Colorectal Polyps as Precursors to Colorectal Cancer (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).

Transformation of any polyp into cancer goes through the adenoma-carcinoma sequence. Polyps that have traditionally been considered nonneoplastic include those of the hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid types. However, in certain circumstances, hamartomatous and juvenile polyps can progress into cancer.

Research, however, does suggest a substantial risk of colon cancer in individuals with juvenile polyposis syndrome and Peutz-Jeghers syndrome, although the nonadenomatous polyps associated with these syndromes have historically been viewed as nonneoplastic.[5-7]

Epidemiological studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[8]

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. Adenocarcinomas are generally considered to arise from adenomas,[9-13] based upon the following important observations:

1. Benign and malignant tissue occur within colorectal tumors.[14]
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.[15]

The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[14]

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.[16,17] 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.[18,19] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[20]

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 percentage of deaths from CRC (3.9%) among the first-degree relatives (FDRs) of patients who had died from CRC than among sex-matched and age-matched controls (1.2%).[21] This difference has since been replicated in numerous studies that have consistently found that FDRs 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.[22-27]

A systematic review and meta-analysis of familial CRC risk has been reported.[28] Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected FDR. 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 FDR. 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 an 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 FDR 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 (RR, 3.87; 95% CI, 2.40–6.22) compared with family members of index cases diagnosed at ages 45 to 59 years (RR, 2.25; 95% CI, 1.85–2.72), and to family members of index cases diagnosed at age 60 years or older (RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in an FDR was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had an FDR with an adenoma.[28] This finding has been corroborated.[29] 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.[30,31] 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.

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.) Computer models are now available to estimate the probability of developing CRC.[32] These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. In addition, at least three validated models are also available for predicting the probability of carrying a pathogenic variant in a mismatch repair (MMR) gene.[33-35]

Figure 1 shows the proportion of CRC cases that arise in various family risk settings.[36]

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 pathogenic variants known to cause a predisposition to CRC are inherited in an autosomal dominant fashion.[37] One example of autosomal recessive inheritance, MUTYH-associated polyposis (MAP), has been identified. (Refer to the MUTYH-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 pathogenic variant. 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 male and female children. 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 the presence of a hereditary CRC syndrome:

   • Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases.[38]
   • 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 nonneoplastic extracolonic features may suggest a hereditary colon cancer predisposition syndrome (e.g., congenital hypertrophy of the retinal pigment epithelium and desmoid tumors in familial adenomatous polyposis [FAP]).
   • An uncommon tumor (e.g., adrenocortical carcinoma, sebaceous adenoma or carcinoma, and trichilemmoma) may serve as a clue to the presence of a hereditary cancer syndrome.
   • 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 gastrointestinal endoscopists in particular, may consider multigene (panel) testing of an ever-expanding list of genes associated with CRC. (Refer to Table 2, Genes Associated with a High Susceptibility of Colorectal Cancer, for more information.) 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.

The two most common causes of hereditary CRC are FAP (including AFAP), due to germline pathogenic variants in the APC gene,[39-46] and Lynch syndrome (previously called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline pathogenic variants in DNA MMR genes.[47-50] (Figure 2 depicts a classic family with Lynch syndrome, highlighting some of the indicators of hereditary CRC 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.[37]

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, a young age at onset in some individuals, and incomplete penetrance. 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. Because the cancer risk is not 100%, individuals who have Lynch syndrome may not develop cancer, such as the mother of the female with colon cancer diagnosed at age 37 years in this pedigree (called incomplete penetrance).

Identification of Individuals at High Genetic Risk of CRC

National Comprehensive Cancer Network (NCCN) guidelines are updated annually to help identify patients who are appropriate for referral to cancer genetic counseling services. Furthermore, NCCN also provides cancer surveillance recommendations for hereditary cancer syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal/family history criteria to help identify at-risk individuals for referral to cancer genetics risk consultations.[51] These practice guidelines consider tumor types, other specific tumor features, and related criteria that would prompt a genetics referral. The authors state that these guidelines from ACMG/NSGC are intended to maximize referral of appropriate at-risk individuals to cancer genetic counseling services, but they are not meant to provide genetic testing or treatment recommendations. In addition, the authors note other sources that discuss updated/evolving genetic testing criteria for hereditary cancer syndromes (e.g., NCCN), and they acknowledge the increasing role of nongenetics professionals in facilitating genetic testing, especially to guide cancer treatment.[52]

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 pathogenic variant testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of pathogenic variants in CRC-associated genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost-effective.

Rather detailed recommendations for surveillance in FAP and Lynch syndrome have been provided by several organizations representing various medical specialties and societies. These organizations include the following:

• American Cancer Society.[53]
• United States Multisociety (American Gastroenterological Association and American Society for Gastrointestinal Endoscopy) Task Force on Colorectal Cancer.[54]
• American Society of Colon and Rectal Surgeons.[55]
• NCCN.[56]
• Gene Reviews.
• American College of Gastroenterology.[57]
• Society of Gynecologic Oncology and American College of Obstetrics & Gynecology.

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.

Difficulties in Identifying a Family History of CRC Risk

The accuracy and completeness of family history data must be considered when using family history to assess individual risk in clinical practice and when identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[62] Increased use of colonoscopy may result in fewer CRCs and more precancerous colon polyps in a family history. Individuals are much less likely to know about their family history of polyps (i.e., type of polyps and total number of polyps in their relatives) than they are to know about their family history of cancer. In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, due to incomplete penetrance, some individuals 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 Lynch syndrome and less reliably reported by some patients. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Several approaches are available to evaluate a patient with newly diagnosed CRC who may or may not be suspected of having a cancer genetics syndrome. The clinician may suspect a potential inherited disposition based on the family history and physical exam, and genetic tests are available to confirm these suspicions. The American College of Medical Genetics and Genomics has published guidelines for evaluating patients with suspected colon cancer susceptibility syndromes.[51] The guidelines aim to identify individuals whose clinical features warrant referral for genetics consultation. If an individual has multiple polyps (>20), depending on the histology, specific gene-directed testing can be a useful diagnostic tool. Similarly, if a patient’s clinical presentation is suspicious for Lynch syndrome, germline genetic testing can be directed towards this syndrome. However, diagnosis is more challenging when the clinical picture is less clear. Currently, tumor screening for Lynch syndrome is the most commonly accepted approach. However, increasingly, panels characterizing somatic variants in tumors are being utilized for a variety of clinical decisions.

A priori risk-assessment testing (which models risk based on a variety of factors, such as age at cancer onset and the spectrum of tumors in the family) may be an appropriate alternative in many cases. Application of such risk models does anticipate the use of multigene (panel) testing; however, their exact role remains to be established.

Molecular Events Associated With Colon Carcinogenesis

Much of our initial understanding of the molecular pathogenesis of CRC derived from rare hereditary CRC syndromes and revealed heterogeneity of CRC both molecularly and clinically. It is well accepted that most CRCs develop from adenomas. The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[63-65] Presently, CRC can be separated into three categories based on similar molecular genetic features, suggesting divergent pathways of tumorigenesis: chromosomal instability (CIN), MSI, and CpG island methylator phenotype (CIMP). The understanding of the molecular genetic pathways of colorectal tumorigenesis is still evolving, and each new level of understanding has occurred in the context of the preceding level of knowledge. In addition, these pathways emerged from important clinical and histological heterogeneity of colorectal polyps and cancers. Thus, the introduction below captures the chronological evolution of our current understanding of colorectal tumorigenesis.

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76. McCann BG: A case of metaplastic polyposis of the colon associated with focal adenomatous change and metachronous adenocarcinomas. Histopathology 13 (6): 700-2, 1988. [PubMed: 2466756]
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78. Koide N, Saito Y, Fujii T, et al.: A case of hyperplastic polyposis of the colon with adenocarcinomas in hyperplastic polyps after long-term follow-up. Endoscopy 34 (6): 499-502, 2002. [PubMed: 12048637]
79. Torlakovic E, Snover DC: Serrated adenomatous polyposis in humans. Gastroenterology 110 (3): 748-55, 1996. [PubMed: 8608884]
80. Torlakovic EE, Gomez JD, Driman DK, et al.: Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol 32 (1): 21-9, 2008. [PubMed: 18162766]
81. Snover DC, Jass JR, Fenoglio-Preiser C, et al.: Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 124 (3): 380-91, 2005. [PubMed: 16191506]
82. Lash RH, Genta RM, Schuler CM: Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol 63 (8): 681-6, 2010. [PubMed: 20547691]
83. Torlakovic E, Skovlund E, Snover DC, et al.: Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27 (1): 65-81, 2003. [PubMed: 12502929]
84. Jass JR, Baker K, Zlobec I, et al.: Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a 'fusion' pathway to colorectal cancer. Histopathology 49 (2): 121-31, 2006. [PMC free article: PMC1619718] [PubMed: 16879389]
85. Goldstein NS: Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases. Am J Clin Pathol 125 (1): 132-45, 2006. [PubMed: 16483002]
86. Lu FI, van Niekerk de W, Owen D, et al.: Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma. Am J Surg Pathol 34 (7): 927-34, 2010. [PubMed: 20551824]
87. Schreiner MA, Weiss DG, Lieberman DA: Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology 139 (5): 1497-502, 2010. [PubMed: 20633561]
88. Toyota M, Ahuja N, Ohe-Toyota M, et al.: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96 (15): 8681-6, 1999. [PMC free article: PMC17576] [PubMed: 10411935]
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90. Samowitz WS, Albertsen H, Herrick J, et al.: Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129 (3): 837-45, 2005. [PubMed: 16143123]
91. Yamashita K, Dai T, Dai Y, et al.: Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4 (2): 121-31, 2003. [PubMed: 12957287]
92. Weisenberger DJ, Siegmund KD, Campan M, et al.: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38 (7): 787-93, 2006. [PubMed: 16804544]
93. Chan AO, Issa JP, Morris JS, et al.: Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol 160 (2): 529-36, 2002. [PMC free article: PMC1850645] [PubMed: 11839573]
94. Kambara T, Simms LA, Whitehall VL, et al.: BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53 (8): 1137-44, 2004. [PMC free article: PMC1774130] [PubMed: 15247181]
95. O'Brien MJ, Yang S, Clebanoff JL, et al.: Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28 (4): 423-34, 2004. [PubMed: 15087661]
96. Yang S, Farraye FA, Mack C, et al.: BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol 28 (11): 1452-9, 2004. [PubMed: 15489648]
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101. McGivern A, Wynter CV, Whitehall VL, et al.: Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3 (2): 101-7, 2004. [PubMed: 15340260]
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Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important pathogenic variants (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 variants 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 colorectal (CRC) cancer genes have been reasonably well characterized over the past decade.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for familial adenomatous polyposis (FAP), Lynch syndrome, and juvenile polyposis syndrome (JPS), among others. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.

