percent of women with a MMR gene mutation will present with endometrial cancer as their first malignancy.[241]

The lifetime risk of endometrial cancer has been estimated to be from 44% in MLH1 mutation carriers to 71% in MSH2 mutation carriers.[233,234,235,236,242] Families with an MSH6 mutation have been reported to have an endometrial cancer predominance. Lifetime risk of endometrial cancer in MSH6 mutation carriers in 113 families was estimated to be 26% at age 70 years and 44% at age 80 years.[236] In PMS2 mutation carriers, the endometrial cancer risk at age 70 years has been reported to be 15%.[237] The same prospective data collection in the Colon Cancer Family Registry program yielded 5-year endometrial cancer risks of about 3% and 10-year endometrial cancer risks of about 10% in women from this cohort.[239] Women with loss of MSH2 protein expression caused by an EPCAM mutation are also at risk of endometrial cancer. One study found a 12% (95% CI, 0%–27%) cumulative risk of endometrial cancer in EPCAM deletion carriers.[243] A study of 127 women with LS who had endometrial cancer as their index cancer were found to be at significantly increased risk of other cancers. The following elevated risks were reported: CRC, 48% (95% CI, 27.2%–58.3%); kidney, renal pelvis, and ureter cancer, 28% (95% CI, 11.9%–48.6%); urinary bladder cancer, 24.3% (95% CI, 8.56%–42.9%; and breast cancer, 2.51% (95% CI, 1.17%–4.14%).[244]

LS-associated endometrial cancer is not limited to the endometrioid subtype. It most commonly arises from the lower uterine segment. Endometrial adenocarcinoma, clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed Müllerian tumors are part of the spectrum of uterine tumors in LS.[245] Three cases of endometrial cancer arising from endometriosis in women with LS have been reported.[246] (Refer to the Screening for endometrial cancer in LS families section of this summary for information about screening methods.)

Several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis and cancers of the stomach, small intestine, liver and biliary tract, brain, breast, ovary, prostate, and adrenal cortex.[247,248,249,250,251,252,253] The largest prospective study to date is of 446 unaffected mutation carriers from the Colon Cancer Family Registry.[239] Participants who were followed for up to 10 years demonstrated an increased standardized incidence ratio (SIR) for colorectal, endometrial, ovarian, gastric, renal, bladder, pancreatic, and breast cancers.[239] With the exception of colorectal, endometrial, and breast cancers, the number of observed cases was very small for most cancers (i.e., two to three cases), resulting in very wide 95% CIs.

The issue of breast cancer risk in LS has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with LS;[254,255,256,257] one of these studies evaluated breast cancer risk in individuals with LS and found that it is not elevated.[257] However, the largest prospective study to date of 446 unaffected mutation carriers from the Colon Cancer Family Registry [239] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[239] The same group subsequently analyzed data on 764 MMR gene mutation carriers with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[258] However, further studies are needed to define absolute risks and age distribution before surveillance guidelines for breast cancer can be developed for MMR mutation carriers.

Prostate cancer was found to be associated with LS in a study of 198 families from two U.S. LS registries in which prostate cancer had not originally been part of the family selection criteria. Prostate cancer risk in relatives of MMR gene mutation carriers was 6.3% at age 60 years and 30% at age 80 years, versus a population risk of 2.6% at age 60 years and 18% at age 80 years, with an overall hazard ratio of 1.99 (95% CI, 1.31–3.03). Notwithstanding prevalent controversy surrounding routine prostate-specific antigen (PSA) screening, the authors suggested that screening by means of PSA and digital rectal exam (DRE) beginning at age 40 years in male MMR gene carriers would be "reasonable to consider."[253]

Another study assessed a series of 114 adrenocortical carcinomas (ACCs). Of 94 patients who had a detailed family history assessment and in whom Li-Fraumeni syndrome testing was nondiagnostic, 3 patients had family histories that were suggestive of LS. The prevalence of MMR gene mutations in 94 families was 3.2%, similar to proportion of LS among unselected colorectal and endometrial cancer patients. In a retrospective review of 135 MMR gene mutation–positive LS families from the same program, two probands were found to have had a history of ACC. Of the four ACCs in which MSI testing could be performed, all were microsatellite stable (MSS). These data suggest that if LS is otherwise suspected in an ACC index case, an initial evaluation of the ACC using MSI or IHC testing may be misleading.[252]

Muir-Torre syndrome is considered a variant of LS and includes a phenotype of multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas). The skin lesions and CRC define the phenotype,[259,260] and clinical variability is common. Both mutations in the MSH2 and MLH1 genes have been found in Muir-Torre families.[261,262,263] A study of 1,914 MSH2 and MLH1 unrelated probands found MSH2 to be more common in individuals with the Muir-Torre syndrome phenotype.[264]

Historical criteria for defining LS families

The research criteria for defining LS families were established by the International Collaborative Group (ICG) meeting in Amsterdam in 1990 and are known as the Amsterdam criteria.[265] These criteria were limited to CRC. In 1999, the Amsterdam criteria were revised to include some extracolonic cancers.[266] These criteria provide a general approach to identifying LS families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline MMR gene mutations, have been reported.

Amsterdam criteria I (1990):

  1. One member diagnosed with CRC 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.

Amsterdam criteria II (1999):

  • Same as Amsterdam criteria I, but tumors of the endometrium, small bowel, ureter, or renal pelvis can be used to substitute an otherwise qualifying CRC.

Although these criteria are the most stringent used to identify potential candidates for microsatellite and germline testing, it must be cautioned that by definition, FCCX includes families meeting Amsterdam criteria but in whom there is no evidence of MSI. (Refer to the Familial colorectal cancer type X [FCCX] section in the Major Genetic Syndromes section of this summary for more information.)

Recognizing both the relative insensitivity of the Amsterdam criteria and the increasing importance of tumor-based testing for detecting LS, the Bethesda guidelines were developed. The Bethesda guidelines and a subsequent revision were formulated to improve sensitivity by targeting patients whose tumors would be most likely to show MSI.[267,268] (Refer to the Genetic/molecular Testing for LS section in the Major Genetic Syndromes section of this summary for more information about testing for MSI and IHC.)

Bethesda guidelines (1997):

  1. Cancer in families that meet the Amsterdam criteria.
  2. The presence of two LS-related cancers, including synchronous and metachronous CRCs or associated extracolonic cancers. Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cell carcinoma of the renal pelvis or ureter.
  3. The presence of CRC and a first-degree relative with CRC and/or LS-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed before age 45 years, and the adenoma diagnosed before age 40 years.
  4. CRC or endometrial cancer diagnosed before age 45 years.
  5. Right-sided CRC with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed before age 45 years. Solid/cribriform defined as poorly differentiated or undifferentiated carcinoma composed of irregular, solid sheets of large eosinophilic cells and containing small gland-like spaces.
  6. Signet-ring-cell-type CRC diagnosed before age 45 years. Composed of more than 50% signet ring cells.
  7. Adenomas diagnosed before age 40 years.

Revised Bethesda Guidelines (2004)*:

  1. CRC diagnosed in an individual younger than 50 years.
  2. Presence of synchronous, metachronous colorectal, or other LS-associated tumors.**
  3. CRC with MSI-H pathologic associated features diagnosed in an individual younger than 60 years. Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.
  4. CRC or LS-associated tumor** diagnosed in at least one first-degree relative younger than 50 years.
  5. CRC or LS-associated tumor** diagnosed at any age in two first-degree or second-degree relatives.

*One criterion must be met to consider the tumor for MSI testing.

**LS-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[268,269] Data from the Cancer Family Registry suggest that breast and prostate cancers may also be considered in the spectrum of LS-associated tumors.[258]

Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are MSS. A number of these families have been found to have mutations in MSH6.[270,271,272,273,274] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.

Currently, there is a move toward universal testing of colorectal and endometrial tumors.[275] (Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section for more information.)

Genetic/molecular testing for LS

Genetic risk assessment of LS generally considers the cancer family history and age at diagnosis of CRC and/or other LS-associated cancers in the patient. Studies of gene testing using DNA sequencing in suspected LS probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative MSH2 or MLH1 mutation, allowing genetically informed management strategies to be developed for the family.[276,277] Computer models analogous to BRCAPro predict the probability of a MMR gene mutation. PREMM1, PREMM2, PREMM6, and the MMRPro models are easy to use and have been validated.[278,279,280,281] Although these models can predict mutation even in the absence of MSI or IHC information, they can incorporate those data as available. All three computer prediction models take family history of endometrial cancer into account. The mutation detection rate is higher for patients with more striking family histories or with informative tumor testing.

In the absence of additional family or personal history suggestive of LS, isolated cases of CRC diagnosed before age 36 years are uncommonly associated with MMR gene mutations. One study found MMR mutations in only 6.5% of such individuals.[282] Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline mutation analysis.

MSI/IHC in adenomas

Current practice is to offer colonoscopy surveillance to those with strong family histories but no prior genetic or tumor testing. At times, adenomas are detected during these colonoscopies. In the instance when an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR mutations found 8 of 12 adenomas to have both MSI and IHC protein loss.[283] However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude LS.


Microsatellites are short, repetitive sequences of DNA (often mononucleotides, dinucleotides, or trinucleotides) located throughout the genome, primarily in intronic sequences.[284,285] The term microsatellite instability (MSI) is used when tumor DNA shows alterations in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic or germline mutations or epigenetic alterations.[286] In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all MSI-H tumors.

Certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. These histologic features have been combined into computational scores that have high predictive value in identifying MSI CRCs.[287,288]

Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma showing MSI depends, in part, on the detection of a specified percentage of unstable loci from a panel of dinucleotide and mononucleotide repeats that were selected at a National Institutes of Health (NIH) Consensus Conference.[289] If more than 30% of a tumor's markers are unstable, it is scored as MSI-H; if at least one, but fewer than 30% of markers are unstable, the tumor is designated MSI-low (MSI-L). If no loci are unstable, the tumor is designated MSS. Most tumors arising in the setting of LS will be MSI-H.[289] The clinical relevance of MSI-L tumors remains controversial. The probability of finding a germline mutation in a MMR gene in this setting is very small. One distinction is that people with germline mutations in MSH6 do not necessarily manifest the MSI-H phenotype. One study presented evidence that MSH6 mutations were associated with cancers having an MSI-L phenotype.[272] However, a second study found that 18 of 21 (86%) of CRCs in MSH6 carriers showed MSI-H.[290] In addition, in sporadic cancers with MSI-L phenotype, MSH6 mutations were not found.[291]

(Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section of this summary for information about the utilization of MSI status in the diagnostic work-up of a patient with suspected LS.)

(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about the practice and feasibility of universal testing and issues related to informed consent for MSI and IHC testing.)

The complexity of aberrant methylation of MMR genes

AberrantMLH1methylation in sporadic CRC

The presence of an MSI-H tumor associated with loss of MSH2, MSH6, or PMS2 protein expression strongly supports a diagnosis of LS. However, MSI-H tumors with absent MLH1 protein expression present a more complex scenario. MSI occurs in approximately 10% to 15% of sporadic CRC (generally, patients aged >50 years and with little or no family history). In sporadic CRC, absent MLH1 protein expression is a consequence of aberrant MLH1 methylation, a somatic event confined to the tumor that in the vast majority of cases is not heritable. Since loss of MLH1 protein expression occurs in both LS and sporadic tumors, its specificity for predicting germline MMR gene mutations is lower than for the other MMR proteins.

Because of this uncertainty, additional molecular testing is often necessary to clarify the etiology of MLH1 absence in these cases. Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals with germline mutations in one of the MMR genes are BRAF mutations and MLH1 promoter methylation.

Aberrant methylation of MLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers.[292] Other mechanisms such as somatic MLH1 mutations may be responsible for the minority of cases where aberrant MLH1 methylation is absent.[292] In most studies, aberrant MLH1 methylation has been detected in only a small percentage of LS colon cancers in individuals with germline mutations in MLH1.[292,293,294,295] Thus, detection of aberrantly methylated MLH1 in colon cancer is more suggestive of a sporadic MSI tumor. Since assays of methylation are complex and resource-intensive, surrogate markers of MLH1 methylation have been examined. One study found that loss of immunohistochemical staining for p16 correlated strongly with both MLH1 methylation and BRAF V600E mutations (BRAF mutations are discussed in detail in the following paragraphs). However, only 30% of sporadic tumors examined in this study exhibited loss of p16 expression, limiting the utility of this assay.[296]

BRAF mutations have been detected predominantly in sporadic MSI tumors.[297,298,299,300] This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing. MLH1 hypermethylation and/or BRAF mutation testing are increasingly utilized in universal LS testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caused by hypermethylation and germline MLH1 mutations.

(Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section of this summary for more information about the clinical role of BRAF and hypermethylation testing.)


Reports of patients with germline MLH1 hypermethylation should not be confused with EPCAM mutation-induced hypermethylation of MSH2, as described below. Prior paragraphs have emphasized the issues associated with the common, acquired somatic hypermethylation of the MLH1 promoter. However, examples of hypermethylation of the MLH1 promoter described in the germline have generally not been associated with a stable Mendelian inheritance.

A comprehensive review of MLH1 constitutional epigenetic alterations involving hypermethylation of one MLH1 allele has been published.[301] Such epimutations are seen in patients with early-onset LS and/or multiple tumors of the LS type. Germline sequence variations or rearrangements are not seen in these patients, although the tumors show MSI-H, loss of MLH1 protein expression, and an absence of BRAF V600E mutations. These patients commonly have no family history of LS-like tumors. Interestingly, inheritance appears to be maternal, and therefore non-Mendelian. The constitutional monoallelic hypermethylation may appear as a mosaic, involving different tissues to a varying extent. In addition, the constitutional epimutation is typically reversible in the course of meiosis, such that offspring are usually unaffected. Because inheritance has been demonstrated in very few families, performing genetic counseling and genetic testing (which requires specialized research techniques) is particularly challenging.


Tumors with MSI and loss of MSH2 protein expression are generally indicative of an underlying MSH2 germline mutation (inferred MSH2 mutation). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter. Nevertheless, in at least 30% to 40% of these cases of inferred MSH2 mutation, no germline mutation can be detected with state-of-the-art technology. One Chinese family with tumors showing MSH2 loss was found to have allele-specific hypermethylation that appeared to have been an inherited phenomenon.[302] Another study of a family with MSH2-deficient MSI-high tumors employed the commonly used diagnostic MLPA analysis of MSH6 and also showed reduced expression of MSH6. In doing so, a decrease in signal was observed for exon 9 of the EPCAM (TACSTD1) gene, which is near MSH2. Use of additional MLPA probes located between exon 3 of EPCAM and exon 1 of MSH2 demonstrated that the deletion spanned most 3' exons of EPCAM, but spared the MSH2 promoter.[303] The mutation in EPCAM was found to induce the observed methylation of the MSH2 promoter by transcription across a CpG island within the promoter region. The presence of EPCAM mutations showing similar methylation-mediated MSH2 loss was found at about the same time in families from Hungary.[304]. On the strength of these observations, EPCAM testing has already been introduced clinically for patients with loss of MSH2 protein expression in their CRCs who lack detectable MSH2 germline mutation. One study of two families with the same EPCAM deletion found few extracolonic cancers and no endometrial cancers.[305] However, a subsequent study demonstrated that women with MSH2 protein expression loss caused by EPCAM mutations are also at risk of endometrial cancer.[243]


A complementary and perhaps even alternative approach to MSI is to test the tumor by IHC for protein expression using monoclonal antibodies of the MSH2, MLH1, MSH6, and PMS2 proteins. Loss of expression of these proteins appears to correlate with the presence of MSI and may suggest which specific MMR gene is altered in a particular patient.[306,307,308,309]

(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about issues related to informed consent for MSI and IHC testing.)