De Novo Pathogenic Variant 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 pathogenic variant rate (de novo pathogenic variant 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 pathogenic variants, in the 25% to 30% range,[3-5] while estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[6-8] These estimates of spontaneous pathogenic variant rates in Lynch syndrome seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[9-11] making the de novo pathogenic variant rate for Lynch syndrome 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 (FDR) 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 FDRs 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 alterations in single low-penetrance genes or combinations of low-penetrance genes.[15] Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.

Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome 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 variants (SNVs).

Several genome-wide association studies (GWAS) have been conducted with relatively large, unselected series of patients with CRC, who have been evaluated for patterns of polymorphisms in candidate and anonymous genes throughout the genome.[16-19] The use of genome-wide scans in thousands of CRC cases and controls has led to the discovery of multiple common, low-risk CRC SNVs, which can be found in the National Human Genome Research Institute GWAS catalog. For more information on GWAS, see Cancer Genetics Overview.

A goal of these studies has been to identify SNVs that may confer mildly increased CRC risks. This risk stratification could potentially enhance usability of CRC screening by influencing patient decision making regarding the ages to begin/end CRC screening and the amount of time between screening studies. There is increasing interest about using SNVs to expand germline risk assessment. This could be expanded from only searching for monogenic forms of CRC predisposition with high-/moderate-penetrance to searching for forms of CRC predisposition with polygenic risk, which may have broader applicability in the general population. Additionally, multiple studies have examined if polygenic risk scores (PRS) can be used to personalize CRC risk assessment in individuals with average risk of developing CRC.[20,21] While the growing body of data on CRC risk SNVs and PRS have been promising, PRS are not currently used in routine clinical settings and are not considered clinically actionable to guide the use of CRC screening procedures. Formal implementation studies are warranted to analyze how PRS can guide CRC risk assessment and screening in routine clinical care.

APC I1307K

The APC I1307K polymorphism deserves special mention, given that it is commonly identified in individuals of Ashkenazi Jewish ancestry undergoing multigene (panel) testing [22,23] and is associated with an increased risk of CRC; however, it 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.[24,25] The I1307K polymorphism results from a transition from T to A at nucleotide 3920 in the APC gene and appears to create a region of hypermutability by virtue of the fact that this results in an A₈ microsatellite coding sequence.[24] Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated CRC risk is not high enough to support their routine use. On the basis of currently available data, it is not yet known whether the I1307K carrier status should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.

References

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Introduction

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 syndrome, 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 four, 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 pathogenic variants in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations due to an APC pathogenic variant at the 3’ or 5’ ends of the gene. MUTYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the pathogenic variants were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for carriers of pathogenic variants (refer to Table 3).

With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for variants 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 variants from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance (VUS) that cannot be used for predictive purposes.

Familial Adenomatous Polyposis (FAP)

Introduction

By 1900, several reports had demonstrated that patients with a large number of polyps (later subclassified as adenomas) were at very high risk of CRC and that the pattern of transmission in families was autosomal dominant. In the 20th century, the adenoma-to-carcinoma progression was confirmed, and FAP was recognized as the prototypical model for this progression.[11] Classic FAP is characterized by numerous (hundreds to thousands) adenomatous polyps in the colon and rectum developing after the first decade of life (refer to Figure 3).

Figure 3. Familial adenomatous polyposis is characterized by multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life.

There is also a subset of classic FAP that has an attenuated phenotype. AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.)

FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,12,13] It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births.[14] The presence of ethnic differences in the prevalence of FAP has been suggested [14] but a large study did not find significant differences in ethnic variation in more than 6,169 individuals with a personal and/or family history of CRC and polyps who were referred for genetic testing at a large reference laboratory.[15] Most cases of FAP result from pathogenic variants in the APC gene on chromosome 5q21. (Refer to the Genetics of FAP section of this summary for more information about the APC gene and genetic testing.)

In addition to a high risk of colon adenomas in FAP patients, various extracolonic manifestations have also been described, including upper gastrointestinal (GI) tract adenomas and adenocarcinomas; fundic gland stomach polyps; nonepithelial benign tumors (osteomas, epidermal cysts, dental abnormalities); desmoid tumors; congenital hypertrophy of retinal pigment epithelium (CHRPE); and malignant tumors (thyroid and brain tumors, hepatoblastoma). Refer to Table 4 for the risks of these extracolonic manifestations in FAP.

Table 4. Extracolonic Tumor Risks in Familial Adenomatous Polyposis

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Malignancy	Relative Risk	Absolute Lifetime Risk (%)
Desmoid tumor	852.0	15.0
Duodenal tumors and cancer	330.8	5.0–12.0
Thyroid cancer	7.6	2.0
Brain cancer	7.0	2.0
Ampullary cancer	123.7	1.7
Pancreatic cancer	4.5	1.7
Hepatoblastoma	847.0	1.6
Gastric cancer	Not defined	0.6a

Adapted from Giardiello et al.,[16] Jagelman et al.,[17] Sturt et al.,[18] Lynch et al.,[19] Bülow et al.,[20] Burt et al.,[21] and Galiatsatos et al.[22]

^aThe Leeds Castle Polyposis Group.

FAP has also been known as familial polyposis coli or adenomatous polyposis coli (APC). Gardner syndrome was previously the diagnosis for FAP patients who manifested with colorectal polyposis, osteomas, and soft tissue tumors. However, Gardner syndrome has been shown genetically to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.[23]

Attenuated Familial Adenomatous Polyposis (AFAP)

MUTYH-Associated Polyposis (MAP)

MAP is an autosomal recessively inherited polyposis syndrome caused by pathogenic variants in the Mut Y homolog gene. The Mut Y homolog gene, which is known as MUTYH, was initially called MYH, but was subsequently corrected because the myosin heavy chain gene already had that designation. MUTYH is located on chromosome 1p34.3-32.1.[215] The protein encoded by MUTYH is a base excision repair glycosylase, which repairs one of the most common forms of oxidative damage. Over one hundred unique sequence variants of MUTYH have been reported. A founder pathogenic variant with ethnic differentiation is assumed for MUTYH pathogenic variants. In White populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic pathogenic variants in MAP patients; 90% of these patients carry at least one of these pathogenic variants.[216] Other causative variants that have been found include P405L (formerly known as P391L) (Netherlands),[217,218] E480X (India),[219] Y104X (Pakistan),[220] 1395delGGA (Italy),[221,222] 1186-1187insGG (Portugal),[223] and p.A359V (Japan and Korea).[224 -226]

The MUTYH gene was first linked to polyposis in 2002 in three siblings with multiple colonic adenomas and CRC but no APC pathogenic variant.[112] 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 Lynch syndrome.[227] MAP patients tend to develop fewer adenomas at a later age than patients with APC pathogenic variants [228,229] but still carry a high risk of CRC (35%–75%).[7,230,231] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MUTYH pathogenic variants of 4% (95% 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.[116] This broad clinical presentation results from the MUTYH 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 an FAP phenotype and without a detectable APC germline pathogenic variant carry biallelic variants in the MUTYH gene.[7,219,229,232]

Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients.[233] The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[215] Clinical management guidelines for MAP recommend screening with colonoscopy and polypectomy every 1 to 2 years if fewer than 20 adenomas are found. Colonoscopy begins no later than age 25 to 30 years (although, screening at a younger age may be considered based on family history).[123,214,230] Upper endoscopic surveillance begins at age 30 to 35 years.[214] (Refer to Table 8 for more information about available clinical practice guidelines for colon surveillance in MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria.[214] Total colectomy with ileorectal anastomosis or subtotal colectomy may be necessary for patients with MUTYH-associated polyposis depending on overall polyp burden.[230,234]

Although MAP is the only known biallelic (recessive) adenoma cancer predisposition syndrome described to date, there are examples of biallelic cases presenting with childhood tumors in which MMR genes are involved. For more information, see the IHC in constitutional mismatch repair deficiency (CMMRD) syndrome section.

Table 8 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.

Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, thyroid, and skin cancers (melanoma, squamous epithelial, and basal cell carcinomas).[236,237] Additionally, noncancerous extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[221,229,237,238] Female MAP patients have an increased risk of breast cancer.[239] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or Lynch syndrome.[240,241]

Oligopolyposis

Oligopolyposis is a term that is used to describe a polyp count that is greater than anticipated in average-risk patients but falls short of the polyp count that is required for an FAP diagnosis. Thus, oligo-, Greek for few, can mean different things to different observers. Here, the term oligopolyposis will be used to describe situations in which the patient's polyp count (generally adenoma) is large enough (with or without family history) to make an endoscopist suspect a hereditary polyposis syndrome. Most patients with oligopolyposis (including adenomas) do not have a known underlying predisposition to polyposis (i.e., pathogenic variants in known polyposis predisposition genes). Such cases are generally managed as if they are at an increased risk for recurrent adenomas, even when the colon can be cleared of polyps endoscopically.