Tumor testing for suspected LS

It appears that clinical practice has shifted from reliance on MSI in the early days of tumor testing to increasing, and in many cases exclusive, reliance on IHC currently. Using both of these tests increases the sensitivity of the initial screen and improves quality assurance; therefore, many laboratories assess both MSI and IHC initially. However, because these tests are so commonly regarded as simple alternatives, cost-effectiveness considerations seem to support IHC and account for its preferential use. Part of this rationale is that the information provided by IHC may direct testing toward a specific MMR gene (the one with loss of protein expression) as opposed to comprehensive testing that would be necessitated by the use of MSI alone.[229,230,310,311,312,313] 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.[314] Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories.[230] To identify a more efficient screening approach, the strategy of performing IHC staining only for PMS2 and MSH6 has been considered, on the assumption that negative staining of either of these would, in most instances, detect the majority of cases of LS.[315] This approach may be more appropriate when all tumors are being screened (universal testing). Although this strategy appears attractive from the standpoint of efficiency, staining for all four MMR proteins remains the current standard of care. Further studies are necessary to validate the utility of the two-protein approach. (Refer to the Diagnostic strategies for all individuals diagnosed with CRC [universal testing] section of this summary for more information.)

Even in centers that rely exclusively on IHC testing, there may be a role for subsequent MSI testing in cases in which the clinical picture suggests LS, notwithstanding the results of IHC.

If greatest weight is given to clinical selection considerations (i.e., Bethesda guidelines being met), then IHC combined with MSI may be appropriate. In fact, in a truly high-risk population (Amsterdam criteria being met), any strategy may be acceptable, including germline testing without the benefit of tumor testing first. (Refer to the Genetic/molecular Testing for LS section of this summary for information about models.) However, as more institutions are adopting universal testing using MSI or IHC, perhaps in part based on some of the outlier (older, family history-negative) cases reported [230,310,314] or in part based on prognostic considerations (MSI-H having better prognosis), concerns about cost effectiveness of screening commonly dictate a more truncated approach. Thus, in a relatively low-risk population of patients with CRC, a screen with IHC or MSI alone may be adequate in cases of normal staining or MSS tumor.

(Refer to the Universal MSI/IHC colorectal cancer screening in clinical practice section of this summary for information about issues related to informed consent for MSI and IHC testing.)

Other techniques

In instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC, germline mutation analysis of MLH1, MSH2, and MSH6 may be considered. This approach is, however, time consuming and expensive. Strategies to screen for mutations using heteroduplex analysis-based techniques have been explored. These techniques are limited by the need to perform DNA sequencing as a subsequent step on all aberrant samples detected in screening. Additionally, such techniques frequently detect numerous variants of uncertain significance. They cannot, therefore, be recommended for routine clinical use at this time.[316]

Genetic testing

Genetic testing for germline mutations in MLH1, MSH2, MSH6, and PMS2 can help formulate appropriate intervention strategies for the affected mutation-positive individual and at-risk family members.

If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members (referred to as predictive testing). Family members who test negative for the familial mutation are generally not at increased risk of CRC or other LS-associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial mutation should follow surveillance and management guidelines for LS. (Refer to the Interventions for LS section of this summary for more information.)

If no mutation is identified in the affected family member, then testing is considered uninformative for the individual and at-risk family members. This would not exclude an inherited susceptibility to colon cancer in the family but rather could indicate that current gene testing technology is not sensitive enough to detect the mutation in the genes tested. The current sensitivity of testing is between 50% and 95%, depending on the methodology used. Mutation testing utilizing sequencing alone will not detect large genomic rearrangements in MSH2 or MLH1 that may be present in a significant number of LS probands.[317,318,319] An assessment of 365 probands with suspected LS showed 153 probands with germline mutations in MLH1 or MSH2, 12 of 67 (17.9%) and 39 of 86 (45.3%) of which were large genomic alterations in MLH1 and MSH2, respectively.[320] Such mutations can be detected by MLPA or Southern blotting (MLPA has largely replaced Southern blotting).[321,322] MLPA analysis of MLH1, MSH2, and MSH6 is commercially available and should be performed in cases in which no mutation is detected by sequence analysis.

Alternatively, the family could have a mutation in a yet-unidentified gene that causes LS or a predisposition to colon cancer. Another explanation for a negative mutation test is that, by chance, the individual tested in the family has developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case), while the other cases in the family are really the result of a germline mutation. If this scenario is suspected, testing another affected individual is recommended. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis. If no mutation can be identified in an affected family member, testing should not be offered to at-risk members. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions for LS section of this summary for more information.)

DNA MMR genes

LS is caused by mutation of one of several DNA MMR genes.[323,324,325,326,327,328,329] The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in LS include MSH2 (mutS homolog 2) on chromosome 2p22-21;[326,327]MLH1 (mutL homolog 1) on chromosome 3p21;[325]PMS2 (postmeiotic segregation 2) on chromosome 7p22;[329,330] and MSH6 on chromosome 2p16. The genes MSH2 and MLH1 are thought to account for most mutations of the MMR genes found in LS families.[331,332]

A variety of LS-associated mutations in MSH2 and MLH1 have been identified. These include founder mutations in the Ashkenazi Jewish, Finnish, Portuguese, and German American populations.[318,332,333,334,335,336] The wide distribution of the mutations in the two genes preclude simple gene testing assays (i.e., assays that would identify only a few mutations). Commercial testing is available to search for mutations in MSH2, MLH1, MSH6, and most recently for PMS2. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for MSH2 and MLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in LS, methods such as Southern blot or MLPA,[337] for detection of large deletions, are being used.[338] (Refer to the Genetic/molecular testing for LS section of this summary for more information about issues to be considered in testing for these mutations.)



MLH1 and MSH2 make up the majority of LS mutations. Up to 50% of mutation-positive LS families harbor an MLH1 mutation, with some geographic variation.[339]

Genotype-phenotype correlations

MLH1 mutations have been associated with the entire spectrum of malignancies associated with LS.[339] The lifetime risk of CRC in MLH1 mutation carriers is estimated to be 41% to 68%.[233,238,340] The lifetime risk of endometrial cancer is estimated to be approximately 40%.[3,238] Muir-Torre syndrome is less commonly associated with MLH1 mutations than are MSH2 mutations.[264]

Practices and pitfalls in testing

In contrast to the scenario of MSI associated with loss of expression of MSH2, MSH6 or PMS2, absence of MLH1 expression is not specific to LS. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Therefore, absent MLH1 expression is less specific for LS than absence of the other MMR proteins. In addition, rare instances of inherited germline MLH1 methylation have added further complexity to the interpretation of MSI associated with absence of MLH1 expression. (Refer to the Microsatellite instability [MSI] section for more information about germline MLH1 hypermethylation.)



The prevalence of MSH2 mutations in individuals or families with LS has varied across studies. MSH2 mutations were reported in 38% to 54% of LS families in studies including large cancer registries, cohorts of early-onset CRC (<55 years), and registries around the world.[235,279]

Genotype-phenotype correlations

The lifetime risk of colon cancer associated with MSH2 mutations is estimated to be between 48% and 68%.[233,238,340] In a case series of LS patients, those carrying germline MSH2 mutations (49 individuals, 45% females) had a lifetime (cutoff of age 60 years) risk of extracolonic cancers of 48% compared with 11% for MLH1 carriers (56 individuals, 50% females).[341] In addition, the same group reported a significantly higher prevalence of poorly differentiated CRCs (44% for MSH2 carriers vs. 14% for MLH1 carriers; P = .002) and Crohn-like reaction (49% for MSH2 carriers vs. 27% for MLH1 carriers; P = .049). Another study reported no significant differences between the prevalence of colorectal and extracolonic cancers in 22 families with germline MLH1 mutations and in 12 families with germline MSH2 mutations.[342]

Multiple groups have reported that MSH2 and MSH6 carriers have a greater chance of presenting with endometrial cancers before CRCs than do MLH1 carriers.[3,270,343] The average age at diagnosis of endometrial cancers differed with genotype in two studies: age 41 years for MSH2 , age 49 years for MLH1, and age 55 years for MSH6 carriers.[344,345] In contrast with early data indicating no increased risk of endometrial cancer, a 2011 study suggests that there may be an increased risk in patients with EPCAM mutations.[243]

Practices and pitfalls in testing

In patients with absence of MSH2 and MSH6 protein expression who have undergone genetic testing with no mutation found by the currently available standard techniques, germline mutation testing for EPCAM/TACSTD1 should be considered. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 mutation identified will have germline deletions in EPCAM/TACSTD1.[346] The latter mechanism accounts for approximately 5% of all LS cases.[346] (Refer to the EPCAM/TACSTD1 section of this summary for more information.)



Most series show a prevalence of germline MSH6 mutations in approximately 10% of LS families. However, the reported range (5%–52%) is large.[270,273,274,347,348,349,350] This wide variation is likely a result of small sample sizes, referral bias, and ascertainment bias.

Genotype-phenotype correlations

The lifetime risk of colon cancer associated with MSH6 mutations is estimated to be between 12% and 22%.[236,238] The lifetime risk of CRC might be lower in MSH6 carriers than in MSH2 and MLH1 carriers. Initial studies have suggested that inactivating germline mutations of MSH6 might be more frequent in persons with a later average age at onset of CRC whose tumors exhibit a non-MSI-H phenotype.

One study reported on 146 MSH6 carriers (59 men and 87 women) from 20 families, all of whom had truncating mutations in MSH6. While the prevalence of CRCs by age 70 years was not significantly different between MSH6 and MLH1 or MSH2 carriers (P = .0854), the mean age at diagnosis for colorectal carcinoma in male MSH6 mutation carriers was 55 years (n = 21; range, 26–84 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively. The prevalence of CRC was significantly lower in women with MSH6 germline mutations than in MLH1 or MSH2 carriers (P = .0049). The mean age at diagnosis for colorectal carcinoma in female MSH6 mutation carriers was 57 years (n = 15; range, 41–81 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively.[290]

In addition, endometrial cancer has been reported to be more common in MSH6 families. In the same study, the cumulative risk of uterine cancer was significantly higher in MSH6 mutation carriers (71%) than in MLH1 (27%) and MSH2 (40%) mutation carriers (P = .02). The mean age at diagnosis of endometrial carcinoma was 54 years in MSH6 mutation carriers (n = 29; range, 43–65 years) versus 48 years and 49 years in MLH1 and MSH2 mutation carriers, respectively.[290] A group of researchers reported on ten MSH6 kindreds with LS in which 70% of females had been diagnosed with endometrial cancer compared with 31% and 29% in MLH1 and MSH2 carriers, respectively.[343] One study found the prevalence of endometrial carcinoma to be 58% in 12 MSH6 families with a mean age at diagnosis of 57 years.[348]

One group of researchers assembled the largest series of MSH6 mutation carrier families to estimate penetrance of cancers.[236] A total of 113 families of MSH6 mutation carriers from five countries were ascertained through family cancer clinics and population-based cancer registries. The families contained an estimated 1,043 mutation carriers. By age 70 years, 22% (95% CI, 14%–32%) of male MSH6 mutation carriers developed CRC compared with 10% (95% CI, 5%–17%) of female MSH6 mutation carriers. By age 80 years, 44% (95% CI, 28%–62%) of male MSH6 mutation carriers were diagnosed with CRC, compared with 20% (95% CI, 11%–35%) of female MSH6 mutation carriers. For all MSH6 mutation carriers, the increased risk of CRC, relative to that of the general population, across all age groups was statistically significantly elevated (HR, 7.6; 95% CI, 5.4–10.8; P < .001). By ages 70 years and 80 years, 26% (95% CI, 18%–36%) and 44% (95% CI, 30%–58%), respectively, of women would be diagnosed with endometrial cancer. Female MSH6 mutation carriers had an endometrial cancer risk that was about 25 times higher than women in the general population (HR, 25.5; 95% CI, 16.8–38.7; P < .001).

In the same study, female MSH6 mutation carriers had a cumulative risk of other Lynch cancers (i.e., ovarian, stomach, small intestine, kidney, ureter, or brain) of 11% (95% CI, 6%–19%) by age 70 years and 22% (95% CI, 12%–38%) by age 80 years.[236] The risk of LS cancers, excluding colorectal and endometrial cancers, was six times that of the general population (HR, 6.0; 95% CI, 3.4–10.7; P < .001). Male MSH6 mutation carriers showed no evidence of an increased risk of these cancers (HR, 0.8; 95% CI, 0.1–8.8; P = .9). The authors estimated that 24% (95% CI, 16%–37%) of men and 40% (95% CI, 32%–52%) of women harboring deleterious MSH6 mutations would be diagnosed with any LS cancer by age 70 years and that these values will increase to 47% (95% CI, 2%– 66%) of men and 65% (95% CI, 53%–78%) of women by age 80 years.

Practices and pitfalls in testing

One study reported that of 42 population-based probands harboring deleterious MSH6 germline mutations who were ascertained independent of their family cancer history, 30 (71%) had a family cancer history that did not meet the Amsterdam II criteria.[236]

MSH6 colorectal tumors can be MSI-H, MSI-L, or MSS. This pitfall illustrates the utility of IHC for the MMR protein expression. Eighteen of 21 (86%) of the colorectal tumors showed an MSI-H phenotype. Of the 16 endometrial tumors tested, 11 were MSI-H (69%); four were MSI-L (25%), and one was MSS (6%).[290]

In endometrial cancers with germline MSH2 mutations, loss of MSH6 frequently occurs with loss of MSH2.[345,351]



The prevalence of PMS2 germline mutations has been underappreciated for many reasons. It is the most recent of the major genes to be identified, probably has the lowest prevalence, was not felt to be worthy of serious investigation, and commercial testing is not widely available.[352,353,354] One registry study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected LS.[355] A population-based study reported a prevalence of approximately 5% (1 of 18).[229]

Genotype-phenotype correlations

A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 mutations, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.[234]

In one study, patients with PMS2 mutations presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 mutations. However, these families were small and did not fulfill Amsterdam criteria.[355]

Polymorphisms in Unrelated Genes Affecting Expression in LS

Polymorphisms potentially affecting expression in MMR genes fall into two categories: those whose mechanisms are already suspected to have an effect on cancer-related pathways, and those that are truly anonymous. Several candidate genes have been studied. Anonymous genes have also been evaluated.