Current NCCN guidelines recommend that patients with 10 or more cumulative adenomatous polyps consider genetic testing.[123] A cross-sectional study included 3,789 patients with 10 or more colorectal polyps who underwent multigene panel testing for the following genes: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53.[247] Pathogenic variants were found in 5% of participants, regardless of the participant's age or polyp cohort. GREM1, POLD1, and POLE were only evaluated in 2,353 patients because these genes were added to the multigene panel testing assay during the study period. Pathogenic variants in adenomatous polyposis genes decreased as participants increased in age in all polyp-count groups in the adenoma cohort. This, however, was not true for the nonpolyposis-related CRC genes. The prevalence of pathogenic variants in hamartomatous polyposis genes was high in the hamartoma cohort, regardless of polyp count (40% of participants had 10–19 polyps, 72.1% of participants had 20–99 polyps, and 50% of participants had 100 or more polyps). The study concluded that multigene panel testing of polyposis and nonpolyposis-related CRC genes may benefit patients with 10 or more CRC polyps, given that more than 5% of patients had pathogenic variants in all age groups. For more information about genetic testing for polyposis, see the Genetic testing for FAP section.

AFAP resulting from pathogenic germline APC variants may be the most common cause of oligopolyposis where a specific causative germline alteration cancer has been identified. Some AFAP cases with oligopolyposis will eventually develop 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 pathogenic variant are clearly variant cases of FAP, as the term AFAP implies.[248] However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC pathogenic variant. The lower the polyp count the lower the probability of having an APC pathogenic variant. Some of these cases are now known to carry biallelic MUTYH pathogenic variants or variants in other genes linked to oligopolyposis.[249]

Pathogenic variants in related DNA polymerase genes, POLE and POLD1, have been described in families with oligopolyposis, CRC, and endometrial cancer. This condition is called polymerase proofreading–associated polyposis (PPAP).[250,251] PPAP is an autosomal dominant hereditary cancer syndrome, in which the main replicative DNA polymerases, POLE and POLD1, are unable to proofread newly synthesized DNA strands. Several other malignancies (including endometrial, ovarian, small bowel, and brain cancers), have also been described in POLE and POLD1 carriers. PPAP-associated tumors often present with an ultramutator phenotype characterized by mutational loads exceeding 100 variants per megabase. PPAP-associated cancers can be highly responsive to immune checkpoint inhibitor therapy, irrespective of microsatellite instability (MSI)/MMR status.[252,253] Identifying POLE and POLD1 carriers can be challenging since all known, putative, causal POLE and POLD1 variants are exonuclease-domain missense variants, which are notoriously difficult to classify. In addition, studies on the prevalence and penetrance of PPAP are limited, since this condition is rare and risk estimates may be subject to ascertainment bias.

The prevalence of POLE and POLD1 pathogenic variants was determined in a prospective cohort of 2,309 unrelated patients with hereditary cancer. These patients all underwent genetic testing with a multigene hereditary cancer panel, in which PPAP was responsible for 0.1% to 0.4% of familial cancer cases (and reaching 0.3% to 0.7% when only CRC and polyposis were considered).[254] The tumors most commonly associated with PPAP included CRC, endometrial cancer, and ovarian cancer.

While PPAP is rare, the age-specific cumulative risks (penetrance) of CRC for POLE and POLD carriers is important to quantify and update, in order to better guide and optimize clinical management. In a retrospective study in which families with POLE or POLD1 pathogenic variants were identified via a PubMed search of relevant studies (prior to 2016) and genotypic data from 669 population-based CRC cases diagnosed in patients under 60 (from the Australasian Colorectal Cancer Family Registry), age-specific cumulative risks were estimated using modified segregation analyses.[255] Sixty-seven CRCs were identified in 364 first-degree relatives (FDRs) and second-degree relatives (SDRs) in 41 POLE families, and 6 CRCs were identified in 69 relatives from 9 POLD1 families. CRC risk to age 70 years for males and females, respectively, was 40% (95% CI, 26%–57%) and 32% (95% CI, 20%–47%) in POLE carriers and 63% (95% CI, 15%–99%) and 52% (95% CI, 11%–99%) in POLD1 carriers. The authors concluded that CRC risk for POLE carriers was high enough to consider annual colonoscopy screening and the possible implementation of management guidelines similar to those used in Lynch syndrome. The authors also concluded that clinical management recommendations for POLD1 carriers could be similar to those used in POLE carriers, but refinement of POLD1 CRC risk estimates (from larger cohorts) are needed to further refine recommendations.

Lifetime risk estimates of CRC in POLE carriers were higher than expected in a subsequent study of 354 individuals with early-onset/familial CRC (n = 218) and/or attenuated adenomatous polyposis (n = 136) at a single center between 2014 and 2017.[256] In 51 POLE carriers (from 10 families), risk estimates for CRC and extracolonic PPAP-associated cancers were calculated using nonparametric methods (based on a survival analysis approach) to account for unknown genotypes in relatives. Risks of CRC at ages 30 years, 50 years, and 70 years were 11.1% (95% CI, 4.2–17.5), 48.5% (96% CI, 33.2–60.3), and 74% (95% CI, 51.6–86.1), respectively. These risk estimates were similar in both men and women. These results provided additional support for frequent CRC surveillance in POLE carriers, similar to the surveillance used in highly-penetrant Lynch syndrome genotypes. Extracolonic cancers like glioblastoma, small bowel cancer, endometrial cancer, and ovarian cancer were observed at low frequencies, limiting the ability to establish screening recommendations for these cancer types.

A study utilizing whole-exome sequencing in 51 individuals with multiple colonic adenomas from 48 families identified a homozygous germline nonsense pathogenic variant in seven affected individuals from three unrelated families in the base-excision repair gene NTHL1.[257] These individuals had CRC, multiple adenomas (8–50), none of which were either hyperplastic or serrated, and in three affected females, there was either endometrial cancer or endometrial complex hyperplasia. There were two other individuals who developed duodenal adenomas and duodenal cancer. All pedigrees were consistent with autosomal recessive inheritance. Upon examining three cancers and five adenomas from different affected individuals, none showed MSI. These neoplasms did show enrichment of cytosine to thymine transitions. Additional studies are needed to further define the phenotype. A subsequent study of 863 families with CRC and 1,600 families without CRC confirmed an association between biallelic NTHL1 pathogenic variants and inherited CRC risk.[258] Currently, there is no known increased risk of cancer for individuals harboring a single monoallelic pathogenic germline NTHL1 variant.

Another study ran whole-exome and whole-genome sequencing on 309 individuals with one of the following: (1) a multigene panel that did not find a pathogenic variant in adenomatous polyposis genes, or (2) a family history of multiple individuals with CRC.[259] This study demonstrated that patients with a biallelic loss of the base excision repair gene, MBD4, presented with oligopolyposis. Cancers observed in affected individuals included uveal melanoma, CRC, and acute myeloid leukemia. The majority of adenomas in these individuals had an accumulation of CpG to TpG transitions in well-known CRC driver genes like APC, KRAS, and AMER1.

Hereditary mixed polyposis, characterized by histology that often includes adenomatous and hyperplastic polyps, has been associated with GREM1 pathogenic variants in a small number of Ashkenazi Jewish families. Polyp number in this syndrome is highly variable but is often in the spectrum consistent with oligopolyposis. (Refer to the Hereditary mixed polyposis syndrome [HMPS] section of this summary for more information.)

NTHL1, POLE, POLD1, and GREM1 pathogenic variant testing is being incorporated into the multigene (panel) tests for CRC susceptibility offered commercially along with APC and MUTYH so that a polyposis panel can be ordered up front for the patients with oligopolyposis. There are minimal data on the optimal surveillance approach for individuals found to have pathogenic germline variants in NTHL1 (biallelic carriers only), POLE, or POLD1, although it is presumed that the risk of CRC is comparable to what is seen in Lynch syndrome, and some guidelines are endorsing similarly early and frequent colonoscopic screening.

Oligopolyposis caused by other polyposis histologies can be distinguished from adenomatous polyposis on simple endoscopic and histologic grounds. For example, individuals with juvenile polyposis syndrome (JPS), PJS, or PTEN hamartoma tumor syndrome (Cowden syndrome) can all manifest oligopolyposis, often inclusive of hamartomatous polyps, as well as other more common polyp histologies (e.g., adenomas).