Studies have demonstrated that a polymorphism in the promoter region of the insulin-like growth factor 1 (IGF1) gene modifies age of onset of CRC in LS.[356,357] The polymorphism is a variable number of CA-dinucleotide repeats approximately 1 kb upstream of the transcription start site of IGF1. There is significant variability between individuals and populations with respect to repeat length. Carriers of shorter repeat lengths (shortest allele ?17 repeats) develop CRC on average 12 years earlier than those with longer repeat lengths. It is unclear whether this polymorphism influences extracolonic malignancies. Additionally, the cyclin D1 polymorphism G870A may be associated with earlier age of onset of CRC in LS,[358,359] although the association appears to be more reproducible in MSH2 mutation carriers than in MLH1 mutation carriers.[359,360]

Two single nucleotide polymorphisms (SNPs) identified in genome-wide association studies have been reported to increase CRC risk in MMR gene mutation carriers. (Refer to the Genome-wide searches section of this summary for more information.) Having the C-allele of either SNP increased the risk of CRC in a dose-dependent fashion (with homozygotes at a higher risk than heterozygotes). The first SNP in 8q23.3 increased CRC risk 2.16-fold for homozygote carriers of the SNP. The second SNP, located in 11q23.1, increased CRC risk only in female SNP carriers by 3.08 for homozygotes and 1.49 for heterozygote SNP carriers.[361]

In a study of 684 mutation carriers from 298 Australian and Polish families, nine SNPs within six previous CRC susceptibility loci were genotyped to investigate their potential as modifiers of disease risk in LS.[362] Two SNPs, rs3802842 (11q23.1) and rs16892766 (8q23.3), were associated with CRC susceptibility in MLH1 mutation–positive LS patients. However, a subsequent study of 748 French MMR mutation carriers did not replicate the association between the IGF1 CA repeat and age of CRC onset or the association between SNPs in 8q23.3 and 11q23.1 and CRC risk.[363]

Given the inconsistent results of these studies, genetic testing for these polymorphisms has no clinical utility at present.

Diagnostic strategies for all individuals diagnosed with CRC (universal testing)

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention, formed a working group to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The Working Group was commissioned to address the following question: Do risk assessment and MMR gene mutation testing in individuals with newly diagnosed CRC lead to improved outcomes for the patient or relatives, or are they useful in medical, personal, or public health decision-making?[364,365] The Working Group constructed economic models to assist in analyzing available evidence on clinical utility in estimating how various testing strategies might function in practice. These included mutation frequency, sensitivity and specificity of both IHC and MSI testing, and the cost of these tests. The performance of these tests is based on the risk of positivity of carrying a mutation including family history, age at diagnosis, and extracolonic cancers. In 2009, the Working Group reported that there was sufficient evidence to recommend offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives. They concluded that there was insufficient evidence to recommend a specific gene-testing strategy among the following four strategies tested:[364,365]

  1. All individuals with CRC tested for germline mutations in MSH2, MLH1, and MSH6. The average cost per LS detected was estimated to be $111,825.
  2. All tumors tested for MSI, followed by germline mutation analysis of MSH2, MLH1, and MSH6 offered to those with MSI-H tumors. The average cost per LS detected was estimated to be $47,268.
  3. All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2, followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. The average cost per LS detected was estimated to be $21,315.
  4. All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF mutation–negative tumors. The average cost per LS detected was estimated to be $18,863.[365]

The EGAPP analysis made several assumptions, including (1) IHC and MSI will not detect all LS patients and (2) not all patients with CRC will opt for testing.

Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify LS among persons with newly diagnosed CRC.[366] The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline mutation testing followed by directed screening and risk-reducing surgery. Similar to the EGAPP working group, IHC followed by BRAF mutation testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life year gained resulted from this strategy. In this model, the number of relatives tested (3 to 4) per proband was a critical determinant of both effectiveness and cost-effectiveness.

A different approach based on risk assessments of 100,000 simulated individuals representative of the U.S. population who were tracked from age 20 and exposed to 20 different screening strategies has been reported.[367] In this study, the strategies involved risk assessment at different ages utilizing the PREMM126 model followed by mutation analysis for MLH1, MSH2, MSH6, and PMS2 in individuals whose mutation risk threshold exceeded 0%, 2.5%, 5%, or 10%. In individuals whose risk assessment (starting at age 25, 30, or 35 years) for carrying a mutation exceeded 5%, colorectal and endometrial cancers in mutation carriers were reduced by 12.4% and 8.8%, respectively. In the whole population, this strategy increased the quality adjusted life-years by 135 years per 100,000 individuals with an average cost-effectiveness ratio of $26,000. The authors suggested that the outlined strategy was more cost effective than current practice and could improve health care outcomes.

Recognizing the controversial conclusions of the EGAPP working group, the Centers for Disease Control and Prevention convened a special meeting of cancer genetics experts to critique these recommendations. The group concluded that "genetic screening of all newly diagnosed CRC cases for LS (universal LS screening) can theoretically result in population health benefits, and feasibility has been demonstrated."[368]

Universal MSI/IHC colorectal cancer screening in clinical practice

Universal screening has been adopted by many institutions in recent years. A 2011 survey of the National Society of Genetic Counselors revealed that more than 25% of respondents had some form of universal screening implemented at their center. Tumor screening methods varied; 34 of 53 (64.2%) started with IHC, 11 of 53 (20.8%) started with MSI testing, and 8 of 53 (15.1%) performed both tests on newly diagnosed colorectal tumors.[369] A 2012 survey suggested that some form of universal screening was being routinely performed at 71% of the National Cancer Institute (NCI) comprehensive cancer centers but that utilization dropped to 15% among a random sample of community hospital cancer programs.[370] NCCN 2014 guidelines support IHC testing of all CRCs diagnosed in patients younger than 70 years if tumor is available and in patients 70 years or older if they meet Bethesda guidelines.[92] Universal screening in all individuals irrespective of age was associated with a doubling of incremental cost per life-year saved compared with screening only those younger than 70 years.[366] The authors of this analysis conclude that screening individuals younger than 70 years appears reasonable, while screening all individuals regardless of age might also be acceptable, depending on societies' willingness to pay.

Several studies have demonstrated the feasibility and usefulness of universal screening for LS. Initial experience from one institution found that among 1,566 patients screened using MSI and IHC, 44 (2.8%) patients had LS. For each proband, an average of three additional family members were subsequently diagnosed with LS.[229] A subsequent pooled analysis of 10,206 incident CRC patients tested with MSI/IHC as part of four large studies revealed a mutation detection rate of 3.1%.[371] This study compared four strategies for tumor testing for the diagnosis of LS.[371] The strategy of tumor testing all individuals diagnosed with CRC at age 70 years or younger and testing older individuals who met one of the revised Bethesda guidelines yielded a sensitivity of 95.1%, a specificity of 95.5%, and a diagnostic yield of 2.1%. This strategy missed 4.9% of LS cases, but 34.8% fewer cases required IHC/MSI testing, and 28.6% fewer cases underwent germline testing than in the universal approach.

An important implication of universal screening for LS is the reality that it does not result in automatic germline testing in appropriate individuals. Subsequent genetic counseling requires coordination between the pathologist, the referring surgeon or oncologist, and a cancer genetics service. In addition, patient consent and compliance with subsequent testing may significantly influence uptake of genetic counseling. As an illustration, a population-based screening study found that only 54% of patients with an IHC-deficient tumor (that was BRAF mutation–negative) ultimately consented to and proceeded with germline MMR testing.[372] One institution found 21 deleterious mutations among 1,100 patients who underwent routine MSI and IHC testing after a diagnosis of CRC. This study found markedly increased uptake of genetic counseling and germline MMR gene testing when both the surgeon and a genetic counselor received a copy of abnormal MSI/IHC results, especially when the genetic counselor played an active role in patient follow-up.[373]

To simplify the process of IHC testing and to help decrease cost, a strategy that employs IHC testing for PMS2 and MSH6 alone has been suggested. This strategy relies on the binding properties of the MMR heterodimer complexes, by which gene mutation and loss of MLH1 and MSH2 invariably result in the degradation of PMS2 and MSH6, respectively, but the converse is not true.[315] The authors do not suggest a definitive algorithm after the finding of an IHC-deficient tumor. However, given the predominance of MLH1 and MSH2 mutations in LS, the authors suggest that a PMS2-deficient tumor should be investigated for either MLH1 hypermethylation (utilizing BRAF mutations status as a proxy) or germline MLH1 mutation analysis. Similarly, MSH6 deficiency would generally result in MSH2 germline testing as a first step. This strategy has not been validated or widely adopted in clinical practice.

There is an ongoing discussion about best practices for the informed consent process for this tumor testing.[374] Identification of genetic predisposition to cancer generally mandates explicit informed consent because of concerns for the possibility of insurance discrimination (irrespective of the Genetic Information Nondiscrimination Act of 2008), adverse psychological outcomes, and costs associated with further testing.[375,376] The EGAPP working group specifically recommends obtaining informed consent for MSI or IHC testing.[364] Nevertheless, debate about this issue continues, partially because of pragmatic concerns surrounding the feasibility of obtaining such consent before the procedure. One proposed approach suggests a preparatory conversation informing patients before their procedure that CRC runs in families and that if their tumor has features characteristic of a heritable type, they will be contacted by a genetic health care provider for further assessment of the genetic basis of their cancer.[374] A cross-sectional survey of U.S. cancer programs (20 NCI–designated comprehensive cancer centers and 49 community hospital cancer programs) found that, of those that performed MSI and/or IHC testing as part of standard pathologic evaluation at the time of colon cancer diagnosis in all or select cases, none required written informed consent before tumor testing.[370]

(Refer to the Informed Consent section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Diagnostic strategies for all individuals diagnosed with endometrial cancer

Based on a Markov mathematical model, a strategy of performing IHC for MMR protein expression in all patients with endometrial cancer, irrespective of the age at diagnosis, who have a first-degree relative with endometrial cancer, was reported to be cost-effective in the detection of LS in patients with LS-related cancer.[377] (Refer to the Genetic testing section of this summary for more information about performing IHC for MMR protein expression.) In this study, incremental cost-effectiveness ratio was defined as the additional cost of a specific strategy divided by its health benefit compared with an alternative strategy. In this model, the strategy of performing IHC on the tumor from all patients diagnosed with LS-related cancer who have a first-degree relative with endometrial cancer had an incremental cost ratio of $9,126 per year of life gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer younger than 50 years with at least one first-degree relative with LS-related cancer.

The model predicted that if all endometrial cancers in the United States (estimated to be 45,000 new cases in 2010) underwent IHC screening, 827 women (1.84%) would be diagnosed as LS patients.[377] However, applying the strategy of testing only those endometrial tumors of patients with at least a first-degree relative with LS-related cancer, 755 affected individuals (1.68%) would be identified. If the Amsterdam II criteria were applied, 539 carriers (1.2%) would be identified. The authors stated that the incremental benefit of the most cost-effective strategy was associated with an average life expectancy gain of only 1 day compared with testing by Amsterdam II criteria. However, they argue that this may be significant, as it is comparable to the life expectancy gain from triennial cervical cancer screening, which is a current recommendation from the American College of Obstetricians and Gynecologists for women older than 30 years in the general population.

Interventions for LS

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

  1. CRCs in LS occur earlier in life than do sporadic cancers. For MLH1 and MSH2 mutation carriers, the estimated risk of CRC at age 40 years is 31% for females and 32% for males; at age 50 years, the estimated risks are 52% and 57%, respectively.[3] This suggests that screening should begin earlier in life.
  2. A larger proportion of LS CRCs (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Annual colonoscopic surveillance is recommended.[378]
  3. The progression from normal mucosa to adenoma to cancer is accelerated,[379,380] suggesting that screening should be done at shorter intervals (every 1–2 years) and with colonoscopy.[380,381] Because patients with LS have an ordinary, or slightly increased, frequency of polyps but a substantially increased rate of cancer, it is clear that a larger proportion of polyps progress to cancer. It has been demonstrated that MMR gene mutation carriers develop adenomas at an earlier age than noncarriers.[240] 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).[240]
  4. Incidence of CRC throughout life is substantially higher, suggesting that the most sensitive test available should be used.
  5. Patients with LS are at an increased risk of other cancers, especially those of the endometrium and ovary. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population.[249] There is some evidence that the rate of individual cancers varies from kindred to kindred.[248,382,383] Expert consensus suggests consideration of endometrial cancer screening by age 25 years.[384]

Evidence-based reviews of surveillance colonoscopy in LS have been reported.[385,386] There is only one controlled trial of CRC screening in LS.[380,381] In a study from Finland, 252 at-risk members of 22 families with LS were offered screening for 15 years. One hundred thirty-three individuals accepted screening by either colonoscopy or barium enema and sigmoidoscopy, and 123 of the at-risk members (93%) completed screening. One hundred nineteen did not accept advice to be screened, although 24 (20%) had screening examinations outside the study. Once genetic testing was performed in these families (starting in 1996, 14 years after the beginning of screening), screening was recommended for mutation-positive controls, 63% of whom chose to begin active screening. The screened group had 62% fewer cancers (P < .03) and 65% fewer CRC deaths (10 vs. 26, P = .003). All of the CRCs detected in the screened population were local and caused no deaths, compared with nine deaths from CRC in the control group. The results, while biologically plausible, are of limited validity, primarily because the main comparison was between compliant and noncompliant patients, and compliant patients have been shown to have an inherently better prognosis, independent of intervention.[387] This assertion is supported by the observed low rates of all causes of mortality. It is noteworthy, however, that these differences were observed in spite of the fact that most mutation-positive controls ultimately entered a screening program.

The data from this Finnish trial were subsequently updated.[388] Over the course of the study (early 1980s to present), the approach to colonoscopy surveillance has evolved. Colonoscopy was the approach used for MMR mutation carriers when this information was obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years. The series limited its attention to subjects with no prior diagnosis of adenoma or cancer. The 420 mutation carriers, at a mean age of 36 years, underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about half were located proximal to the splenic flexure. While the rates for CRC despite colonoscopy surveillance appear high, 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 (see Table 11). Analysis of surveillance data in 242 patients 10 years after mutation testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with mutation-negative relatives. However, this may be attributable to the modest sample size of the study.[389]

In other series, the risk of developing adenomas in an MMR gene mutation carrier has been reported to be 3.6 times higher than the risk in noncarriers.[240] 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.[240] 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.[390,391]

Although screening the intact colon is usually recommended for at-risk LS family members, some patients, faced with the high risk of CRC and the fallibility of screening, elect to undergo risk-reducing colectomy. However, there is a risk of developing cancer in the remaining rectum.[392]

Level of evidence: 3a

Table 11 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance for LS.

Table 11. Practice Guidelines for Diagnosis and Colon Surveillance of Lynch Syndrome
Organization Tumor MSI Tumor IHC MMR /EPCAMGenetic Testing Age Screening Initiated Frequency Method Comments
C = colonoscopy; GI = gastrointestinal; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; NA = not addressed; NCCN = National Comprehensive Cancer Network.
a GI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.
American Society of Colon and Rectal Surgeons (2001, 2003)[140,141,142] Yes Yes MMR: Yes NA NA NA  
American Cancer Society (2002)[143] NA NA MMR: Counseling to consider genetic testing 21 y 1–2 y until age 40 y, then annually C  
GI Societies (2003)a [138] NA NA MMR: NA 20–25 y 1–2 y C  
Europe Mallorca Group (2007)[393] Yes Yes MMR: Yes 20–25 y; consider stopping at age 80 y 1–2 y C Despite acknowledging that existing data support a 3-y screening interval, this group elected to recommend a shorter screening interval.
NCCN (2014)[92] Yes Yes MMR: Yes 20–25 y OR 2–5 y before the youngest age at diagnosis in the family if it is before age 25 y, whichever comes first 1–2 y C Additional recommendations for families in whom a tumor has shown informative IHC and MSI, but no germline mutation found. Refer to page LS-A-2 of the NCCN guidelines for more information.[92]

Chemoprevention in LS

The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with LS who were in surveillance programs at a number of international centers.[394] The study randomly assigned 861 participants to aspirin (600 mg/day), aspirin placebo, resistant starch (30 g/day), or starch placebo for up to 4 years. At a mean follow-up of 55.7 months (range: 1–128 mo), 53 primary CRCs developed in 48 participants (18 of 427 in the aspirin group and 30 of 434 in the aspirin placebo group). Seventy-six patients who refused randomization to the aspirin groups (because of an aspirin sensitivity or a history of peptic ulcer disease) were randomly assigned to receive resistant starch or resistant starch placebo. The intention-to-treat analysis yielded an HR for CRC of 0.63 (95% CI, 0.35–1.13; P = .12). However, five of the patients who developed CRC developed two primary colon cancers. A Poisson regression was performed to account for the effect of the multiple primary CRCs and yielded a protective effect for aspirin (incidence rate ratio [IRR], 0.56; 95% CI, 0.32–0.99; P = .05). For participants who completed at least 2 years of treatment, the per-protocol analysis yielded an HR of 0.41 (95% CI, 0.19–0.86; P = .02) and an IRR of 0.37 (0.18–0.78; P = .008). An analysis of all LS cancers (endometrial, ovarian, pancreatic, small bowel, gall bladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin versus placebo (HR, 0.65; 95% CI, 0.42–1.00; P = .05). There were no significant differences in adverse events between the aspirin and placebo groups, and no serious adverse effects were noted with any treatment. The authors concluded that 600 mg of aspirin per day for a mean of 25 months substantially reduced cancer incidence in LS patients. A limitation of the trial is that the frequency of surveillance studies at the various centers was not reported as being standardized. Earlier CAPP2 trial results for 746 LS patients enrolled in the study were published in 2008 [395] and failed to show a significant preventive effect on incident colonic adenomas or carcinomas (relative risk [RR], 1.0; 95% CI, 0.7–1.4) with a shorter mean follow-up of 29 months (range: 7–74 mo). The CAPP3 trial, which will evaluate the effect of lower doses of aspirin, is expected to begin in 2013.