Serrated polyposis can likewise present in highly variable fashion. The World Health Organization (WHO) criteria for serrated polyposis (≥5 serrated polyps proximal to sigmoid with 2 polyps ≥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. Rarely, families with serrated polyposis can be identified to harbor pathogenic germline RNF43 variants, but most cases of serrated polyposis cannot be linked to an underlying genetic basis.[260-262] Consequently, such patients are increasingly being referred for genetic counseling and for consideration of genetic testing. Occasional cases of MUTYH biallelic pathogenic variants have been found in patients with at least some features of serrated polyposis and serrated polyps can be seen in Lynch syndrome. However, germline evaluation of individuals with serrated polyposis is typically unrevealing.[263-267]

Two very small case series have described oligopolyposis with varying polyp histologies (e.g., adenomas, serrated, inflammatory, and hamartomatous polyps) in individuals previously treated with chemotherapy and radiation therapy for a prior childhood malignancy.[268,269] This phenomenon, termed therapy-associated polyposis (TAP), may be an acquired, nonfamilial phenotype caused by prior antineoplastic therapy, and is on the differential diagnosis when nonfamilial oligopolyposis is identified in individuals previously treated with chemotherapy and/or radiation. Another recent study identified oligopolyposis fulfilling WHO criteria for serrated polyposis syndrome (SPS) in 6% of a cohort of 101 Hodgkin lymphoma survivors treated with prior chemotherapy and/or radiation therapy, suggesting that Hodgkin lymphoma survivors may be a particularly important population in whom TAP can manifest.[270]

Lynch Syndrome

Genetics of Lynch syndrome

The genetics of both the tumor and the germline have an important role in the development and diagnosis of Lynch syndrome. Tumor DNA in Lynch syndrome–associated tumors exhibits characteristic MSI, and in these cases, there is typically loss of IHC expression for one or more of the proteins associated with the MMR genes. Molecular testing with MSI and/or IHC has been adopted as a universal screen for diagnosis of Lynch syndrome in newly diagnosed patients with CRC and endometrial cancer. IHC testing results can potentially direct gene-specific germline testing. Many genetic testing laboratories offer multigene (panel) tests that simultaneously test for pathogenic variants in all of the Lynch syndrome–associated genes (and often additional genes associated with inherited cancer susceptibility).

Genetic and molecular testing for Lynch syndrome

MSI

The presence of MSI in colorectal tumor specimens is a hallmark feature of Lynch syndrome and can be cause for suspicion of a germline pathogenic MMR gene variant. Microsatellites are short, repetitive sequences of DNA (mononucleotides, dinucleotides, trinucleotides, or tetranucleotides) located throughout the genome, primarily in intronic or intergenic sequences.[299,300] The term MSI is used when colorectal, endometrial, or metastatic tumor DNA [301] shows insertions or deletions in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic variants, germline variants, or epigenetic alterations.[302] 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 tumors with MSI and not all tumors with loss of protein expression on IHC will be microsatellite unstable.

Certain histopathologic features are strongly suggestive of MSI phenotype, including the presence of tumor-infiltrating lymphocytes (refer to Figure 4), Crohn-like reaction, mucinous histology, and histological heterogeneity.[303]

Figure 4. Tumor-infiltrating lymphocytes are a histopathologic feature suggestive of microsatellite instability.

Initial designation of a colorectal adenocarcinoma as microsatellite unstable was based on the detection of a specified percentage of unstable loci from a panel of three dinucleotide and two mononucleotide repeats that were selected at a National Institutes of Health (NIH) Consensus Conference and referred to as the Bethesda panel. If more than 30% of a tumor's markers were unstable, it was scored as MSI-H; if at least one, but fewer than 30% of markers were unstable, the tumor was designated MSI-low (MSI-L). If no loci were unstable, the tumor was designated microsatellite stable (MSS). Most tumors arising in the setting of Lynch syndrome will be MSI-H.[304] The clinical relevance of MSI-L tumors remains controversial; the probability is very small that these tumors are associated with a germline pathogenic variant in an MMR gene.

The original Bethesda panel has been replaced by a pentaplex panel of five mononucleotide repeats,[304] which has improved the detection of MSI-H tumors.

(Refer to the Prognostic and therapeutic implications of MSI section of this summary for more information about the treatment implications of MSI testing.)

(Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for information about the utilization of MSI status in the diagnostic workup of a patient with suspected Lynch syndrome.)

IHC

IHC methods are cheaper, easier to understand, and more widely available as a surrogate for MSI and, for these reasons, have replaced polymerase chain reaction (PCR)–based MSI testing in most institutions. IHC is performed in the colorectal or endometrial tumor (or metastatic sites) [301] for protein expression using monoclonal antibodies for the MLH1, MSH2, MSH6, and PMS2 proteins. Isolated loss of expression of any one of these proteins may suggest which specific MMR gene is altered in a particular patient.[305-308] However, certain proteins can form heterodimers (or have other binding partners) and yield loss of two proteins expressed on IHC.

MSI can lead to nucleotide-pairing slippage (looping) in which single nucleotide mispairs are introduced. Heterodimers of MMR proteins are formed to identify the errors and bind the DNA at these sites.[302,309] For example, MSH2 protein complexes with MSH6 protein to form MutSα, which has the main ability to repair single base pair mismatches and single base pair loop-out lesions that can occur during the replication of a mononucleotide repeat sequence. In the absence of MSH6 protein, the MSH2 protein will dimerize with the MSH3 protein forming the MutSβ complex, which has the ability to trigger repair of larger loop-out DNA mismatches, but also has some overlapping activity to repair lesions usually repaired by MutSα.

Figure 5. Immunohistochemical tumor testing for protein expression of the mismatch repair genes associated with Lynch syndrome, depicted for a single patient with colorectal cancer. Protein expression is preserved for MSH2 and MSH6 (inset) and absent for MLH1 and PMS2 (inset). Absence of MMR protein expression is suggestive of Lynch syndrome and warrants additional evaluation.

As a result, when the germline pathogenic variant is in the MSH2 gene, the tumor IHC may not express both MSH2 and MSH6, as the latter protein requires binding to MSH2 for stability. In this case, if no pathogenic variant is found in either gene, germline pathogenic variant testing for EPCAM should be considered if it was not already included. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 pathogenic variant identified will have germline deletions in EPCAM.[310] The latter mechanism accounts for approximately 5% of all Lynch syndrome cases.[310] A deletion of one exon 9 allele in the EPCAM (TACSTD1) gene, which is immediately upstream of MSH2's start site and in the same orientation, can lead to transcriptional read-through and methylation of the MSH2 promoter. This can lead to subsequent silencing of MSH2 in any tissue that expresses EPCAM. The presence of EPCAM pathogenic variants showing similar methylation-mediated MSH2 loss has been reported in numerous families.[311] On the strength of these observations, germline EPCAM testing is performed in patients with loss of MSH2 protein expression on IHC testing of their CRCs but who lack a detectable MSH2 germline pathogenic variant and is included with MSH2 testing in all colon cancer gene panels. For more information, see the EPCAM section.

In patients with no variants in any of these genes, tumor sequencing may reveal biallelic, somatic MSH2 variants. For more information, see the Somatic biallelic mismatch repair deficiency (sometimes called Lynch-like syndrome) section.

Similarly, the loss of MLH1 (either by germline pathogenic variant or hypermethylation of the MLH1 promoter) results in the absence of expression of both MLH1 and PMS2 proteins in the tumor. The most common abnormal IHC pattern for DNA MMR proteins in colorectal adenocarcinomas is loss of expression of MLH1 and PMS2. PMS2 and MLH1 function as a stable heterodimer known as MutLα. MutLα binds to MutSβ and guides excision repair of the newly synthesized DNA strand.[302] A functional defect in MLH1 results in degradation of both MLH1 and PMS2, while a defect in PMS2 negatively affects only PMS2 expression. Thus, a loss of MLH1 and PMS2 indicates that there is an alteration in MLH1 (promoter hypermethylation or germline variant), while loss of PMS2 expression often indicates that there is a germline PMS2 variant. However, among 88 individuals with PMS2-deficient CRC, PMS2 germline pathogenic variant testing followed by MLH1 germline pathogenic variant testing revealed pathogenic PMS2 variants in 49 individuals (74%) and MLH1 pathogenic variants in 8 individuals (12%).[312] Eighty-three percent of the alterations in MLH1 were missense variants, but two relatives carried identical MLH1 variants, and one individual, who developed two tumors with retained MLH1 expression, carried an intronic variant that led to skipping of exon 8.[312] Therefore, in CRCs with solitary loss of PMS2 expression, an MLH1 germline pathogenic variant should be sought if no PMS2 germline variant is found. Tumors with MSI and loss of MSH2 and MSH6 protein expression are generally indicative of an underlying MSH2 germline variant (inferred MSH2 pathogenic variant). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter.

Unlike MLH1 and MSH2 (which both dimerize with other proteins or have other binding partners), germline pathogenic variants in MSH6 and PMS2 result in the isolated loss of those specific proteins by IHC. However, tumors from MSH6 pathogenic variant carriers may not display the MSI phenotype at a frequency as high as MLH1 and MSH2 carriers (despite an inactive DNA MMR system), as there are pathogenic missense variants that do not completely abrogate protein expression yielding false negative results by IHC testing.[291,313] In a study that reported tumor testing results among MMR germline carriers enrolled through the Colon Cancer Family Registry, 7 of 24 carriers (28%) with MSH6 pathogenic variants had tumors that displayed normal protein expression on IHC staining. IHC tumor testing was more informative for MLH1 and MSH2 pathogenic variant carriers in which 93% of MLH1 carriers had correlating loss of MLH1 protein expression and 96% of MSH2 carriers had loss of MSH2 protein expression.[291]

In some cases, tumors manifest MSI and/or IHC shows loss of DNA MMR protein expression, but no germline pathogenic variant is identified. This tumor phenotype is predominantly due to biallelic somatic inactivation of the DNA MMR genes and is not a pathogenic germline alteration. This phenomenon has been labeled Lynch-like syndrome (sometimes called LLS in the literature), although this terminology may cause confusion since this term represents a mechanism of sporadic carcinogenesis, rather than a stand-alone genetic syndrome. For more information, see the Somatic biallelic mismatch repair deficiency (sometimes called Lynch-like syndrome) section.

Table 9. Protein Loss and Potential Germline Defect(s)

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Loss of Protein Expression	Germline MMR Defect Predicted by IHC Protein Expression Loss
	MLH1	MSH2	MSH6	PMS2	EPCAM
MLH1/PMS2	X
MSH2/MSH6		X			X
MSH6			X
PMS2	X			X
MLH1	X			X
MSH2		X	X

IHC = immunohistochemistry; MMR = mismatch repair.