Screening for endometrial cancer in LS families

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

Cancer of the endometrium is the second most common cancer observed in LS families with initial estimates of cumulative risk in LS carriers of 30% to 39% by age 70 years.[248,250] In a large Finnish study of 293 putative LS gene carriers, the cumulative lifetime risk of endometrial cancer was 43%. Endometrial cancer risk was directly related to age, ranging from 3.7% at age 40 years to 42.6% by age 80 years, compared with a 3% endometrial cancer risk in the general population.[232] The maximal risk of endometrial cancer in LS families occurs 15 years earlier than in the general population, with the highest risk occurring between ages 55 and 65 years. In a community study of unselected endometrial cancer patients in central Ohio, at least 1.8% (95% CI, 0.9%–3.5%) of newly diagnosed patients had LS.[396] Adenocarcinomas of the lower uterine segment may carry a greater risk of manifesting LS.[397]

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 symptoms of stage I disease. There are no data suggesting the clinical presentation in women with LS differs from the general population.

Given their substantial increased risk of endometrial cancer, endometrial screening for women with LS has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. Although the Pap test occasionally leads to a diagnosis of endometrial cancer, the sensitivity is too low for it to be a useful screening test. The presence of endometrial cells in a Pap smear obtained from a postmenopausal woman not taking hormone replacement therapy is abnormal and warrants further investigation.[398,399] Two studies have examined the use of TVUS in endometrial screening for women with LS.[400,401] In one study of 292 women from LS or LS-like families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women.[400] In a second study, 41 women with LS were enrolled in a TVUS screening program. Of 179 TVUS procedures performed, there were 17 abnormal scans. Three of the 17 women had complex atypical hyperplasia on endometrial sampling, while 14 had normal endometrial sampling. However, TVUS failed to identify one patient who presented 8 months after a normal TVUS with abnormal vaginal bleeding, and was found to have stage IB endometrial cancer.[401] Both of these studies concluded that TVUS is neither sensitive or specific. A study of 175 women with LS, which included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity over TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS.[402] While this cohort study demonstrates that endometrial sampling may have benefits over TVUS for endometrial screening, there are no data that predict screening with any other modality has benefits for endometrial cancer survival in women with LS. Given the favorable survival for endometrial cancer diagnosed by symptoms, it is unlikely that a sufficiently powered screening study will be able to demonstrate a survival advantage. Certainly, women with LS should be counseled that abnormal or postmenopausal vaginal bleeding warrants an endometrial sampling or D&C.

Routine screening for endometrial cancer has not been shown to be beneficial in the general population, but expert consensus suggests that it be considered in women who are members of high-risk LS families. Some studies suggest that women with a clinical or genetic diagnosis of LS do not universally adopt intensive gynecologic screening.[403,404] (Refer to the Gynecologic cancer screening in LS section of this summary for more information.) Despite absence of a survival advantage, a task force organized by NIH has suggested annual endometrial sampling beginning at age 30 to 35 years. TVUS can also be considered annually to evaluate the ovaries.[386,393]

The published literature on TVUS for endometrial cancer screening has shown it to be insensitive and nonspecific, but because there may still be a role for TVUS in ovarian cancer screening, clinical practice guidelines have been reluctant to date to recommend against TVUS.

Level of evidence: 5

Surgical management in LS

One of the hallmarks of LS is the presence of synchronous and metachronous CRCs. The incidence of metachronous CRCs has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy.[405] Because of the increased incidence of synchronous and metachronous neoplasms, the treatment of choice for a patient with LS with neoplastic lesions in the colon is generally an extended colectomy (total or subtotal). Nevertheless, treatment has to be individualized. Mathematical models suggest that there are minimal benefits of extended procedures in individuals older than 67 years, compared with the benefits seen in younger individuals with early-onset cancer. In one Markov decision analysis model, the survival advantage for a young individual with early-onset CRC undergoing an extended procedure could be up to 4 years longer than that seen in the same individual undergoing a segmental resection.[406] The recommendation for an extended procedure must be balanced with the comorbidities of the patient, the clinical stage of the disease, the wishes of the patient, and surgical expertise. No prospective or retrospective study has shown a survival advantage for patients with LS who underwent an extended resection versus a segmental procedure. Two studies have shown that patients who undergo extended procedures have fewer metachronous CRCs and additional surgical procedures related to CRC than do patients who undergo segmental resections.[405,407] Balancing functional results of an extended procedure versus a segmental procedure is of paramount importance. Although the majority of patients adapt well after an abdominal colectomy, some patients will require antidiarrheal medication. A decision model compared quality-adjusted life years (QALYs) for a 30-year-old patient undergoing an abdominal colectomy versus a segmental colectomy.[408] In this model, there was not much difference between the extended and segmental procedure, with QALYs being 0.3 years more in patients undergoing a segmental procedure than in those undergoing an extended procedure.[408]

When considering surgical options, it is important to recognize that a subtotal or total colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant after an abdominal colectomy has been reported to be 12% at 12 years post-colectomy.[392] In addition to the general complications of surgery, there are the potential risks of urinary and sexual dysfunction and diarrhea after an extended 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 patients with LS and rectal cancer, similar surgical options (extended vs. segmental resection) and considerations must be given. Extended procedures include restorative proctocolectomy and IPAA if the sphincter can be saved or proctocolectomy with loop ileostomy if the sphincter cannot be saved. Two retrospectives studies reported a 15% and 18% incidence of metachronous colon cancer after segmental rectal cancer–resection in patients with LS.[409,410] In one of the studies, the combined risk of metachronous high-risk adenomas and cancers was 51% at a median follow-up of 101.7 months after proctectomy.[410]

There are no data about fertility in LS patients based on type of surgery. In FAP patients, no difference in fecundity after abdominal colectomy and IRA has been reported, whereas there is a 54% decrease in fecundity in patients who undergo restorative proctocolectomy with ileal pouch anastomosis compared with the general population.[411]

Most clinicians who treat patients with LS will favor an extended procedure at the time of CRC diagnosis. However, as stated above, the choice of surgery must be made on an individual basis by the surgeon and the patient. The topic of surgical management in LS has been summarized in the following reviews.[412,413,414]

Level of Evidence: 4

Advances in Endoscopic Imaging in Hereditary CRC

Performance of endoscopic therapies for adenomas in FAP and LS, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and LS the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in LS.


The need for sensitive means to endoscopically detect subtle polyps has increased with the recognition of flat adenomas and sessile serrated polyps in otherwise average-risk subjects, very attenuated adenoma phenotypes in AFAP, and subtle flat adenomas in LS. Modern high-resolution endoscopes improve adenoma detection yield, but the use of various vital dyes, especially indigo carmine dye-spray, has further improved detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue),[390,415,416,417,418,419,420] with or without magnification, or possibly newer imaging techniques such as narrow-band imaging,[421] may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper gastrointestinal endoscopy may be informative if duodenal adenomas or fundic gland polyps with surface dysplasia are found. Such findings will increase the likelihood of mutation detection if APC or MYH testing is pursued.

In various large series of average-risk populations, subtle flat lesions were detected in about 5% to 10% of cases, including adenomas with high-grade dysplasia and invasive adenocarcinoma.[422] Some of these studies involved tandem procedures—white-light exam followed by randomization to "intensive" (> 20-minute pull-back from cecum) inspection versus chromoendoscopy—with significantly more adenomas detected in the chromoendoscopy group.[423] However, in several randomized trials, no significant difference in yield was seen.[424,425]

In a randomized trial of subjects with LS,[426] standard colonoscopy, with polypectomy as indicated, was followed by either indigo carmine chromoendoscopy or repeat "intensive" white-light colonoscopy (a design very nearly identical to the average-risk screening group noted above). In this series, no significant difference in adenoma yield between the chromoendoscopy and intensive white-light groups was detected. However, these patients were younger and in many cases had undergone several previous exams that might have resulted in polyp clearing.

In a German study,[427] one series of LS patients underwent white-light exam followed by chromoendoscopy, while a second series underwent colonoscopy with narrow-band imaging followed by chromoendoscopy. Significant differences in flat polyp detection favored chromoendoscopy in both series, although some of the detected lesions were hyperplastic. In a French series of LS subjects that also employed white-light exam followed by chromoendoscopy, significantly more adenomas were detected with chromoendoscopy.[391]

Fewer evaluations of chromoendoscopy have been performed in attenuated FAP than in LS. One study examined four patients with presumed AFAP and fewer than 20 adenomas upon white-light examination.[428] All had more than 1,000 diminutive adenomas found on chromoendoscopy, in agreement with pathology evaluation after colectomy.

A similar role for chromoendoscopy has been suggested to evaluate the duodenum in FAP. One study from Holland that used indigo carmine dye-spray to detect duodenal adenomas showed an increase in the number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.[429]

Small bowel imaging

Patients with PJS and juvenile polyposis syndrome are at greater risk of disease-related complications in the small bowel (e.g., bleeding, obstruction, intussusception, or cancer). FAP patients, although at great risk of duodenal neoplasia, have a relatively low risk of jejunoileal involvement. The RR of small bowel malignancy is very high in LS, but absolute risk is less than 10%. Although the risks of small bowel neoplasia are high enough to warrant consideration of surveillance in each disease, the technical challenges of doing so have been daunting. Because of the technical challenges and relatively low prevalences, there is virtually no evidence base for small-bowel screening in LS.

Historically, the relative endoscopic inaccessibility of the mid and distal small bowel required radiographic measures for its evaluation, including the barium small bowel series or a variant called tube enteroclysis, in which a nasogastroduodenal tube is placed so that all of the contrast goes into the small intestine for more precise imaging. None of these measures were sensitive for small lesions. Any therapeutic undertaking required laparotomy. This entailed resection in most cases, although intraoperative endoscopy, with or without enterotomy for scope access, has been available for many years. Peroral enteroscopy (aided by stiffening overtubes with two balloons, one balloon, or spiral ribs) has been employed to overcome the technical problem of excessive looping, enabling deep jejunal access with therapeutic (polypectomy) potential.

Most data relate that PJS with double-balloon enteroscopy is the preferred method for endoscopy of the small bowel.[430] This may involve only peroral enteroscopy, although subsequent retrograde enteroscopy has been described for more complete evaluation of the total small bowel. Because these procedures are time-consuming and involve some risk of complication, deep enteroscopy is usually preceded by more noninvasive imaging, including traditional barium exams, capsule endoscopy, and CT or magnetic resonance enterography.[80]

In FAP, data from capsule endoscopy [80] show a 50% to 100% prevalence of jejunal and/or ileal polyps in patients with Spigelman stage III or stage IV duodenal involvement but virtually no such polyps in Spigelman stage I or stage II disease. All polyps were smaller than 10 mm and were not biopsied or removed. Consequently, their clinical significance remains uncertain but is likely limited, given the infrequency of jejunoileal cancer reports in FAP.

Capsule endoscopy in the small series of PJS patients described above [80] showed the presence of a similar frequency (50%–100%) of polyps, but the prevalent polyps were much larger than in FAP, were more likely to become symptomatic, and warranted endoscopic or surgical excision. Capsule studies were suggested as an appropriate replacement for radiographic studies because of the sensitivity of capsule.

Familial CRC

An estimated 7% to 10% of people have a first-degree relative with CRC,[431,432] and approximately twice that many have either a first-degree or a second-degree relative with CRC.[432,433] A simple family history of CRC (defined as one or more close relatives with CRC in the absence of a known hereditary colon cancer) confers a twofold to sixfold increase in risk. The risk associated with family history varies greatly according to the age of onset of CRC in the family members, the number of affected relatives, the closeness of the genetic relationship (e.g., first-degree relatives), and whether cancers have occurred across generations.[431,434] A positive family history of CRC appears to increase the risk of CRC earlier in life such that at age 45 years, the annual incidence is more than three times higher than that in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals.[431] The incidence in a 35- to 40-year-old is about the same as that of an average-risk person at age 50 years. There is no evidence to suggest that CRC in people with one affected first-degree relative is more likely to be proximal or is more rapidly progressive.

A personal history of adenomatous polyps confers a 15% to 20% risk of subsequently developing polyps [435] and increases the risk of CRC in relatives.[436] The RR of CRC, adjusted for the year of birth and sex, was 1.78 (95% CI, 1.18–2.67) for the parents and siblings of the patients with adenomas as compared with the spouse controls. The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% CI, 1.46–4.58), compared with the siblings of patients who were 60 years or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex, with a parental history of CRC.

While familial clusters account for approximately 20% of all CRC cases in developed countries,[437] the rare and highly penetrant Mendelian CRC diseases contribute to only a fraction of familial cases, which suggests that other genes and/or shared environmental factors may contribute to the remainder of the cancers. Two studies attempted to determine the degree to which hereditary factors contribute to familial CRCs.

The first study utilized the Swedish, Danish, and Finnish twin registries that cumulatively provided 44,788 pairs of same-sex twins (for men: 7,231 monozygotic [MZ] and 13,769 dizygotic [DZ] pairs; for women: 8,437 MZ and 15,351 DZ pairs) to study the contribution of heritable and environmental factors involved in 11 different cancers.[438] The twins included in the study all resided in their respective countries of origin into adulthood (>50 years). Cancers were identified through their respective national cancer registries in 10,803 individuals from 9,512 pairs of twins. The premise of the study was based on the fact that MZ twins share 100% and DZ twins share 50% of their genes on average for any individual twin pair. This study calculated that heritable factors accounted for 35%, shared environmental factors for 5%, and nonshared environmental factors for 60% of the risk of CRC. For CRC, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that although nonshared environmental factors constitute the major risk of familial CRC, heredity plays a larger-than-expected role.