Somatic MLH1 hypermethylation

It is important to recognize that hypermethylation of the MLH1 promoter, a somatic event confined to the tumor, can lead to abnormal protein expression of MLH1 on IHC. Approximately 10% to 15% of sporadic CRC cases have a microsatellite unstable tumor phenotype due to MLH1 hypermethylation and are not heritable. These sporadic MSI colon cancers [314] have a generalized excess of DNA methylation referred to as CIMP.[315] (Refer to the CIMP and the serrated polyposis pathway section in the Introduction section of this summary for more information.) Because loss of MLH1 protein expression on IHC occurs in both Lynch syndrome and sporadic tumors, its specificity for predicting germline MMR gene variants is lower than for the other MMR proteins, and additional molecular testing is often necessary to clarify the etiology of MLH1 absence.

BRAF pathogenic variants have been detected in 68% of CRC tumors with MLH1 promoter hypermethylation and very rarely, if ever, in CRC from patients with Lynch syndrome.[316-319] This suggests that detection of somatic BRAF V600E variant detection in CRC may be useful in excluding individuals from germline variant testing. As a result, BRAF V600 testing and/or MLH1 hypermethylation assays are increasingly utilized in universal Lynch syndrome–testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caused by hypermethylation and germline MLH1 pathogenic variants. Making such a distinction is also a more cost-effective approach in excluding individuals from germline testing.

Somatic biallelic mismatch repair deficiency (sometimes called Lynch-like syndrome)

Prior to the widespread use of somatic tumor sequencing, somatic MLH1 hypermethylation was thought to be the only major sporadic pathway for a tumor to have MSI-H/MMR-deficient (MMR-D) biology. It was presumed that any MSI-H/MMR-D CRC or endometrial cancer with patterns of MMR deficiency (other than MLH1/PMS2 loss) was due to Lynch syndrome, even if a germline pathogenic variant in an MMR gene could not be identified. However, as IHC is more routinely performed for all CRCs and endometrial cancers, it has become clear that other patterns of MMR deficiency can arise via sporadic mechanisms, typically by somatic biallelic MMR gene inactivation.[320] This phenomenon has been labeled Lynch-like syndrome (sometimes called LLS in the literature), although this terminology may cause confusion since this term represents a mechanism of sporadic carcinogenesis, rather than a stand-alone genetic syndrome.

Work from the Ohio Colorectal Cancer Prevention Initiative found that 88.4% of CRCs and 100% of endometrial cancers with unexplained MMR-D statuses (i.e., cancers did not have a germline pathogenic variant in an MMR gene or MLH1 promoter hypermethylation) had somatic biallelic MMR deficiency found on somatic tumor sequencing.[321,322] In an additional series of MMR-D cancers (mostly CRCs and endometrial cancers) that underwent paired germline and somatic MMR variant analyses, somatic biallelic genetic alterations were found in 49% of the tumors that lacked causal germline pathogenic variants, MLH1 promoter hypermethylation, and BRAF V600E variants.[323]

When CRCs, endometrial cancers, or other tumors have unexplained MMR-deficiency, in which somatic sequencing fails to identify somatic biallelic MMR deficiency, it is possible that a small fraction of these cases could represent occult Lynch syndrome (or other forms of unidentifiable inherited cancer risk). In these cases, it is recommended that patients' clinical and family histories be carefully examined for possible inherited cancer risk. This will help determine if patients and their families will be clinically managed as if they have suspected Lynch syndrome. In these cases, careful scrutiny of any germline MMR gene VUS is also warranted to assess whether these VUSs could harbor pathogenicity. For more information about VUS genetic test results, see the Value of testing an affected family member first section in Cancer Genetics Risk Assessment and Counseling.

Some studies have attempted to define the risk of CRC and other Lynch syndrome–associated malignancies in cohorts of individuals with Lynch-like syndrome. However, the ability to clinically interpret these data may be limited since these populations presumably include a mix of individuals with sporadic MMR-D cancers and others with inherited cancer risk.[324,325]

IHC in constitutional mismatch repair deficiency (CMMRD) syndrome

In contrast with Lynch syndrome (which is defined by the presence of a single, germline, heterozygous, deleterious variant in an MMR gene), rarely, individuals can have deleterious germline variants in both alleles of the same MMR gene. These cases can present with homozygous or compound heterozygous genotypes. This is termed biallelic mismatch repair deficiency (BMMRD) or constitutional mismatch repair deficiency (CMMRD). The likelihood of CMMRD involving homozygous MMR gene pathogenic variants will inevitably be higher among consanguineous unions. Rates of consanguinity may be higher in rural and geographically and/or culturally isolated populations.[326]

Tumor studies yield characteristic abnormalities. In a series of 28 patients with CMMRD,[115] 17 brain tumors showed loss of staining for MMR protein in normal stromal cells and in neoplastic cells. This differs from tumors in patients with Lynch syndrome, in which normal staining is retained in nontumor cells. In contrast to this characteristic feature seen with IHC, PCR-based MSI analysis was not reliable, as 20 of 28 tumors from patients with CMMRD were MSS. Essentially all of the MSI-H tumors were colon cancers.

The PMS2 gene is markedly overrepresented in cases of CMMRD. It has been suggested that the presence of homozygosity in other MMR gene variants is a prenatally lethal state, while milder expression of PMS2 variants is consistent with survival when present in both parental alleles.

For more information about CMMRD's clinical phenotype, see the CMMRD section.

Table 10. Hereditary Colorectal Cancer (CRC) Syndromes and Associated Tumor Phenotypes^a

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Clinical Phenotype	Pathogenic Germline Variant in DNA MMR	Somatic Inactivation of DNA MMR	Tumor Phenotype
Lynch syndrome	Present in one allele	Present in one allele	MSI
Sporadic CRC with hypermethylation of MLH1 promoter	Absent	+BRAF	MSI
CMMRD	Present in two alleles	Absent	MSI (tumor and normal tissue)
Somatic biallelic MMR deficiency (sometimes called Lynch-like syndrome)	Absent	Present in two alleles	MSI
FCCX	Absent	Absent	MSS

CMMRD = constitutional mismatch repair deficiency; FCCX = familial colorectal cancer type X; MMR = mismatch repair; MSI = microsatellite instability; MSS = microsatellite stable.

^aAdapted from Carethers et al.[325]

Constitutional epimutation

While somatic hypermethylation of the MLH1 promoter is acquired and not uncommon, examples of MLH1 promoter hypermethylation have been described in the germline and are generally not associated with a stable Mendelian inheritance. This constitutional methylation of MMR genes occurs most often in MLH1 and, to a lesser extent, MSH2 and is termed constitutional epimutation.[327] A constitutional epimutation (also referred to as a primary epimutation) is an acquired alteration in normal tissue that silences an active gene or activates an inactive gene.[328] Such epimutations occur most often in maternal alleles. In some cases, all somatic cells appear involved, while in others there is evidence of mosaicism. Tumors in patients with primary epimutations are generally indistinguishable from those otherwise typical of Lynch syndrome germline variant carriers, including age at onset, tumor spectrum, and presence of abnormal MSI and IHC. Since these are not inherited in a Mendelian fashion, antecedent family history of tumors is minimal, and risk to offspring somewhat unpredictable. Epimutations present in a de novo case seem to typically be "erased" in the process of gametogenesis and to not be passed to the next generation. Very rare cases of inherited MLH1 epimutations have been reported.[329,330]

Interpreting molecular alterations in tumors and distinguishing the likely primary epimutation cases from those of sporadic MSI poses significant challenges. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Rare instances of a de novo constitutional epimutation in MLH1 [331] or an inherited germline MLH1 methylation [332] add some complexity to the interpretation of MSI associated with absence of MLH1 expression. Akin to sporadic MSI, primary epimutation tumors show methylation of the MLH1 promotor and may show BRAF variants as well. As noted above, family history of cancer in such cases tends to be minimal or absent, as in true sporadic MSI. Distinguishing such cases from sporadic cases may call for assaying normal tissue (e.g., blood or normal colon mucosa) for evidence of MLH1 methylation, which will be absent from true sporadic cases and absent from carriers of conventional Lynch syndrome MMR pathogenic variants.

Such MLH1-predominant primary epimutations are to be distinguished from secondary epimutations such as those occurring when MSH2 is methylated as a consequence of inherited variants in the upstream EPCAM gene. (Refer to the EPCAM section of this summary for more information.)

Molecular diagnostic tumor testing to screen for Lynch syndrome in clinical practice

While many molecular pathology laboratories can assess both MSI and IHC, an approach that uses IHC testing as the initial screen for defective MMR activity has been favored because it is less labor intensive and more cost-effective.[333,334] Part of this rationale is that the information provided by IHC may target germline genetic testing toward one specific MMR gene (with the exception of loss of MLH1 expression) as opposed to a comprehensive testing strategy of all Lynch syndrome–related MMR genes that would be directed by the use of MSI alone.[280,333,335-338] While MSI testing was originally favored in the oncologic evaluation of individuals with CRC for its prognostic and therapeutic implications, screening for Lynch syndrome can be more effectively directed by IHC testing.

Universal tumor testing to screen for Lynch syndrome

Use of MSI and/or IHC testing in all newly diagnosed cases of CRC, regardless of the age at diagnosis or family history of cancer, increases the sensitivity of the initial screen for Lynch syndrome. This approach is more sensitive than existing clinical criteria, as many individuals with Lynch syndrome are diagnosed at older ages (>50 y) and have less striking family histories of CRC than previously appreciated. This universal testing of colorectal (and endometrial) tumors using either MSI or IHC testing has been recommended by many professional organizations and is being widely adopted.[123,339-342]

Genetic risk assessment and MMR gene variant testing in individuals with newly diagnosed CRC can lead to improved outcomes for the patient and at-risk family members. Dating back to 2009, 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 (CDC), reported that there was sufficient evidence to recommend offering tumor screening for Lynch syndrome to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives.[343,344] At that time, there was insufficient evidence to recommend a specific testing strategy between MSI and IHC.