The second study utilized the Swedish Family-Cancer Database, which contained 6,773 and 31,100 CRCs in offspring and their parents, respectively, from 1991 to 2000.[439] The database included 253,467 pairs of spouses, who were married and lived together for at least 30 years, and who were used to control for common environmental effects on cancer risk. The overall SIR for cancers of the colon, rectum, and colon and rectum combined in the offspring of an affected parent was 1.81 (95% CI, 1.62–2.02), 1.74 (95% CI, 1.53–1.96), and 1.78 (95% CI, 1.53–1.96), respectively. The risk conferred by affected siblings was also significantly elevated. Because there was no significantly increased risk of CRC conferred between spouses, the authors concluded that heredity plays a significant role in familial CRCs; however, controls for shared environmental effects among siblings were absent in this study.

Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members,[431,432,434,435,436,440,441,442,443,444,445] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for LS. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of familial CRC remains a research challenge.

Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families,[446] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[445] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[447] A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.[448]

Familial colorectal cancer type X (FCCX)

Families meeting Amsterdam-I criteria for LS who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic LS and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCCX,[225,449,450,451,452,453] and it has been suggested that these families be classified as a distinct group.

The genetic etiology of FCCX remains unclear. Utilizing whole-genome linkage analysis and exome sequencing, a truncating mutation in ribosomal protein S20 (RPS20), a ribosomal protein gene, was identified in four individuals with CRC from an FCCX family.[453] The mutation cosegregated with CRC in the family, with a logarithm of the odds score of 3. Additionally, the mutation was not identified in 292 controls. No LOH was observed in tumor samples, and in vitro analyses of mature RNA formation confirmed a model of haploinsufficiency for RPS20. No germline mutations in RPS20 where found in 25 additional FCCX families studied, suggesting RPS20 mutations are an infrequent cause of FCCX. The same group had previously identified variants in the bone morphogenetic protein receptor type 1A (BMPR1A) gene in affected individuals from 2 of 18 families with FCCX.[454] Additional studies are necessary to definitively confirm or refute a role for RPS20 or BMPR1A in FCCX.

Age of CRC onset in LS ranges from 44 years (registry series) to a mean of 52 years (population-based series).[229,230,231] There are no corresponding population-based data for FCCX because FCCX by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between FCCX and LS have suggested that the age of onset is slightly older in FCCX,[225,449,451] but the lifetime risk of cancer is substantially lower. The SIR for CRC among families with intact MMR (type X families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective MMR (LS families).[225] The risk of extracolonic tumors was also not found to be elevated for the type X families, suggesting that enhanced surveillance for CRC was sufficient. Although further studies are required, tumors arising within type X families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those from families with LS.[450]

Interventions for family history of CRC

There are no controlled comparisons of screening in people with a mild or modest family history of CRC. Most experts, if they accept that average-risk people should be screened starting at age 50 years, suggest that screening should begin earlier in life (e.g., at age 35–40 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.[138]

A common but unproven clinical practice is to initiate CRC screening 10 years before the age of the youngest CRC case in the family. There is neither direct evidence nor a strong rational argument for using aggressive screening methods simply because of a modest family history of CRC.

These issues were weighed by a panel of experts convened by the American Gastroenterological Association before publishing clinical guidelines for CRC screening, including those for persons with a positive family history of CRC.[384] These guidelines have been endorsed by a number of other organizations.

The American Cancer Society and the United States Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[138,455,456,457,458] These guidelines address screening issues related to modest family history of CRC or adenomas. Given the heterogeneity of this grouping, it is beyond the scope of this more targeted discussion of major gene conditions.

Rare Colon Cancer Syndromes

PTENhamartoma tumor syndromes (including Cowden syndrome)

Cowden syndrome and Bannayan-Riley-Ruvalcaba Syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable mutation of PTEN.[459] In addition, PTEN mutations have been identified in patients with very diverse clinical phenotypes.[460] The term PTEN hamartoma tumor syndromes refers to any patient with a PTEN mutation, irrespective of clinical presentation.

PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, 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.[461] Individuals with mutations in the 5' end or within the phosphatase core of PTEN tend to have more organ systems involved.[462]

Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[463,464] These included pathognomonic criteria consisting of certain mucocutaneous manifestations and adult onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria have been suggested based on a systematic review.[465] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multigene cancer panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTEN mutations who do not meet these criteria. Until then, whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous.

Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTEN testing in the United States, Europe, and Asia.[466] The vast majority of individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline PTEN mutations. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline PTEN mutations. A second study of approximately 100 patients with a germline PTEN mutation confirmed these findings and suggested a cumulative cancer risk of 85% by the age of 70 years.[467]

The age-adjusted risk of CRC was increased in mutation carriers in both studies (SIR, 5.7–10.3).[466,467] In addition, one study found that 93% of individuals with PTEN mutations who had undergone at least one colonoscopy had polyps. The most common histology was hyperplastic, although adenomas and sessile serrated polyps were also observed. The increased risk of CRC among PTEN mutation carriers has led to the recommendation of surveillance colonoscopy in these patients.[467,468] However, both the age at which to begin (30–40 years) and the subsequent frequency of colonoscopies (biennial to every 3–5 years) vary considerably and are based on expert opinion.

Table 12. Cancer Risk in Individuals with GermlinePTENMutationsa
Cancer Age-Adjusted SIR (95% CI) Age-Related Penetrance Estimates
CI = confidence interval; SIR = standardized incidence ratio.
a Adapted from Tan et al.[466]
b Other historical studies have suggested a lower lifetime risk of breast cancer, in the range of 25%–50%.[465](Refer to the PTEN hamartoma tumor syndromes [including Cowden syndrome]section in the PDQ summary on Genetics of Breast and Gynecologic Cancersfor more information.)
Breast 25.4 (19.8–32.0) 85% starting around age 30 yb
Colorectal 10.3 (5.6-17.4) 9% starting around age 40 y
Endometrial 42.9 (28.1–62.8) 28% starting around age 25 y
Kidney 30.6 (17.8–49.4) 34% starting around age 40 y
Melanoma 8.5 (4.1–15.6) 6% with earliest age of onset 3 y
Thyroid 51.1 (38.1–67.1) 35% at birth and throughout life

Peutz-Jeghers syndrome (PJS)

PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[469,470,471] Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[472,473,474,475,476] The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancies. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer [6,477,478] and 21% for ovarian cancer.[477] A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[479]Table 13 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.

Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[480] In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;[481] although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in over-estimates of these risks should be considered.

Table 13. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea
Site Age (y) Cumulative Risk (%)b Reference(s)
GI = gastrointestinal.
a Reprinted with permission from Macmillan Publishers Ltd: Gastroenterology[479], copyright 2010.
b All cumulative risks were increased compared with the general population (P < .05), with the exception of cervix and testes.
c GI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.
d Westerman et al.: GI cancer does not include pancreatic cancer.[482]
e Did not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.
Any cancer 60–70 37–93 [6,476,477,478,482,483]
GI cancerc,d 60–70 38–66 [6,478,482,483]
Gynecological cancer 60–70 13–18 [6,478]
Per origin      
Stomach 65 29 [477]
Small bowel 65 13 [477]
Colorectum 65 39 [6,477]
Pancreas 65–70 11–36 [6,477]
Lung 65–70 7–17 [6,477,478]
Breast 60–70 32–54 [6,477,478]
Uterus 65 9 [477]
Ovary 65 21 [477]
Cervixe 65 10 [477]
Testese 65 9 [477]

Peutz-Jeghers gene(s)

PJS is caused by mutations in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[473,474] Unlike the adenomas seen in familial adenomatous polyposis, 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.[484,485] 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.[486] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[487] indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.[488]

Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, and splice-site variants and large deletions.[6,472] 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.[6]

STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% mutation detection rate in STK11, studies adding techniques to detect large deletions have found mutations in up to 94% of individuals meeting clinical criteria for PJS.[472,479,489] Given the results of these studies, it is unlikely that other major genes cause PJS.

Juvenile polyposis syndrome (JPS)

JPS is a genetically heterogeneous, rare, childhood- to early adult-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract, although colorectal polyps predominate.[490] JPS can present with diarrhea, GI tract hemorrhage, protein-losing enteropathy, and prolapsing polyps.[490,491,492] JPS is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, often in the setting of a family history of JPS. The diagnosis of a juvenile polyp is based on its histologic appearance, rather than age at onset. Solitary juvenile polyps of the colon or rectum are seen sporadically in infants and young children and do not imply a diagnosis of JPS. A clinical diagnosis of JPS is met by individuals fulfilling one or more of the following criteria:[493]

  1. More than five juvenile polyps of the colon or rectum.
  2. Juvenile polyps in other parts of the GI tract.
  3. Any number of juvenile polyps and a positive family history of JPS.

JPS is caused by germline mutations in the SMAD4 gene, also known as MADH4/DPC4, at chromosome 18q21 [494] in approximately 15% to 60% of cases,[490] and by mutations in the gene-encoding bone morphogenic protein receptor 1A (BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases.[495,496] Genotype/phenotype correlations suggest SMAD4 mutations may be associated with a greater risk of severe gastric polyposis and features of hereditary hemorrhagic telangiectasia (HHT) (see below).[490] The lifetime CRC risk in JPS has been reported to be 39%.[497] There appears to be an increased risk of gastric cancer, albeit much lower than the risk of CRC.[490] Cardiac valvular abnormalities were present in 12% of individuals with JPS who were followed through a single-institution based polyposis registry,[490] and all those with identifiable mutations had SMAD4 mutations.

JPS patients may also have signs and symptoms of HHT, such as arteriovenous malformations, mucocutaneous telangiectasias, digital clubbing, osteoarthropathy, hepatic arteriovenous malformations, and cerebellar cavernous hemangioma, suggesting that the two syndromes overlap.[498] Most HHT patients will have a mutation in the activin receptor-like kinase 1 (ALK1) gene or in the endoglin (ENG) gene, but SMAD4 mutations have also been reported, although they are quite rare (approximately 1%–2% of patients with HHT).[499] In one series, 3 of 30 patients (10%) with HHT without a clinical diagnosis of JPS were found to have germline mutations in SMAD4.[500] Conversely, features of HHT were noted in 21% to 22% of SMAD4 mutation carriers in two studies of individuals with a clinical diagnosis of JPS.[490,501] In a study of 21 SMAD4 mutation carriers from nine JPS families, 81% (17 of 21) of patients had HHT manifestations.[502] The high prevalence in this study may have been a result of the inclusion of several relatives from a single family and the inclusion of several families with the same mutation.[502]

Surveillance for HHT has been suggested in JPS patients with germline SMAD4 mutations.[490,502] On the other hand, patients with HHT without germline mutations in ALK1 or ENG may be considered for SMAD4 germline genetic testing; the GI tract should be evaluated if a SMAD4 germline mutation is confirmed.[503] (Refer to Table 15, Published Recommendations for Diagnosis and Surveillance of JPS, for more information.)

A severe form of JPS, in which polyposis develops in the first few years of life, is referred to as JPS of infancy. JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN. (Refer to the PTEN hamartoma tumor syndromes (including Cowden syndrome) section of this summary for more information about PTEN.) The phenotype often includes features such as macrocephaly and developmental delay, possibly as a result of loss of PTEN function.[504] Recurrent GI bleeding, diarrhea, exudative enteropathy, in addition to associated developmental delay, are associated with a very high rate of morbidity and mortality in these infants, thereby limiting the heritability of such cases.[504]

Juvenile polyposis gene(s)

JPS is caused by germline mutations in the SMAD4 gene in approximately 15% to 60% of cases, and to mutations in BMPR1A in approximately 25% to 40% of cases.[490,495,496] The large variability in mutation frequency likely reflects the relatively small number of patients reported in individual studies. A subset of individuals meeting clinical criteria for JPS will not have an identified mutation in either SMAD4 or BMPR1A.

SMAD4 encodes a protein that is a mediator of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline mutations in SMAD4 predispose individuals to forming juvenile polyps and cancer,[494] 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.[501,505]

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 JPS who did not have identifiable mutations in SMAD4. Mutations in BM PR1A include nonsense, frameshift, missense, and splice-site mutations.[495] Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with JPS.[501,505] Rare JPS families have demonstrated mutations in the ENG and PTEN genes, but these have not been confirmed in other studies.[506,507]

JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN.[504]


Several studies initially suggested that a subset of families with hereditary breast and colon cancers may have a cancer family syndrome caused by a mutation in the CHEK2 gene.[508,509,510] However, subsequent studies have suggested that CHEK2 mutations are associated with only a modest increase in CRC risk (i.e., low penetrance). One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (OR, 1.5; 95% CI, 1.2–3.0) of CRC.[511]

Similar results were obtained in another study conducted in Poland.[512] In this study, 463 probands from LS and LS-related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS-related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to FCCX. On the basis of available data thus far, clinical testing for CHEK2 mutations is not routinely recommended in clinical practice. There are no established guidelines for CRC screening in individuals with CHEK2 mutations.

(Refer to the CHEK2 section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Hereditary mixed polyposis syndrome (HMPS)

HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas, atypical juvenile polyps and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[513,514] 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. Linkage analysis of Ashkenazi Jewish families with HMPS revealed shared haplotypes on chromosome 15q13.3.[515] An unusual heterozygous 40kb single-copy duplication was discovered upstream of gremlin 1 (GREM1) that segregated perfectly with individuals and family members with HMPS and not with unaffected controls.[515] The presence of this duplication in HMPS individuals was associated with increased expression of GREM1 transcript levels in the normal intestinal epithelium.[515]GREM1 is a bone morphogenetic protein (BMP) antagonist and thus theoretically would promote the stem cell phenotype in the intestine. Germline mutations leading to defective BMP signaling also underlie JPS, thus drawing a potential link between HMPS and JPS.

Serrated polyposis syndrome (SPS)/Hyperplastic polyposis syndrome (HPPS)

Isolated and multiple hyperplastic polyps (HPs) (typically white, flat, and small) are common in the general population, and their presence does not suggest an underlying genetic disorder. Historically, the clinical diagnosis of SPS, as defined by WHO, must satisfy one of the following criteria:

  • At least five histologically diagnosed HP occurring proximal to the sigmoid colon (of which at least two are >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.
  • More than 30 HPs distributed throughout the colon.[516]

Other groups have included serrated adenomas as part of the revised clinical criteria for SPS.[517]

Although the vast majority of cases of SPS lack a family history of HPs, approximately half of the SPS cases have a positive family history of CRC.[518,519] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for SPS is 50% or more.[520,521,522,523,524,525,526,527] One study, using a variation of the WHO criteria for SPS (SPS was defined as at least five histologically diagnosed HPs and/or sessile serrated adenomas (SSAs) proximal to the sigmoid colon, of which two are greater than 10 mm in diameter, or more than 20 HPs and/or SSAs distributed throughout the colon), found a relative risk for CRC in 347 first-degree relatives (41% male) from 57 pedigrees of 5.4 (95% CI, 3.7–7.8).[517]

The WHO criteria are based on expert opinion; and, there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Only two studies to date have found potentially causative germline mutations in SPS individuals.[518,528]

In a 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.[518] 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 SNPs of uncertain significance. Only two patients had a known family history of SPS, and ten of the 38 patients developed CRC. This series presumably included patients with sporadic HPs mixed in with other patients who may have SPS.

In a cohort of 40 SPS 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).[528] The patient had serrated adenomas and more than 100 HPs in her colon at age 58 years, and her mother died of colon cancer at age 36 years. EPHB2 germline mutations were not found in 100 additional patients with a personal history of CRC or in 200 population-matched healthy control patients.

Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in SPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF mutation (V600E) was found in polyp tissue.[529] Fifty percent of HPs (20 of 40) from these patients demonstrated the V600E BRAF mutation. The HPs from these patients also demonstrated significantly higher CpG island methylation phenotypes (CIMP-high), and fewer KRAS mutations than left-sided sporadic HPs. In a previous study from this group, HPs from patients with SPS 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.[521]

Many of the genetic and histological alterations found in HPs of patients with SPS are common with the recently defined CIMP pathway of colorectal adenocarcinoma.

Interventions for rare colon cancer syndromes

Individuals with PJS and JPS are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Because of the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion).[139,530,531,532,533] Clinical judgment must be used in making screening recommendations based on published guidelines.

Table 14. Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS)
Organization STK11Gene Testing Recommendeda Age Colon Screening Initiated Frequency Method Extracolonic Screening Recommendations Comment
ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; FS = flexible sigmoidoscopy; NCCN = National Comprehensive Cancer Network.
a STK11mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing.
b Lung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.
(Refer to the Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancersection in the PDQ summary on the Genetics of Breast and Gynecologic Cancersfor more information about PJS and the risk of breast and ovarian cancer.)
Johns Hopkins (2006)[532] Yes, at age 8 y 18 y 2–3 y C Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes  
Johns Hopkins (2007)[533] Yes, age not specified Late teens or at onset of symptoms 3 y C Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes Genetic testing in the late teens or at onset of symptoms.
ACPGBI(2007)   18 y 3 y C or FS + BE No mention of extracolonic screening No recommendation for genetic testing; need to considerSTK11/LKB1testing.
Cleveland Clinic (2007)[534]   18 y 3 y C Breast, gynecologic (cervix, ovaries), pancreas, small intestine, stomach, testes  
Erasmus University Medical Center (2010)[479]   25–30 y   C Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach  
NCCN (2014)[92] No specific recommendation Late teens 2–3 y C Breast, gynecologic (cervix, ovaries, uterus), lungb, pancreas, small intestine, stomach, testes Refer to specialized team.

Level of evidence: 5

Table 15. Published Recommendations for Diagnosis and Surveillance of Juvenile Polyposis Syndrome (JPS)
Organization/ Author SMAD4 / BMPR1ATesting Recommendeda Age Screening Initiated Frequency Method Comment
ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; NCCN = National Comprehensive Cancer Network.
a SMAD4/BMPR1Amutation analysis includes sequencing followed by analysis for deletions (e.g., multiplex ligation-dependent probe amplification), if no mutation found by sequencing.[505]
b Younger, if patient has presented with symptoms.
ACPGBI(2007)   15–18 yb 1–2 y C or FS + BE Surveillance for gene carriers and affected until age 70 y and discussion of prophylactic surgery.
Cleveland Clinic (2007)[534]   15 y 3 y C, EGD Some families withSMAD4mutation also have HHT; these individuals may need to be screened for HHT.
Johns Hopkins (2007)[533] Yes, genetic testing preferred over colonoscopy 15 y or at onset of symptoms Yearly until polyp free then every 2–3 y C Prophylactic surgery if >50–100 polyps, unable to manage endoscopically, severe GI bleeding, JPS with adenomatous changes, strong family history of CRC.
St. Mark's (2012)[490] Yes, genetic testing at age 4 y 12 y 1–3 y based on severity C, EGD Consider HHT workup.
NCCN (2014)[92] Yes ~15 y 2–3 y or 1 y if polyps are found C Refer to specialized team.

Level of evidence: 5


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Psychosocial Issues in Hereditary Colon Cancer Syndromes


Psychosocial research in cancer genetic counseling and testing focuses on the interest in testing among populations at varying levels of disease risk, psychological outcomes, interpersonal and familial effects, and cultural and community reactions. The research 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 the following:

  • Decision-making about risk-reduction interventions, risk assessment, and genetic testing.
  • Evaluation of psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification of genetic testing.
  • Resolution of ethical concerns.

This section of the summary will focus on psychosocial aspects of genetic counseling and testing for Lynch syndrome (LS), familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome (PJS), including issues surrounding medical screening, risk-reducing surgery, and chemoprevention for these syndromes.

Participation in Genetic Counseling and Testing for Hereditary CRC


There are an increasing number of studies examining the actual uptake of genetic counseling and testing for LS (see Table 16). Studies have included colorectal cancer (CRC) 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.[1,2,3,4,5,6,7,8] Participation or uptake was defined at various points in the process, including genetic counseling before testing; provision of a blood sample for testing; and genetic counseling for disclosure of test results.

Table 16. Summary of Prospective Studies Evaluating Participation in Genetic Counseling and Testing for Hereditary Colorectal Cancer (CRC)a,b,c
Syndrome Study Population Nd GC and GT Participatione
FAP = familial adenomatous polyposis; FDR = first-degree relative; GC = genetic counseling; GT = genetic testing; HCCR = hereditary colon cancer registry; LS = Lynch syndrome.
a All studies used a prospective, observational design with the exception of one randomized trial evaluating two recruitment methods.[6]
b All studies offered free GC and GT, with the exception of one study.[9]
c All studies were conducted in the United States, with the exception of one Finnish study and one German study.[5,8]
d Indicates number of participants older than 18 years, unless otherwise specified.
e GC = participated in pretest or posttest genetic counseling; GT = participated in genetic testing and received results; GT (blood) = only provided blood sample for genetic testing.
f Affected = current or previous CRC diagnosis; Unaffected = no previous diagnosis of CRC.
LS Affectedf and unaffectedf members of four extended families from HCCR with a known LS mutation inkindred [3] 219 59% pretest GC; posttest GC, GT
LS Unaffected FDRs of CRC patients from HCCR[1] 505 21% pretest GC; 26% pending pretest GC; 15% GT (blood); 4% pending GT (blood)
LS Affected and unaffected members of four extended families from HCCR with a known LS mutation in kindred[2] 208 47% pretest GC; 43% posttest GC, GT
LS CRC patients from an oncology clinic and HCCR[4] 510 89% GT (blood)
LS Unaffected members of 36 Finnish families with a known LS mutation in kindred[5] 446 78% pretest GC; 75% posttest GC, GT
LS and familial CRC Affected and unaffected persons who underwent GC in a high-risk colon cancer clinic[9] 57 (LS); 91 (familial CRC) LS: 14% posttest GC, GT
APCI130K: 85% posttest GC, GT
LS CRC patients diagnosed age <60 y with affected FDR orsecond-degree relativerecruited through physicians[6] 101 47% pretest GC; 36% posttest GC, GT
LS Unaffected FDRs of known LS mutation carriers[7] 111 51% pretest GC; 50% posttest GC, GT
LS CRC patients from HCCR, relatives, and spouses[8] 140 26% pretest GC
FAP Unaffected persons from HCCR age >5 y with FAP-affected parent and knownAPCmutation in family[10] 57 adults; 38 minors 87% pretest GC; posttest GC, GT (82% adults; 95% minors)

Participation in both pretest genetic counseling and posttest counseling for disclosure of results ranged from 14% to 59% across studies (see Table 16). The wide range of uptake rates suggests that factors such as cost, test characteristics, and the context in which counseling and testing were offered may have influenced participants' decisions. For example, among studies that offered free genetic counseling and testing in the context of a research protocol, counseling uptake ranged from 21% to 59%, and testing uptake ranged from 36% to 59%.[1,2,3,5,6,7,8] Most of those who had participated in a free pretest counseling or education session almost always followed through with genetic testing. Further research is needed to evaluate LS genetic counseling and testing participation in the clinical setting.

Although limited in number, these studies offer insight into why individuals from families at risk of LS decide to undergo or decline genetic counseling and testing. Participation in LS genetic counseling was associated with having children, having a greater number of relatives affected by CRC, and greater social support.[6] A study of CRC patients who had donated a blood sample for genetic testing also showed that those who intended to follow through with receiving results were more worried that they carried a LS-predisposing gene mutation, believed that testing would help family members, and more strongly endorsed the benefits and importance of having testing.[4] Factors associated with both counseling and testing uptake included having: children, a greater number of affected relatives, a greater perceived risk of developing CRC, and more frequent thoughts about CRC.[1,2,3,5,6,7,11]

Less is known about the characteristics of persons who decide to not undergo LS genetic counseling and testing. Studies have found that persons who declined counseling and testing reported to have a lower perceived risk of CRC,[1] to have fewer first-degree relatives affected with cancer,[7] to be less likely to have had a previous colonoscopy,[1] to have a college education,[2] to have previously participated in cancer genetics research,[2] or to be employed.[5] Psychological factors also may limit the uptake of genetic counseling and testing. Those who declined counseling and testing, especially women, reported a lower perceived ability to cope with mutation-positive test results,[1] and were more likely to report having depressive symptoms.[2] 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.[7]

In contrast to the LS genetic counseling and testing uptake studies that have been conducted in the United States, findings from similar studies conducted in other countries may differ. A Finnish study found that 75% of individuals at risk of developing LS underwent genetic testing and counseling for disclosure of test results.[5] 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.[5]

The majority of these studies that evaluated the uptake of genetic testing for LS have focused on genetic testing for mismatch repair (MMR) mutations associated with this syndrome. Few studies have examined uptake of microsatellite instability (MSI) and immunohistochemical (IHC) testing. One study reported low levels of knowledge and awareness of MSI testing among a sample of CRC patients who met the revised Bethesda guidelines for LS and were offered MSI testing.[12] Patients in this study generally reported positive attitudes about the benefits of MSI testing; however, patients with higher levels of cancer-specific distress also perceived a greater number of barriers to having MSI testing.

Research is emerging on the usefulness of decision aids for LS genetic testing. One study showed that a decision aid, in booklet format, was effective in reducing uncertainty about the testing decision, assisting individuals to make an informed decision about testing, and improving testing knowledge among men. However, the decision aid did not appear to influence actual testing decisions.[13] Another study evaluated the impact of an educational intervention in high-risk CRC patients before MSI and IHC testing but not MMR mutation testing. Patients who received a brief educational session delivered by a health educator plus a CD-ROM decision aid about MSI and IHC testing were found to have greater increases in knowledge about testing, higher satisfaction with preparation for decision-making about testing, lower decisional conflict, and greater decisional self-efficacy compared with patients who received only a brief educational session.[14]


The uptake for genetic testing for FAP may be higher than testing for LS. A study of asymptomatic individuals in the United States at risk of FAP who were enrolled in a CRC registry and were offered genetic counseling found that 82% of adults and 95% of minors underwent genetic testing.[10] Uptake rates close to 100% have been reported in the United Kingdom.[15] A possible explanation for the greater uptake of APC genetic testing is that it may be more cost-effective than annual endoscopic screening [16] 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;[17] 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 because of a greater awareness of the disease and more experience with multiple family members being affected.

Genetic testing for FAP 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 optimal to diagnose FAP before age 18 years to prevent CRC 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. (Refer to the Testing in children section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed discussion regarding the ethical, psychosocial, and genetic counseling issues related to genetic testing in children.)

In a survey conducted in the Netherlands of members of families with FAP, one-third (34%) believed that it was most suitable to offer APC gene testing to children before age 12 years, whereas 38% preferred to offer testing to children between the ages of 12 and 16 years, when children would be better able to understand the DNA testing process. Only 4% felt that children should not undergo DNA testing at all.[18]

Results of qualitative interview data from 28 U.S. parents diagnosed with FAP showed that 61% favored genetic testing of APC mutations in their at-risk children (aged 10–17 years); 71% believed that their children should receive their test results. The primary reasons why parents chose to test their children included early detection and management, reduction in parental anxiety and uncertainty, and help with decision making regarding surveillance. Reasons provided for not testing focused on discrimination concerns and cost.[19]

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.[10] 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.[10]

Interest in the Use of Assisted Reproductive Technology (ART)

The possibility of transmitting a mutation to a child may pose a concern to families affected by hereditary CRC syndromes to the extent that some carriers may avoid childbearing. These concerns also may prompt individuals to consider using prenatal diagnosis (PND) methods to help reduce the risk of transmission. PND is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling.[20,21] Both procedures carry a small risk of miscarriage.[20,22] Moreover, discovering the fetus is a carrier of a cancer susceptibility mutation may impose a difficult decision for couples regarding pregnancy continuation or termination and may require additional professional consultation and support.

An alternative to these tests is preimplantation genetic diagnosis (PGD), a procedure used to test fertilized embryos for genetic disorders before uterine implantation.[23,24] Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGD can be used to detect mutations in hereditary cancer predisposing genes, including APC.[18,25,26]

From the limited studies published to date, there appears to be interest in the use of ART for FAP, LS, and PJS.[18,25,27,28] However, actual uptake rates have not been reported.

Table 17. Summary of Studies Evaluating Attitudes Toward, Interest in, or Intention to Use Assisted Reproductive Technology (ART) for FAPa, LSb, and PJSa
Study Population Nc Interest or Intention in ART Comments
FAP = familial adenomatous polyposis; GT = genetic testing; LS = Lynch syndrome; PGD = preimplantation genetic diagnosis; PJS = Peutz-Jeghers syndrome; PND = prenatal diagnosis.
a Studies used a cross-sectional design and were conducted in the United States,[25]and in the Netherlands.[18,28].
b Participants were invited to complete questionnaires before clinical genetic testing for LS and at 3 months and 1 year after disclosure of genetic test results.
c Indicates number of participants older than 18 y, unless otherwise specified.
d Represents the number who indicated that they were considering having children in the future, out of a total of 130 individuals who answered a questionnaire before genetic testing.[27]
FAP-affected individuals[25] 20 95% would consider prenatal GT for FAP; 90% would consider PGD; 75% would consider amniocentesis or chorionic villous sampling  
FAP-affected individuals[18] 341 33% would consider PND for FAP; 30% would consider PGD; 15% felt terminating pregnancy for FAP was acceptable 24% and 25% of patients did not respond to questions about attitudes toward PND and PGD, respectively.
Individuals undergoing genetic testing for LS[27] 48d 21% would consider PND and/or PGD; 19% would consider only PND; 2% would consider only PGD At 1 year after disclosure of GT results, two of nine mutation carriers reported that they were considering PGD for future pregnancy.
PJS-affected individualsa[28] 52 15% indicated that pregnancy termination was acceptable if PND identified a fetus with PJS; 52% indicated PGD was acceptable for persons with PJS Ten (19%) individuals, nine of whom were female, reported that they had decided not to conceive a child because of PJS.