Several studies have demonstrated the feasibility of universal screening for Lynch syndrome. Initial experience from one institution found that among 1,566 patients screened using MSI and IHC, 44 patients (2.8%) had Lynch syndrome. For each proband, an average of three additional family members were subsequently diagnosed with Lynch syndrome.[280] A subsequent pooled analysis of 10,206 incident CRC patients tested with MSI/IHC as part of four large studies revealed a pathogenic variant detection rate of 3.1%.[345] This study compared four strategies for tumor testing for the diagnosis of Lynch syndrome: (1) testing all individuals meeting at least one criterion of the Bethesda guidelines; (2) testing all individuals meeting Jerusalem recommendations;[346] (3) testing all individuals with CRC aged 70 years or younger, or older than 70 and meeting at least one criterion of the Bethesda guidelines; and (4) universal testing of all individuals with CRC.[345] Tumor testing with MSI involved panels individualized at each institution and IHC involved testing all four of the DNA MMR genes involved with Lynch syndrome, across all institutions. The strategy of tumor testing in all individuals diagnosed with CRC at age 70 years or younger and testing individuals over age 70 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 Lynch syndrome cases, but 34.8% fewer cases required IHC/MSI testing, and 28.6% fewer cases underwent germline testing than in the universal approach.

The consideration to further stratify the recommendation for molecular tumor testing by age (i.e., 70 y) warrants attention as it influences the cost-effectiveness of universal screening strategy.

Loss of MLH1 and PMS2 due to somatic hypermethylation is not uncommon, and is more frequently detected with increasing age at CRC diagnosis.[347] Therefore, additional molecular tumor testing including BRAF and MLH1 hypermethylation testing is recommended in cases in which there is loss of MLH1 and PMS2 expression on IHC, thereby decreasing the number of individuals referred for unnecessary germline genetic testing. A testing strategy including MLH1 hypermethylation analyses in individuals aged 70 years or younger with CRC who had loss of MLH1 on IHC was shown to be cost-effective in a population-based study of 1,117 individuals.[348]

Screening individuals with CRC for Lynch syndrome is most often performed in a stepwise fashion based on IHC tumor testing results that evaluate protein expression for the four MMR genes related to Lynch syndrome. One proposed strategy is summarized in Figure 6. This framework does not incorporate a germline testing approach that simultaneously evaluates multiple cancer susceptibility genes (multigene [panel] testing), which may be useful in select patient populations. (Refer to the Multigene [panel] testing section of this summary for more information.)

Figure 6. A proposed strategy to evaluate individuals with colorectal cancer for Lynch syndrome based on immunohistochemical tumor testing results. Adapted from Geiersbach KB, Samowitz WS. Microsatellite instability and cancer. Arch Pathol Lab Med 135(10):1269-77, 2011.

Clinicians are increasingly utilizing tumor sequencing to advance therapeutic decisions in a more personalized approach, particularly in patients with metastatic disease. The performance of next-generation tumor sequencing (NGS) of CRCs for the detection of Lynch syndrome was compared with existing screening protocols that include MSI testing and IHC staining (with BRAF p.V600E testing) in 419 CRC cases recruited in a multicenter, population-based study.[349] Twelve participants were identified as Lynch syndrome carriers by germline DNA testing and all were correctly identified by tumor sequencing, while MSI plus BRAF testing and IHC plus BRAF testing missed five and six Lynch syndrome cases, respectively. Tumor sequencing had a higher sensitivity than IHC plus BRAF testing (100% vs. 89.7%; P = .04) and MSI plus BRAF testing (100% vs. 91.4%; P = .07) while specificity was comparable across all strategies (95.3% for tumor sequencing, 94.6% for IHC plus BRAF, and 94.8% for MSI plus BRAF; P = not significant). In a validation cohort of 46 known Lynch syndrome pathogenic variant carriers with CRC, tumor sequencing yielded similar results and correctly identified 100% of carriers. In addition, the authors highlighted potential therapeutic implications by reporting on somatic alterations identified by tumor sequencing in 283 participants. This study suggested that tumor sequencing is a highly effective mode of identifying Lynch syndrome; however, the cost-effectiveness of this strategy remains to be determined.

A 2019 retrospective study using data from a large, community-based, integrated U.S. health care system compared the diagnostic performance of age-restricted screening strategies for Lynch syndrome by reflex MMR IHC of all CRCs versus a universal screening strategy without an upper age limit.[350] Lynch syndrome identification decreased substantially after age 70 years to age 75 years, with minimal incremental gain after age 80 years. The number of CRCs needed to be screened to identify one Lynch syndrome case was 20 among patients diagnosed with CRC at age 50 years or younger but increased to 208 for those with CRC at age 71 years to age 80 years, and 668 for those diagnosed after age 80 years.

Cost-effectiveness of universal tumor screening for Lynch syndrome

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 Lynch syndrome among individuals aged 70 years or younger with newly diagnosed CRC.[334] The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline pathogenic variant testing followed by directed screening and risk-reducing surgery. IHC followed by BRAF pathogenic variant 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 (3–4) per proband was a critical determinant of both effectiveness and cost-effectiveness. These results were similar to earlier analyses conducted by EGAPP which found that the most cost-effective approach was to test all tumors for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline testing of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF variant-negative tumors.[344]

NCCN 2023 guidelines support using universal screening on all CRCs to help identify individuals who may have Lynch syndrome. Universal screening can include the following testing methods: IHC testing, MSI testing, and comprehensive tumor NGS panel testing.[123] 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.[334] 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 willingness to pay.

However, it is important to note that the conclusions from this study were contingent upon the number of at-risk relatives who underwent germline testing (through a process known as cascade screening) based on the identification of a germline MMR gene variant in the index case of CRC in the family. In their model, to meet the accepted $50,000 cost-effective threshold, testing a minimum of three to four relatives was necessary.[334] This emphasizes the importance of provider-to-patient communication, family communication, and the need to ensure improved uptake of germline testing in Lynch syndrome families with a known causative gene. (Refer to the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for more information about family communication and uptake of genetic testing in families with Lynch syndrome.)

Another study addressed the cost-effectiveness of testing for pathogenic variants in the Lynch syndrome–associated genes and evaluated 21 screening strategies, including clinical criteria, use of clinical Lynch syndrome prediction models, and molecular tumor testing.[351] The model included two steps: (1) measurement of the newly identified number of Lynch syndrome diagnoses; and (2) measurement of the life-years gained as a result of confirming Lynch syndrome in a healthy carrier. Among all of the strategies modeled, screening the proband with a predictive model such as PREMM(1,2,6) followed by IHC for MMR protein expression and germline genetic testing was the best approach, with an incremental cost-effectiveness ratio of $35,143 per life-year gained. Germline genetic testing on all probands was the most effective approach, but at a cost of $996,878 per life-year gained. The authors concluded that the initial step of Lynch syndrome screening should utilize a predictive model in the proband, and that both universal testing and general population screening strategies were not cost-effective screening strategies for Lynch syndrome.

Establishment of an upper age limit for universal tumor testing remains controversial. Some experts have endorsed testing only individuals with CRC who are younger than 70 years (reserving testing in individuals ≥70 y for only those meeting the revised Bethesda criteria; with this strategy, 5% of carriers would be missed).[352] However, others have advocated against an upper age limit for testing given the potential benefit to younger generations via cascade screening and the opportunity for increased surveillance and other prophylactic interventions in individuals found to carry a known familial pathogenic variant.

Another cost-effectiveness analysis was performed using data from 179 consecutive endometrial cancer patients diagnosed at or before age 70 years and screened with MMR IHC and reflex MLH1 promoter hypermethylation, among whom seven Lynch syndrome carriers (3.9%) were identified.[353] Only one of the seven Lynch syndrome probands was age 50 years or younger at endometrial cancer diagnosis. The authors calculated that screening women diagnosed with endometrial cancer at age 51 to 70 years resulted in an additional 29.3 life-years gained (on top of the 45.4 life-years gained by screening women diagnosed at age ≤50 y), and the incremental cost-effectiveness ratio for screening all diagnoses at age 70 years or younger versus diagnoses at age 50 years or younger was 5,252 euro per life-year gained. Universal tumor-based screening of all women age 70 years or younger was also cost-effective, compared with strategies using the Bethesda guidelines to guide MMR and MSI testing with an incremental cost-effectiveness ratio of 6,668 euro per life-year gained.

The cost-effectiveness of universal tumor testing in both CRC and endometrial cancer is largely driven by the assumption of cascade screening through which other at-risk family members will be identified, tested, and subsequently pursue their own cancer risk reduction.[334]

The cost of germline genetic testing continues to decrease with advancements in DNA analyses, including simultaneous testing of multiple germline variants associated with malignancy, through multigene (panel) tests. As a result, additional cost-effective analyses using more updated data related to germline testing will need to be conducted. Multigene (panel) testing may become a more favorable and cost-effective approach in the future.

Considerations and limitations related to universal tumor testing for Lynch syndrome

While universal screening continues to be adopted nationally, there is significant variability in the uptake and approach to molecular testing. 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 (64.2%) of 53 centers started with IHC, 11 (20.8%) of 53 centers started with MSI testing, and 8 (15.1%) of 53 centers performed both tests on newly diagnosed colorectal tumors.[354] 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 utilization dropped to 15% among a random sample of community hospital cancer programs.[355]

Because adherence to universal screening for Lynch syndrome may be poor (many patients are not referred for genetic evaluation and testing), a prospective quality improvement study utilizing the Six Sigma conceptual framework was conducted to improve the implementation of universal genetic screening among young patients with CRC.[356] The main aim of the study was to increase the proportion of tumor studies for deficient MMR among patients with early-onset CRC (aged 18–50 y). The intervention involved patient and provider education, in addition to visual cues provided at point of care. The study demonstrated an improvement of 21.5% in the rate of IHC testing in young adults with CRC over the 12-month postintervention period compared with the preintervention period.

Studies reporting uptake of genetic testing for Lynch syndrome have largely focused on individuals and families who were selected for potential risk of Lynch syndrome based on family history or clinical characteristics. While universal tumor screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, few studies have examined the uptake of genetic testing after universal tumor testing. An important implication of universal screening for Lynch syndrome is that it does not result in automatic germline testing in appropriate individuals. In the clinical setting, more follow-up by health care teams to facilitate referral to genetic counseling for patients with abnormal tumor screening results may improve completion of genetic testing.[357] Higher levels of patient completion of genetic testing after abnormal tumor screening may be associated with having genetic counselors involved in this process to disclose screen-positive results, provide counseling after tumor testing, or facilitate referrals.[358]

Subsequent genetic counseling requires coordination between the pathologist, the referring surgeon or oncologist, and a cancer genetics service. As an illustration, a population-based screening study found that only 54% of patients with an IHC-deficient tumor (that was BRAF pathogenic variant–negative) ultimately consented to and proceeded with germline MMR testing.[359] One institution found 21 pathogenic variants 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.[357]

In contrast to tumor testing, which is commonly performed without a patient's prior knowledge, germline genetic testing, such as germline testing for MMR pathogenic variants, generally includes genetic counseling and requires patient permission before it is performed. 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.[355]

Diagnostic strategies for all individuals diagnosed with endometrial cancer

Given the increased prevalence of endometrial cancer among carriers of MMR pathogenic variants, there is a growing consensus to screen patients with endometrial cancer for Lynch syndrome.

In a study that examined the feasibility and desirability of performing tumor screening of all endometrial cancers, regardless of age at diagnosis or family history of cancer, at least 2.3% (95% CI, 1.3%–4.0%) of newly diagnosed patients had Lynch syndrome.[360,361] Eight of thirteen cases diagnosed with Lynch syndrome were aged 50 years or older, eight did not meet published family history criteria for Lynch syndrome, and two would have been missed by MSI testing. Because of the increased prevalence of endometrial cancer and the results of this study, the authors support universal screening of endometrial cancers for Lynch syndrome. (Refer to the IHC section of this summary for more information about performing IHC for MMR protein expression.)

Another smaller study of 242 consecutive endometrial cases demonstrated a 4.5% (11/242) prevalence of MMR-deficient cases lacking somatic MLH1 promoter hypermethylation, including four cases (1.7%) with germline MMR variants, four cases (1.7%) with two somatic MMR alterations on NGS, and two cases (0.8%) with otherwise unexplained MMR-deficiency.[362] Such findings demonstrate that universal MMR tumor screening of endometrial cancers will identify individuals with underlying Lynch syndrome and a spectrum of non-Lynch syndrome cases with various forms of MMR-deficiency.

Another study prospectively evaluated universal IHC-based screening of both CRC and endometrial cancer cases, irrespective of age at diagnosis.[363] In both the tertiary and community settings, 1,290 CRC and 484 endometrial cancer cases were screened between 2011 and 2013. The study additionally calculated PREMM(1,2,6) and PREMM5 scores for all patients in whom a germline pathogenic variant was detected. Abnormal staining was observed in 22% of endometrial cancers and 18.8% of CRCs. After excluding those cases felt to be sporadic because of the presence of BRAF and/or hypermethylation of MLH1, 10.8 % of patients with CRC and 6.6% of patients with endometrial cancer were referred for genetic counseling. Lynch syndrome was diagnosed in 24 individuals (1.4%), 66% of whom had CRC. The overall detection rate of Lynch syndrome was 1.7% in endometrial cancer cases and 1.2% in CRC cases. Among Amsterdam criteria, Bethesda guidelines, PREMM(1,2,6), and PREMM5, the best performing model was PREMM5, which would have detected 82% of cases identified by universal screening.

The cost-effectiveness of tumor testing of women diagnosed with endometrial cancer was examined in a model-based simulation study and included IHC testing in the following scenarios: (1) diagnosis before age 50 years; (2) diagnosis before age 60 years; (3) any age at diagnosis with the presence of an FDR with any Lynch syndrome–associated cancer; and (4) all cases irrespective of diagnosis age and family history. Women fulfilling Amsterdam II criteria or those diagnosed before age 50 years with at least one FDR with any Lynch syndrome–associated cancer were directly referred for genetic counseling and genetic testing without IHC testing. A strategy of IHC testing for MMR protein expression in all patients with endometrial cancer and an FDR with any Lynch syndrome–associated cancer was reported to be cost-effective in the detection of Lynch syndrome.[364] This strategy had an incremental cost ratio of $9,126 per life-year gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer before age 50 years with at least one FDR with a Lynch syndrome–related cancer. Life expectancy was highest with the most inclusive testing strategy of IHC testing of all women with endometrial cancer irrespective of age at diagnosis or family history but had the least favorable incremental cost ratio of $648,494 per life-year gained. NCCN recommends tumor testing with IHC and/or MSI and a comprehensive tumor NGS panel testing for all endometrial cancers.[123] Despite these recommendations, the uptake of universal screening in women newly diagnosed with endometrial cancer is unclear.

(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about endometrial cancer as a component of Lynch syndrome.)

MSI in all cancers

Use of MSI testing across all tumor types has become an important screening tool to select cases that may have a favorable response to immune checkpoint inhibitor therapy. These results may potentially be used to screen for Lynch syndrome in tumors other than CRC. A study evaluated MSI across a wide variety of malignancies and evaluated its use as a potential means to identify Lynch syndrome, regardless of tumor type.[365] In a study of more than 15,000 patients with more than 50 types of cancers evaluated in a single-center study, data on well-annotated tumor and matched normal DNA sequencing results with paired germline MMR gene testing, were used to determine MSI status. MSI was determined using a software tool that reports the percentage of unstable microsatellites as a score from paired tumor-normal genome sequencing data and allows for comprehensive investigation of MSI sites simultaneously. The approach used has been reported to be more sensitive across cancers not typically screened for MMR-deficiency (dMMR) than MSI testing of five mononucleotide microsatellite foci using PCR.[366] CRC and endometrial cancer comprised the majority of cancers with MSI-H in this study, but 38% (125 of 326) of MSI-H tumors and more than 90% of those with intermediate-level MSI were other cancer types. Germline testing confirmed a diagnosis of Lynch syndrome in 16.3% and 1.9% of tumors with MSI-H and intermediate-level MSI, respectively, in addition to 0.3% of cases that lacked MSI. Importantly, half of all Lynch syndrome carriers with MSI-H/intermediate tumors had primary cancers other than CRC or endometrial cancer, with many malignancies not associated with Lynch syndrome. Among those individuals with a noncanonical Lynch syndrome cancer, nearly half failed to meet clinical criteria for Lynch syndrome testing on the basis of their cancer diagnosis or family cancer history. Furthermore, intermediate-level MSI and MSS phenotypes were most often observed in cancers not classically related to Lynch syndrome and in individuals with germline PMS2 variants. This study supports other findings related to the variable phenotypic expression of Lynch syndrome on the basis of the altered MMR gene and its broad constellation of associated malignancies that make it difficult to be identified by clinical criteria alone. In addition, the investigators further analyzed a unique gene variant signature in every tumor and correlated results to the observed MSI phenotype and germline MMR status to provide some indirect data on whether a gene variant carrier’s cancer was caused by Lynch syndrome and MMR deficiency or possibly an incidental finding. This is pertinent in evaluating those cancers whose association with Lynch syndrome is unclear and debatable, such as breast and prostate cancer. The authors’ finding that none of the breast cancer patients with Lynch syndrome in this very large cohort had tumors with MSI lends support to the hypothesis that these individuals’ germline MMR gene variants may simply be incidental findings and not etiologic to their cancer diagnosis.

A single-institution study of 100 histologically confirmed small bowel adenocarcinomas with MSI/MMR tumor studies identified 26 cases with MMR deficiency, 10 of which were due to Lynch syndrome. Most cancers were located in the duodenum, followed by the jejunum and the ileum. The authors recommended that individuals with small bowel adenocarcinomas be screened for Lynch syndrome, given the implications of MMR deficiency on treatment and clinical management.[367]

Germline genetic testing

Genetic testing for germline pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM can help formulate appropriate intervention strategies for the affected variant-positive individual and at-risk family members, many of whom may be unaffected by cancer.

If a pathogenic variant is identified in an affected person, then testing for that same pathogenic variant should be offered to all at-risk family members. At-risk relatives who test negative for the identified pathogenic variant in the family are not at increased risk of CRC or other Lynch syndrome–associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial pathogenic variant are referred to surveillance and management guidelines for Lynch syndrome. (Refer to the Management of Lynch syndrome section of this summary for more information.)

If no pathogenic variant is identified in the affected family member, then testing is considered negative for Lynch syndrome in that individual. With advances made in DNA sequencing technologies, it is unlikely that current gene testing is not sensitive enough to detect a pathogenic variant in the genes tested. Advances in testing, including the common use of NGS by most commercial testing laboratories have improved upon the detection of certain alterations such as large deletions or genomic rearrangements as well as the presence of a pseudogene PMSCL in PMS2.