Psychological Impact of Participating in Hereditary CRC Genetic Counseling and Testing


Studies have examined the psychological status of individuals before, during, and after genetic counseling and testing for LS. Some studies have included only persons with no personal history of any LS-associated cancers,[29,30,31,32] and others have included both CRC patients and cancer-unaffected persons who are at risk of having a LS mutation.[33,34,35,36,37] Cross-sectional evaluations of the psychosocial characteristics of individuals undergoing LS genetic counseling and testing have indicated that mean pretest scores of psychological functioning for most participants are within normal limits,[33,34,35] although one study comparing affected and unaffected individuals showed that affected individuals had greater distress and worry associated with LS.[38]

Several longitudinal studies have evaluated psychological outcomes before genetic counseling and testing for LS and at multiple time periods in the year after disclosure of test results. One study examined changes in anxiety based on personal cancer history, gender, and age (younger than 50 years vs. older than 50 years) before and 2 weeks after a pretest genetic-counseling session. Affected and unaffected female participants in both age groups and affected men older than 50 years showed significant decreases in anxiety over time. Unaffected men younger than 50 years maintained low levels of anxiety; however, affected men younger than 50 years showed no reductions in the anxiety levels reported at the time of pretest counseling.[39] A study that evaluated psychological distress 8 weeks postcounseling (before disclosure of test results) among both affected and unaffected individuals found a significant reduction in general anxiety, cancer worry, and distress.[38] In general, findings from studies within the time period immediately after disclosure of mutation status (e.g., 2 weeks to 1 month) suggested that MMR mutation carriers may experience increased general distress,[31,36] cancer-specific distress,[29,30] or cancer worries [36] relative to their pretest measurements. Carriers often experienced significantly higher distress after disclosure of test results than do individuals who do not carry a mutation previously identified in the family (noncarrier).[29,30,31,36] However, in most cases, carriers' distress levels subsided during the course of the year after disclosure [31,36] and did not differ from pretest distress levels at 1 year postdisclosure.[29,30] Findings from these studies also indicated that noncarriers experienced a reduction or no change in distress up to 1 year after results disclosure.[29,30,31,36] A study that included unaffected individuals and CRC patients found that distress levels among patients did not differ between carriers and individuals who received results that were uninformative or showed a variant of unknown significance at any point up to 1 year posttest and were similar compared with pretest distress levels.[37]

A limited number of studies have examined longer-term psychosocial outcomes after LS genetic counseling and testing.[29,40,41] Longitudinal studies that evaluated psychological distress before and after genetic testing found that long-term distress levels (measured at 3 or 7 years posttesting) among mutation carriers and noncarriers were similar to distress levels at baseline.[29,41] with one exception: noncarriers' cancer-specific distress scores in one study [29] showed a sustained decrease posttesting and were significantly lower than their baseline scores and with carriers' scores at 1 year posttesting, with a similar trend observed at 3 years posttesting. In one study, carriers were more likely to be worried about CRC risk at 7 years posttesting; however, noncarriers who reported worry about CRC (i.e., "worried to some extent" or "very worried") were more likely to doubt the validity of their test result than were noncarriers who reported no worry.[41] When asked about their satisfaction with the decision to have testing, the majority of carriers and noncarriers were extremely satisfied up to 7 years posttesting and indicated they would be willing to undergo testing again.[41]

Findings from some studies suggested that there may be subgroups of individuals at higher risk of psychological distress after disclosure of test results, including those who present with relatively higher scores on measures of general or cancer-specific distress before undergoing testing.[33,34,35,36,37,42] A study of CRC patients who had donated blood for LS testing found that higher levels of depressive symptoms and/or anxiety were found among women, younger persons, nonwhites, and those with less formal education and fewer and less satisfactory sources of social support.[33] A subgroup of individuals who showed higher levels of psychological distress and lower quality of life and social support were identified from the same population; in addition, this subgroup was more likely to worry about finding out that they were LS mutation carriers and being able to cope with learning their test results.[34] In a follow-up report that evaluated psychological outcomes after the disclosure of test results among CRC patients and relatives at risk of having a LS mutation, a subgroup with the same psychosocial characteristics experienced higher levels of general distress and distress specific to the experience of having genetic testing within the year after disclosure, regardless of mutation status. Nonwhites and those with lower education had higher levels of depression and anxiety scores at all times compared with whites and those with higher education, respectively.[36] 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.[37,42] While further research is needed in this area, case studies indicate that it is important to identify persons who may be at risk of experiencing psychiatric distress and to provide psychological support and follow-up throughout the genetic counseling and genetic testing process.[43]

Studies also have examined the effect of LS genetic counseling and testing on cancer risk comprehension. One study reported that nearly all mutation carriers and noncarriers could accurately recall the test result 1 year after disclosure. More noncarriers than carriers correctly identified their risk of developing CRC at both 1 month and 1 year after result disclosure. Mutation carriers who incorrectly identified their CRC risk were more likely to have had lower levels of pretest subjective risk perception compared with those who correctly identified their level of risk.[31] Another study reported that accuracy of estimating colorectal and endometrial cancer risk improved after disclosure of mutation status in carriers and noncarriers.[32]


Studies evaluating psychological outcomes after genetic testing for FAP suggest that some individuals, particularly mutation carriers, may be at risk of experiencing increased distress. In a cross-sectional study of adults who had previously undergone APC genetic testing, those who were mutation carriers exhibited higher levels of state anxiety than noncarriers and were more likely to exhibit clinically significant anxiety levels.[44] Lower optimism and lower self-esteem were associated with higher anxiety in this study,[44] and FAP-related distress, perceived seriousness of FAP, and belief in the accuracy of genetic testing were associated with more state anxiety among carriers.[45] However, in an earlier study that compared adults who had undergone genetic testing for FAP, Huntington disease, and hereditary breast/ovarian cancer syndrome, FAP-specific distress was somewhat elevated within 1 week after disclosure of either positive or negative test results and was lower overall than the other syndromes.[17]

In a cross-sectional Australian study focusing on younger adults aged 18 to 35 years diagnosed with FAP (N = 88), participants most frequently reported the following FAP-related issues for which they perceived the need for moderate-to-high levels of support or assistance: anxiety regarding their children's risk of developing FAP, fear about developing cancer, and uncertainty about the impact of FAP.[46] Seventy-five percent indicated that they would consider prenatal testing for FAP; 61% would consider PGD, and 61% would prefer that their children undergo genetic testing at birth or before age 10 years. A small proportion of respondents (16%) reported experiencing some FAP-related discrimination, primarily indicating that attending to their medical or self-care needs (e.g., time off work for screening, need for frequent toilet breaks, and physical limitations) may engender negative attitudes in colleagues and managers.

Another large cross-sectional study of FAP families conducted in the Netherlands included persons aged 16 to 84 years who either had an FAP diagnosis, were at 50% risk of having an APC mutation, or were proven APC noncarriers.[47] Of those who had APC testing, 48% had done so at least 5 years or longer before this study. Of persons with an FAP diagnosis, 76% had undergone preventive colectomy, and 78% of those were at least 5 years postsurgery. The study evaluated the prevalence of generalized psychological distress, distress related specifically to FAP, and cancer-related worries. Mean scores on the Mental Health Index-5, a subscale of the SF-36 that assessed generalized distress, were comparable to the general Dutch population. Twenty percent of respondents were classified as having moderate to high levels of FAP-specific distress as measured by the Impact of Event scale (IES), with 23% of those with an FAP diagnosis, 11% of those at risk of FAP, and 17% of noncarriers reporting scores in this range. Five percent reported scores on the IES that indicated severe and clinically relevant distress; of those, the majority (78%) had an FAP diagnosis. Overall, mean scores on the Cancer Worry Scale were comparable to those found in another study of families with LS. Persons with an FAP diagnosis were more likely to report more frequent cancer worries, and the most commonly reported worries were the potential need for additional surgery (26%) and the likelihood that they (17%) or a family member (14%) will develop cancer. In multivariate analysis, factors associated with higher levels of FAP-specific distress included greater perceived risk of developing cancer, more frequent discussion about FAP with family or friends, and having no children. Factors associated with higher levels of cancer-specific worries included being female, poorer family functioning, greater actual and desired discussion about FAP with family or friends, greater perceived cancer risk, poorer general health perceptions, and having been a caregiver for a family member with cancer. The authors noted that most factors that were associated with higher levels of cancer- and FAP-specific distress or worry were psychosocial factors, rather than clinical or demographic factors.

Another cross-sectional study conducted in the Netherlands found that among FAP patients, 37% indicated that the disease had influenced their desire to have children (i.e., wanting fewer or no children). Thirty-three percent indicated that they would consider PND for FAP; 30% would consider PGD. Higher levels of guilt and more positive attitudes towards terminating pregnancy were associated with greater interest for both PND and PGD.[18] In a separate U.S. study, predictors of willingness to consider prenatal testing included having an affected child and experiencing a first-degree relative's death secondary to FAP.[25]

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 after 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.[48] 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.[49] 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 after disclosure.[44] Mutation-negative children in this study experienced less anxiety and improved self-esteem over this same time period.

Psychosocial Aspects of Screening and Risk Reduction Interventions for LS and FAP

Colorectal screening for LS

Benefits of genetic counseling and testing for LS include the opportunity for individuals to learn about options for the early detection and prevention of cancer, including screening and risk-reducing surgery. Studies suggest that many persons at risk of LS may have had some CRC screening before genetic counseling and testing, but most are not likely to adhere to LS screening recommendations. Among persons aged 18 years or older who did not have a personal history of CRC and who participated in U.S.-based research protocols offering genetic counseling and testing for LS, between 52% and 62% reported ever having had a colonoscopy before genetic testing.[1,3,50,51] 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.[32,52] Factors associated with ever having a colonoscopy before genetic testing included higher income and older age,[50] higher perceived risk of developing CRC,[52] higher education level, and being informed of increased risk of CRC.[51]

In a study of cancer-affected and cancer-unaffected persons who fulfilled clinical criteria for LS, 92% reported having had a colonoscopy and/or flexible sigmoidoscopy at least once before genetic testing.[53] Another study of unaffected individuals presenting for genetic risk assessment and possible consideration of LS, FAP, or APC I1307K genetic testing reported that 77% had undergone at least one screening exam (either colonoscopy, flexible sigmoidoscopy, or barium enema).

Three studies determined whether cancer-unaffected persons adhered to LS colonoscopy screening recommendations before genetic testing, and reported adherence rates of 10%,[32] 28%,[51] and 47%.[53]

Several longitudinal studies examined the use of screening colonoscopy by cancer-unaffected persons after undergoing testing for a known LS mutation.[32,50,51,52] These studies compared colonoscopy use before LS genetic testing with colonoscopy use within 1 year after disclosure of test results. One study reported that LS mutation carriers were more likely to have a colonoscopy than were noncarriers and those who declined testing (73% vs. 16% vs. 22%) and that colonoscopy use increased among carriers (36% vs. 73%) in the year after disclosure of results.[51] 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,[50,52] although noncarriers' colonoscopy rates decreased in the same time period. Factors associated with colonoscopy use at 1 year after disclosure of results included carrying a LS-predisposing mutation,[50,51,52] older age,[50] and greater perceived control over CRC. These findings suggest that colonoscopy rates increase or are maintained among mutation carriers within the year after disclosure of results and that rates decrease among noncarriers. Data from a longitudinal study including 134 MMR mutation carriers with and without a prior LS-related cancer diagnosis found that those who did not undergo colonoscopy for surveillance within 6 months after receiving genetic test results were six times more likely to report clinically significant depressive symptoms as measured by the Center for Epidemiological Studies-Depression (CES-D) scale (odds ratio [OR], 6.06; 95% confidence interval [CI], 2.09–17.59). Higher levels of CRC worry measured before genetic testing also were associated with clinically significant depressive symptoms (OR, 1.53; 95% CI, 1.19–1.97).[54]

Two studies examined the level of adherence to published screening guidelines after LS genetic testing, based on mutation status. One study reported a colonoscopy adherence rate of 100% among mutation carriers.[32] Another study found that 35% of mutation carriers and 13% of noncarriers did not adhere to published guidelines for appropriate CRC screening;[50] in both groups, about one-half screened more frequently than published guidelines recommend, and one-half screened less frequently.

The longitudinal studies described above examined colorectal screening behavior within a relatively short period of time (1 year) after receiving genetic test results, and less is known about longer-term use of screening behaviors. A longitudinal study (N = 73) that examined psychological and behavioral outcomes among cancer-unaffected persons at 3 years after disclosure of genetic test results found that all carriers (n = 19) had undergone at least one colonoscopy between 1 and 3 years postdisclosure.[29] A longitudinal study of similar outcomes up to 7 years posttesting also found that all carriers had undergone colonoscopy; most (83%) underwent the procedure every 3 years or more frequently as recommended, and 11% reported longer screening intervals.[41] In this study, those who reported longer screening intervals than recommended also were more likely to report a fear of dying soon. Also, 16% of noncarriers reported undergoing colonoscopy within the 7 years posttesting; those who indicated doubts about the validity of their test result were more likely to have had a colonoscopy.[41] 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.[32] A cross-sectional study conducted in the Netherlands examined the use of flexible sigmoidoscopy or colonoscopy among persons with CRC, endometrial cancer, or a clinical or genetic diagnosis of LS during a time that ranged from 2 years to 18 years after risk assessment and counseling.[55] Eighty-six percent of LS mutation carriers, 68% of those who did not test or who had an uninformative LS genetic test result, and 73% of those with a clinical LS diagnosis were considered adherent with screening recommendations, based on data obtained from medical records. Participants also answered questions regarding screening adherence, and 16% of the overall sample reported that they had undergone screening less frequently than recommended. For the overall sample, greater perceived barriers to screening were associated with screening nonadherence as determined through medical record review, and embarrassment with screening procedures was associated with self-reported nonadherence. A second cross-sectional study, also conducted in the Netherlands, surveyed cancer-unaffected LS mutation carriers (n = 42) regarding their colorectal screening behaviors after learning their mutation status (range, 6 months–8.5 years). Thirty-one percent of respondents reported that they had undergone annual colonoscopy before LS genetic testing, and 88% reported that they had undergone colonoscopy since their genetic diagnosis (P < .001).[40]

Gynecologic cancer screening in LS

Several small studies have examined the use of screening for endometrial and ovarian cancers associated with LS (see Table 18). There are several limitations to these studies, including small sample sizes, short follow-up, retrospective design, reliance on self-report as the data source, and some not including patients who had undergone LS genetic testing. Several studies have included individuals in the screening uptake analysis who do not meet the minimum age criteria for undergoing screening. Of the studies that assessed screening use after a negative test result for a known mutation in the family, only a few assessed indications for that screening, such as follow-up of a previously identified abnormality. Last, some studies have included patients in the uptake analysis who were actively undergoing treatment for another cancer, which could influence provider screening recommendations. Therefore, Table 18 is limited to studies with patients who had undergone LS genetic testing, larger sample sizes, longer follow-up, and analysis that included individuals of an appropriate screening age.

Table 18. Uptake of Gynecologic Screening Among Women Who Have Undergone Lynch Syndrome (LS) Genetic Testing
Study Citation Study Population Uptake of Gynecologic Screening Before Genetic Counseling and Testing Uptake of Gynecologic Screening After Receipt of Genetic Test Results Length of Follow-up Comments
EC = endometrial cancer; ES = endometrial sampling; RRH = risk-reducing total abdominal hysterectomy; RRSO = risk-reducing salpingo-oophorectomy; TVUS = transvaginal ultrasound.
Noncarrier(s) = negative for known mutation in family.
1 Prospective study design.
2 Retrospective study design.
a Self-report as data source.
Claes et al. (2005)1,a[32] Carriers (n = 7) Not reported TVUS 1 y One noncarrier reported undergoing TVUS for a previous endometrial problem, while three noncarriers reported undergoing the procedure for preventive reasons.
– Carriers 86% (6/7)
Noncarriers (n = 16)
– Noncarriers 27% (4/15)
Collins et al. (2007)1,a[29] Carriers (n = 13) Not reported TVUS 3 y Two of four carriers had an RRH/RRSO by the 3-year follow-up assessment.
– Carriers 69% (9/13)
– Noncarriers 6% (2/32)
Noncarriers (n = 32) ES
– Carriers 54% (7/13)
– Noncarriers 3% (1/32)
Yurgelun et al. (2012): Cohort 12,a[56] 77 at risk of LS-associated EC; 45 carriers; 19 no genetic testing but LS-associated family history 75% (58/77) engaged in EC screening or EC risk-reduction intervention; 42 underwent annual TVUS and/or ES; 16 underwent RRH Not reported N/A  
Yurgelun et al. (2012): Cohort 21,a[56] 40 women at clinical risk of LS 65% (26/40) adhered to EC screening or risk reduction; 6 underwent RRH; 13 underwent annual ES and/or TVUS; 6 had not reached recommended screening age Carriers: 100% (n = 16) adhered to EC screening or risk-reducing strategies; 4 underwent pretest RRH; 5 underwent RRH; 5 underwent EC screening (TVUS and/or ES); 2 had not reached recommended screening age 1 y  
Carriers (n = 16)
Noncarriers (n = 9); 14 indeterminate results; 1 variant of uncertain significance Noncarriers: 11% (1/9) underwent EC screening; 11% (1/9) underwent RRH

Overall, these studies have included relatively small numbers of women and suggest that screening rates for LS-associated gynecologic cancers are low before genetic counseling and testing. However, after participation in genetic education and counseling and the receipt of LS mutation test results, uptake of gynecologic cancer screening in carriers generally increases, while noncarriers decrease use.