Possible reasons why a pathogenic variant may not be detected include the following:

• The family could have a variant in a yet-unidentified gene that causes Lynch syndrome or a predisposition to colon cancer.
• The individual tested in the family may have developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case also known as a phenocopy), while the other cases in the family are really the result of a germline variant. If this scenario is suspected, testing another affected individual who has had a Lynch syndrome–associated cancer is recommended.
• In cases in which a CRC tumor displayed MSI and/or abnormal IHC, but no germline pathogenic variant was detected, biallelic somatic variants may be the resulting etiology. These are sometimes, confusingly, called Lynch-like syndrome cases, even though they are typically not considered to be familial.

Failure to detect a pathogenic variant could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis (e.g., the patient may have biallelic somatic variants in an MMR gene). If no variant can be identified in an affected family member, testing should not be offered to at-risk members because results would be uninformative for the relatives. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening.

(Refer to the Management of Lynch syndrome section of this summary for more information.)

Multigene (panel) testing

Germline variant analysis of MLH1, MSH2 (including EPCAM), MSH6, and PMS2 may be considered in instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC. This approach has become less expensive with the advent of multigene (panel) testing, which is now offered by several clinical laboratories at a cost that may be comparable to single-gene testing. The cost of multigene testing may also approach the cost of tumor screening and may prove to be a cost-effective approach in individuals affected by CRC. At present, multigene tests are not routinely recommended for universal screening for Lynch syndrome among all newly diagnosed CRC patients, but they may be very useful in select populations, such as those with early-onset CRC [368] or from familial, high-risk clinic-based populations. It is also important to note that pathogenic variants may be detected in other cancer-associated genes beyond Lynch syndrome. In a study of 1,112 individuals who met NCCN criteria for Lynch syndrome testing and who underwent multigene testing with a 25-gene panel, as expected, 114 individuals (9.0%) were found to have pathogenic variants in MMR genes; however, 71 individuals (5.6%) were found to have a pathogenic variant in non-Lynch syndrome cancer predisposition genes, such as BRCA1, BRCA2, APC, MUTYH (biallelic), and STK11. Lastly, multigene tests yield a high proportion of VUS. In the aforementioned study, a total of 479 patients (38%) had one or more VUS.[369]

Individuals with early-onset CRC have been shown to have a high frequency and wide spectrum of germline pathogenic variants, indicating that panel testing in this population may be beneficial. In a study of 450 patients with early-onset CRC (mean age at diagnosis, 42.5 y) and a family history including at least one FDR with colon, endometrial, breast, ovarian, and/or pancreatic cancer, 75 germline pathogenic or likely pathogenic variants were identified in 72 patients (16%).[368] The spectrum of variants identified included Lynch syndrome and non-Lynch syndrome–associated genes, including several genes that have not traditionally been associated with CRC (e.g., BRCA1/BRCA2, ATM, CHEK2, PALB2, and CDKN2A). Given the high frequency and variety of hereditary cancer syndromes identified, the authors suggested that multigene testing in this population may be warranted. Similarly, another smaller single-institution analysis of 151 individuals with CRC identified pathogenic germline variants in 9.9% of individuals.[370]

Multigene testing has also been examined in a larger study of 1,058 individuals with CRC who were unselected for age at diagnosis, personal or family history, or MSI/MMR test results.[371] Germline pathogenic variants in cancer susceptibility genes were identified in 105 individuals (9.9%). While 33 individuals (3.1%) carried pathogenic variants in Lynch syndrome genes, 74 (7.0%) had pathogenic variants in non-Lynch syndrome–associated genes, including APC, MUTYH, BRCA1/BRCA2, PALB2, CDKN2A, TP53, and CHEK2. These data illustrate the breadth of variants that may be identified in unselected CRC patients; thus, use of a comprehensive multigene test may be warranted.

A 2017 study examined the frequency of pathogenic Lynch syndrome–associated gene variants in individuals undergoing multigene testing at a single commercial United States laboratory between 2012 and 2015, and reported on the characteristics of those carriers identified with Lynch syndrome.[372] The study reports on the largest cohort of individuals tested through multigene testing to date; data was reported on 34,980 individuals who had undergone various multigene panel tests that included the MMR and EPCAM genes, where the indication for testing was not limited to Lynch syndrome. A total of 618 pathogenic variants were identified in 612 individuals (1.7%) and analyses were conducted on 579 subjects (after exclusion of 33 individuals who had a Lynch syndrome–associated variant and a second MMR variant or other pathogenic alteration in another cancer predisposition gene). The majority of carriers were affected by cancer, including non-Lynch syndrome–associated malignancies, where breast cancer was most frequently reported (124/423, 23.5%). MSH6 variants were most prevalent (29.3%), followed by PMS2 (24.2%), MSH2 (23.7%), MLH1 (21.6%), and EPCAM (1.2%). This finding differs from previous data where MSH2 and MLH1 variants were more prevalent, as individuals were more often selected for Lynch syndrome–specific testing due to a personal and/or family history of CRC.

The study reports on genotype-phenotype correlations on 528 Lynch syndrome carriers, the majority of whom had CRC (186, 35.2%) and endometrial cancer (136, 25.8%), followed by breast cancer (124, 23.5%) and ovarian cancer (74, 14%).[372] One hundred forty-five carriers presented with breast or ovarian cancer as their sentinel tumor and did not carry a prior diagnosis of CRC or endometrial cancer prior to the time of multigene testing. When examining MMR gene variant distribution among tumor-specific subgroups, a higher frequency of MSH6 and PMS2 variants were detected in carriers with breast cancer only than MLH1 and MSH2, where the latter pathogenic variants were more frequent in subjects with CRC only. For patients with breast cancer only, the frequency of PMS2 gene variants was significantly higher than population estimates, which was not the case for MLH1, MSH2, or MSH6. A comparable retrospective study reported similar findings. Standardized incidence ratios (SIRs) of breast cancer were calculated by comparing observed breast cancer frequencies in a population of 423 women with pathogenic or likely pathogenic variants in MMR genes with those in the general population. The authors reported a statistically significant age-standardized risk of breast cancer for MSH6 carriers (SIR = 2.11; 95% CI, 1.56–2.86) and PMS2 carriers (SIR = 2.92; 95% CI, 2.17–3.92).[373] A critical limitation of both of these studies was the excess of breast cancer cases in the overall referral population as well as the known high background population prevalence of MSH6 and PMS2 germline pathogenic variants.

Clinical criteria for the identification of Lynch syndrome, including the Amsterdam criteria, revised Bethesda guidelines, or the PREMM(1,2,6) risk prediction model, would have failed to identify 27.3% of Lynch syndrome carriers in this study.[372] Given the increased prevalence of breast and ovarian cancers, 58.9% met the NCCN guidelines for BRCA1/BRCA2 testing and of these, 36.7% also met NCCN guidelines for Lynch syndrome testing. Lastly, there were limited data on tumor testing results, available only on 18.8% of pathogenic variant carriers, where results were often discordant with the altered gene, which was most often reported in MSH6 and PMS2 carriers. Results of this study support the use of multigene testing for Lynch syndrome and further study of the respective cancer risks, as current testing strategies limit identification of Lynch syndrome carriers and associated malignancies.

Lastly, germline MMR genes have been detected unexpectedly among individuals undergoing multigene testing for cancers not commonly associated with Lynch syndrome, such as breast and prostate cancer. As a result, the cancer spectrum associated with Lynch syndrome may be wider than previously appreciated. For more information, see the Breast cancer and Prostate cancer sections and Genetics of Prostate Cancer.

(Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations, and research examining the use of multigene testing.)

Cost-effectiveness of multigene (panel) testing

As genetic testing becomes routine rather than the exception, questions regarding the cost of testing are inevitable. Historically, a cost-effectiveness ratio of $50,000 per quality-adjusted life-year (QALY) has been utilized as the benchmark for good value for care.[374] Over time it has been suggested that this threshold is too low and that other thresholds such as $100,000 or $150,000 be utilized.[374]

A 2015 study evaluated the cost-effectiveness of multigene testing for CRC and polyposis syndromes in patients referred to a cancer genetics clinic.[375] These authors developed a decision model to estimate the immediate and downstream costs for patients referred for evaluation and of CRC surveillance in family members identified as carriers of pathogenic variants. The costs were estimated on the basis of published models from the CDC and from an academic molecular genetics laboratory. They classified the syndromes on the basis of inheritance pattern and penetrance of CRC. Four custom panels were compared with the standard of care. The four panels tested for (1) Lynch syndrome–associated genes only (MLH1, MSH2, MSH6, PMS2, and EPCAM); (2) genes in panel 1 and additional genes associated with autosomal dominant inheritance and high CRC penetrance (APC, BMPR1A, SMAD4, and STK11); (3) genes in panels 1 and 2 and those associated with autosomal recessive inheritance with high CRC penetrance (MUTYH); or (4) all genes in the first three panels and those associated with autosomal dominant conditions with low penetrance (PTEN, TP53, CDH1, GALNT12, POLE, POLD1, GREM1, AKT1, and PIK3CA). The respective costs were as follows: panel 1, $144,235 per QALY; panel 2, $37,467 per QALY; panel 3, $36,500 per QALY; and panel 4, $77,300 per QALY when compared with panel 3. The authors concluded that the use of an NGS multigene test that includes highly penetrant CRC and polyposis syndromes and Lynch syndrome cancer genes was the approach most likely to provide clinically meaningful results in a cost-effective fashion.

The cost of germline genetic testing continues to decrease with advancements in technology since the time this model analysis was conducted; additional studies are needed to continue to assess the cost-effectiveness of this testing approach.

Advances in Endoscopic Imaging in Hereditary CRC

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

Familial CRC

Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families,[576] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[577] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[578] A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.[579] For more than a decade, little progress has been made on these putative familial cancer loci.

Rare Syndromes With Associated Colorectal Cancer Susceptibility

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