Risk-reducing surgery for LS

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

Among persons who received positive test results, a greater proportion indicated interest in having risk-reducing colectomy after disclosure of results than at baseline.[3] This study also indicated that consideration of risk-reducing surgery for LS may motivate participation in genetic testing. Before receiving results, 46% indicated that they were considering risk-reducing colectomy, and 69% of women were considering risk-reducing total abdominal hysterectomy (RRH) and risk reducing bilateral salpingo-oophorectomy (RRSO); however, this study did not assess whether persons actually followed through with risk-reducing surgery after they received their test results. Before undergoing LS genetic counseling and testing, 5% of cancer-unaffected individuals at risk of a MMR mutation in a longitudinal study reported that they would consider colectomy, and 5% of women indicated that they would have an RRH and an RRSO, if they were found to be mutation-positive. At 3 years after disclosure of results, no participants had undergone risk-reducing colectomy.[29,52] Two women who had undergone an RRH before genetic testing underwent RRSO within 1 year after testing,[52] however, no other female mutation carriers in the study reported having either procedure at 3 years after test result disclosure.[29]

In a cross-sectional quality-of-life and functional outcome survey of LS patients with more extensive (subtotal colectomy) or less extensive (segmental resection or hemicolectomy) resections, global quality-of-life outcomes were comparable, although patients with greater extent of resection described more frequent bowel movements and related dysfunction.[57]

Colorectal screening for FAP

Less is known about psychological aspects of screening for FAP. One study of a small number of persons (aged 17–53 years) with a family history of FAP who were offered participation in a genetic counseling and testing protocol found that among those who were asymptomatic, all reported undergoing at least one endoscopic surveillance before participation in the study.[53] Only 33% (two of six patients) reported continuing screening at the recommended interval. Of the affected persons who had undergone colectomy, 92% (11 of 12 patients) were adherent to recommended colorectal surveillance. In a cross-sectional study of 150 persons with a clinical or genetic diagnosis of classic FAP or attenuated FAP (AFAP) and at-risk relatives, 52% of those with FAP and 46% of relatives at risk of FAP, had undergone recommended endoscopic screening.[58] Among persons who had or were at risk of AFAP, 58% and 33%, respectively, had undergone screening. Compared with persons who had undergone screening within the recommended time interval, those who had not screened were less likely to recall provider recommendations for screening, more likely to lack health insurance or insurance reimbursement for screening, and more likely to believe that they are not at increased risk of CRC. Only 42% of the study population had ever undergone genetic counseling. A small percentage of participants (14%–19%) described screening as a "necessary evil," indicating a dislike for the bowel preparation, or experienced pain and discomfort. Nineteen percent reported that these issues might pose barriers to undergoing future endoscopies. Nineteen percent reported that improved techniques and the use of anesthesia have improved tolerance for screening procedures.

Risk-reducing surgery for FAP

When persons at risk of FAP develop multiple polyps, risk-reducing surgery in the form of subtotal colectomy or proctocolectomy is the only effective way to reduce the risk of CRC. Most persons with FAP can avoid a permanent ostomy and preserve the anus and/or rectum, allowing some degree of bowel continence. (Refer to the Interventions for FAP section of this summary for more information about surgical management procedures in FAP.) Evidence on the quality-of-life outcomes from these interventions continues to accumulate and is summarized in Table 19.

Table 19. Studies Measuring Quality-of-Life Variables in Familial Adenomatous Polyposis (FAP)
Population Length of Follow-up Type of Procedure Stool Frequency Stool Continency Body Image Sexual Functioning Comments
EORTC QLQ = European Organization for Research and Treatment of Cancer Colorectal Quality of Life Questionnaire; IPAA = ileal pouch-anal anastomosis; IRA = ileorectal anastomosis; SD = standard deviation; SF-36 = Short Form (36) Health Survey.
a EORTC QLQ-C38scores range from 0–100. Functional scales: 0 = lowest level of function and 100 = highest/healthy level of function. Symptom scales: 0 = lowest level of symptomatology and 100 = highest level of symptomatology.
b SF-36scores range from 0–100, with 0 = lowest possible health status and 100 = best possible health status.
c Within normal ranges for same age group.
279 FAP-affected individuals (135 females and 144 males) after colectomy; controls included 1,771 individuals from the general Dutch population[59] IRA mean: 12 y (SD, 7.5 y) IRA: n = 161 Not assessed Not assessed EORTC QLQ-CR38 a EORTC QLQ-CR38 a SF-36b scores (Dutch version) on all subscales were significantly lower than the scores in the general population (IRA:P< .001; IPAA:P< .001).
IRA: 87.5 (SD, 21.9) IRA: 38.9 (SD, 26.6)
IPAA mean: 6.8 y (SD, 4.9 y) IPAA: n = 118 IPAA: 84.4 (SD, 22.7) IPAA: 42.2 (SD, 26.3)
88 Australian individuals (63 females and 25 males) aged 18–35 y, including 57 after colectomy and 14 with FAP but no surgery[60] Not reported IRA: n = 33 Not assessed Not assessed SF-36 b SF-36 b  
IPAA: n = 21 IRA: 89.9 (SD, 16.1) IRA: 86.2 (SD, 21.6)
Ileostomy: n = 1 IPAA: 72.1 (SD, 23) IPAA: 77.5 (SD, 26.2)
Unknown surgery type: n = 2 No surgery: 94.1 (SD, 9.4) No surgery: 91 (SD, 19)
525 individuals (283 females and 242 males) including 296 after colectomy, 45 with FAP but no surgery, 50 at risk for FAP and no surgery, and 134 noncarriers[61] Range: 0–1 y to >10 y IRA: n = 136 Not assessed Not assessed EORTC QLQ-CR38 a EORTC QLQ-CR38 a 41% of FAP patients reported employment disruptions:
After colectomy: 85.4 (SD, 20.5) After colectomy: 42.2 (SD, 23.2) Part or complete disability: n = 73 (59%)
IPAA: n = 112 FAP no surgery: 91.9 (SD, 16.1) After colectomy: 42.2 (SD, 23.2) Worked less: n = 30 (24%)
Ileostomy: n = 42 At risk: 94.0 (SD, 13.1) At risk: 47.6 (SD, 23.7) Worked more n = 5 (4%)
Other: n = 6 Noncarrier: 92.3 (SD, 13.1) Noncarrier: 45.7 (SD, 21.2) Worked more or less at different periods: n = 16 (13%)
209 Swedish FAP-affected individuals (116 females and 93 males) after colectomy aged 18–75 y[62] Mean time since last surgery: 14 y (SD, 10; range, 1–50 y) IRA: n = 71 Not assessed Day: 71% (n = 149) Not assessed Not assessed The mean number of 21 abdominal symptoms assessed was 7 (SD, 4.61; range, 1–18). Women reported more symptoms than men, but there were no differences between genders regarding the degree the symptoms were troublesome. Higher symptom number was an independent predictor of poorer physical and mental health.
IPAA: n = 82
Ileostomy: n = 39 Night: 61% (n = 128)
Continent ileostomy: n = 14
Other: n = 3
28 individuals (10 females and 18 males) who underwent colectomy at age 14 y or younger[63] 12 y (SD, 8.4; range, 1–37 y) IRA: n = 7 Day: Day: Rosenberg self-esteem score : 25.53/30c Not assessed 10/28 reported cancer-related worry post colectomy, with a trend that young age (<18 y) was associated with more cancer-related worry.
IRA: 3.8 (SD, 1.5) IRA: 71.4% (n = 7)
IPAA: 5.3 (SD, 2.4) IPAA: 85.7% (n = 21)
IPAA: n = 21 Night: Night:
IRA: 1.3 (SD, 0.6) IRA: 50.0% (n = 7)
IPAA: 1.3 (SD, 0.5) IPAA: 61.9% (n = 21)

Studies of risk-reducing surgery for FAP have found that general measures of quality of life have been within normal range, and the majority reported no negative impact on their body image. However, these studies suggest that risk-reducing surgery for FAP may have negative quality-of-life effects for at least some proportion of those affected.


Chemoprevention trials are currently under way to evaluate the effectiveness of various therapies for persons at risk of LS and FAP.[64,65] 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.[66] 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

Family communication about genetic testing for hereditary CRC susceptibility, and specifically about the results of such testing, is complex. It is generally accepted that communication about genetic risk information within families is largely the responsibility of family members themselves. A few studies have examined communication patterns in families who had been offered LS genetic counseling and testing. Studies have focused on whether individuals disclosed information about LS genetic testing to their family members, to whom they disclosed this information, and family-based characteristics or issues that might facilitate or inhibit such communication. These studies examined communication and disclosure processes in families after notification by health care professionals about a LS predisposition and have comprised relatively small samples.

Research findings indicate that persons generally are willing to share information about the presence of a LS-predisposing mutation within their families.[67,68,69,70] Motivations for sharing genetic risk information include a desire to increase family awareness about personal risk, health promotion options and predictive genetic testing, a desire for emotional support, and a perceived moral obligation and responsibility to help others in the family.[68,69,70] Findings across studies suggest that most study participants believed that LS genetic risk information is shared openly within families; however, such communication is more likely to occur with first-degree relatives (e.g., siblings, children) than with more distant relatives.[67,68,69,70]

One Finnish study recruited parents aged 40 years or older and known to carry an MMR mutation to complete a questionnaire that investigated how parents shared knowledge of genetic risk with their adult and minor offspring. The study also identified challenges in the communication process.[71] Of 248 parents, 87% reported that they had disclosed results to their children. Reasons for nondisclosure were consistent with previous studies (young age of offspring, socially distant relationships, or feelings of difficulty in discussing the topic).[68,69,72] Nearly all parents had informed their adult offspring about their genetic risk and the possibility of genetic testing, but nearly one-third were unsure of how their offspring had used the information. Parents identified discussing their children's cancer risk as the most difficult aspect of the communication process. Of the 191 firstborn children informed, 69% had undergone genetic testing. One-third of the parents suggested that health professionals should be involved in disclosure of the information and that a family appointment at the genetics clinic should be made at the time of disclosure.

In regard to informing second- and third-degree relatives, individuals may favor a cascade approach; for example, it is assumed that once a relative is given information about the family's risk of LS, he or she would then be responsible for informing his or her first-degree relatives.[67,68,69] This cascade approach to communication is distinctly preferred in regard to informing relatives' offspring, particularly those of minor age, and the consensus suggests that it would be inappropriate to disclose such information to a second-degree or third-degree relative without first proceeding through the family relational hierarchy.[67,68,69,72] In one study, persons who had undergone testing and were found to carry a LS-predisposing mutation were more likely than persons who had received true negative or uninformative results to inform at least one second-degree or third-degree relative about their genetic test results.[70]

While communication about genetic risk is generally viewed as an open process, some communication barriers were reported across studies. Reasons for not informing a relative included lack of a close relationship and lack of contact with the individual; in fact, emotional, rather than relational, closeness seemed to be a more important determinant of the degree of risk communication. A desire to not worry relatives with information about test results and the perception that relatives would not understand the meaning of this information also have been cited as communication barriers.[70] Disclosure seemed less likely if at-risk individuals were considered too young to receive the information (i.e., children), if information about the hereditary cancer risk had previously created conflict in the family,[69] or if it was assumed that relatives would be uninterested in information about testing.[68] Prior existence of conflict seemed to inhibit discussions about hereditary cancer risk, particularly if such discussions involved disclosure of bad news.[69]

For most participants in these studies, the news that the pattern of cancers in their families was attributable to a LS-predisposing mutation did not come as a surprise,[67,68] as individuals had suspected a hereditary cause for the familial cancers or had prior family discussions about cancer. Identification of a LS-predisposing mutation in the family was considered a private matter but not necessarily a secret,[67] and many individuals had discussed the family's mutation status with someone outside of the family. Knowledge about the detection of a LS-predisposing mutation in the family was not viewed as stigmatizing, though individuals expressed concern about the potential impact of this information on insurance discrimination.[67] 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.[72] In a few cases, individuals reported that their relatives expressed anger, shock, or other negative emotional reactions after receiving news about the family's LS risk;[69] however, most indicated little to no difficulty in informing their relatives.[68] 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.[69]

In some cases, probands reported feeling particularly obliged to inform family members about a hereditary cancer risk [69] and were often the strongest advocates for encouraging their family members to undergo genetic counseling and testing for the family mutation.[67] 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.[68] Another study suggested that mothers may be particularly influential members of the family network in regard to communicating health risk information.[73] 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.[67]

Various modes of communication (e.g., in-person, telephone, or written contact) may typically be used to disclose genetic risk information within families.[67,68,69] In one study, communication aids such as a genetic counseling summary letter or LS booklet were viewed as helpful adjuncts to the communication process but were not considered central or necessary to its success.[68] Studies have suggested that recommendations by health care providers to inform relatives about hereditary cancer risk may encourage communication about LS [69] and that support by health care professionals may be helpful in overcoming barriers to communicating such information to family members.[72]

Much of the literature to date on family communication has focused on disclosure of test results; however, other elements of family communication are currently being explored. One study evaluated the role of older family members in providing various types of support (e.g., instrumental, emotional, crisis help, and dependability when needed) among individuals with LS and their family members (206 respondents from 33 families).[7,74] Respondents completed interviews about their family social network (biological and non-biological relatives and others outside the family) and patterns of communication within their family. The average age of the respondents and the members of their family social network did not differ (~ age 43 years). The study found that 23% of the members of the family social network encouraged CRC screening (other types of support, such as social support, were reported much more frequently). Those who encouraged screening were older, female, and significant others or biological family members, rather than nonfamily members. Given that many of the members of the family social network did not live in the same household, the study points out the importance of extended family in the context of screening encouragement and support.


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Changes to This Summary (02 / 20 / 2015)

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.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of colorectal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

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Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Colorectal Cancer are:

  • Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)
  • Donald W. Hadley, MS, CGC (National Human Genome Research Institute)
  • Jennifer Lynn Hay, PhD (Memorial Sloan-Kettering Cancer Center)
  • Scott Kuwada, MD, AGAF, FACP (University of Hawaii)
  • Patrick M. Lynch, MD, JD (University of Texas, M.D. Anderson Cancer Center)
  • Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
  • Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
  • Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
  • Miguel A. Rodriguez-Bigas, MD (University of Texas, M.D. Anderson Cancer Center)
  • Danielle Kim Turgeon, MD (University of Michigan Comprehensive Cancer Center)
  • Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)
  • Kevin Zbuk, MD, FRCPC (Margaret and Charles Juravinski Cancer Centre)

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National Cancer Institute: PDQ® Genetics of Colorectal Cancer. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: Accessed <MM/DD/YYYY>.

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Last Revised: 2015-02-20