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Patients in Whom to Consider Genetic Evaluation and Testing for Hereditary Colorectal Cancer Syndromes

Kupfer, Sonia S. MD1; Burke, Carol A. MD2

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The American Journal of Gastroenterology: January 2020 - Volume 115 - Issue 1 - p 1–4
doi: 10.14309/ajg.0000000000000362
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Hereditary colorectal cancer syndromes (HCCS) confer markedly increased risks of colorectal and extracolonic tumors (Table 1). Many individuals with HCCS go unrecognized until the time of a cancer diagnosis, whereas others are identified through genetic testing based on family history of cancer. Frequently, gastroenterologists are a first touch point for patients with HCCS and must be prepared to recognize “the needles in the haystack” and identify who should undergo genetic risk assessment and appropriate evaluation and testing.

Table 1
Table 1:
Hereditary colorectal cancer syndromes

Individuals in whom to consider evaluation for HCCS

Evaluation and testing for HCCS should be considered in individuals with suggestive personal and family characteristics (Table 2).

Table 2
Table 2:
Features that warrant evaluation and possible testing for HCCS

Colorectal cancer in patients younger than 50 years

Benign and malignant tumors occurring at an age less than 50 years increases the chances of HCCS. Studies of patients with early-onset colorectal cancer (CRC) found that 16%–18% carried germline genetic mutations (1,2). However, a cancer diagnosis in patients older than 50 years does not rule out the possibility of HCCS. In a study of unselected patients with CRC, 10% carried genetic mutations in CRC-associated genes (3).

Suspicious family cancer history

Family history of cancer is a hallmark of a heritable syndrome especially when family members develop the same or related cancers (i.e., CRC and endometrial cancer in the case of Lynch syndrome (LS) or colonic polyposis and thyroid cancer in the case of familial adenomatous polyposis [FAP]). Clinical tools based on personal and family cancer history can identify individuals to consider for LS testing (Table 3). Amsterdam II and revised Bethesda guidelines can be used to identify patients with LS but do not have ideal test characteristics with limitations in sensitivity and specificity, respectively. PREMM5 has improved characteristics (4) and was implemented successfully in a community gastroenterology practice (5). A simple 3-question survey tool also can identify high-risk individuals with good sensitivity (6), and implementation of a modified version was feasible in an academic endoscopy center (7).

Table 3
Table 3:
Clinical tools for identification of LS

Tumor features of deficient mismatch repair

Testing all colon cancers (called universal testing) is a strategy to identify patients with LS. Interrogation of tumors for evidence of deficient mismatch repair (the hallmark of LS) is endorsed by numerous organizations including the US Multisociety Task Force (8) and the American College of Gastroenterology (9). Tumor testing involves staining biopsy or resection specimens for mismatch repair protein expression (called immunohistochemistry). The absence of expression of MLH1 and/or PMS2 or MSH2 and/or MSH6 is suggestive of LS with some caveats. An alternate approach is to perform microsatellite instability by polymerase chain reaction. Abnormal tumor testing requires patients to follow up with a risk assessment and genetic testing if appropriate. Although universal testing is becoming more widespread, follow-up of abnormal results remains variable and differs by medical center and race among other factors (10). When optimally implemented, universal testing has been found to be cost effective for LS and helps identify additional at-risk family members who benefit from surveillance (11).

>10–20 cumulative colonic adenomas

The most common adenomatous polyposis syndromes are FAP and MutYH-associated polyposis (MAP). FAP can be profuse (100s to 1000s of adenomas) or attenuated (10s to a 100 adenomas). Most patients with FAP have a family history of polyposis, although 25% can arise as a new mutation and would not report a family history of FAP. MAP, a recessive condition, is overwhelmingly an attenuated polyposis syndrome similar to attenuated FAP. Current guidelines recommend genetic testing for individuals with greater than 10–20 cumulative adenomas (9,12). Recently, mutations in polymerase proofreading genes, POLE and POLD1, and 2 copies of NTHL1 and MSH3 mutations have been associated with hereditary adenomatous polyposis as well as other cancers. In individuals of Ashkenazi Jewish ancestry, hereditary mixed polyposis syndrome associated with adenomas and polyps containing a mixture of hyperplastic and inflammatory changes has been associated with mutations in GREM1 (13).

Numerous gastrointestinal hamartomatous polyps

Hamartomatous syndromes are recognized by the presence of hamartomas and cancer within and outside of the gastrointestinal tract. Juvenile polyposis syndrome and Peutz-Jeghers syndrome should be considered in individuals with greater than 3 colonic and greater than 2 small bowel hamartomas, respectively, as well as other clinical criteria. Cowden syndrome is associated with a high risk of nongastrointestinal and slightly increased risk of CRC and can manifest with a polyposis phenotype including several colonic polyp types such as hamartomas, ganglioneuromas, serrated polyp, and adenomas (14). A risk calculator can be used to assess probability of a PTEN mutation and guide genetic testing (

Numerous and large colonic serrated polyps

Serrated polyposis syndrome is defined clinically by revised 2019 World Health Organization criteria (Table 4). To date, a definitive genetic basis for this condition has not been established, and genetic testing is typically not offered.

Table 4
Table 4:
World Health Organization criteria for serrated polyposis syndrome (updated in 2019)


Genetic counseling

Patients with suspected HCCS should meet with a genetic counselor or a provider knowledgeable in principles of genetic testing for pre-test and post-test counseling. During a precounseling session, personal and family histories as well as testing options and potential outcomes are reviewed if appropriate. If testing is pursued, post-test counseling involves reviewing results and implications. Additional issues such as insurance coverage, genetic discrimination, testing in family members, and family planning are discussed.

Multigene panel testing

Technological advances have revolutionized genetic testing enabling sequencing of many genes at the same time. Multigene panel tests enable assessment for multiple syndromes simultaneously and lower cost and reduced test “fatigue” for patients. In the case of genetic evaluation for multiple adenomas, multigene panel testing shows increasing yield with increasing number of polyps, although yield decreases with older patient age. For patients with 10–19 cumulative adenomas, germline mutations (primarily APC and MutYH) were detected in 4–8% of patients, while this rate was 7%–14% for 20–99 adenomas and 50% or greater for >100 adenomas (15,16). Depending on the panel used, genetic testing can have additional outcomes including the possibility of finding a mutation in less understood genes. Although risks and management are known for LS and polyposis syndromes, this is not the case for genes with low or moderate CRC risk (e.g., CHEK2, ATM, TP53, and 1 allele of MutYH) or genes with limited data on CRC risk (e.g., AXIN2, NTHL1, MSH3, RNF43, GALNT12, and RPS20) (12). Another outcome is finding an “unanticipated” mutation in a gene(s) that appear unrelated to personal or family history but for which management guidelines exist (e.g., LS genes, BRCA1, BRCA2, CDH1, CDKN2A, and PALB2). Finally, multigene panel testing increases the chance of identifying a variant of uncertain significance (VUS). A VUS should not be confused with a pathogenic variant because the health consequence of a VUS is not yet established and should not guide clinical management.

Timing of genetic testing

For syndromes with childhood onset (e.g., FAP, juvenile polyposis, and Peutz-Jeghers syndrome), genetic testing is performed in children. For families with LS, testing in family members should occur between ages 18–20 years since colonoscopy screening commences between ages 20 and 25 years. In newly diagnosed CRC with features of HCCS, genetic evaluation and testing before surgery allows shared decision-making about surgical options.


Gastroenterologists are in a unique position to recognize, diagnose, and manage HCCS. However, this requires providers to be equipped with knowledge and tools to identify at-risk individuals. In a busy clinical and endoscopic practice, time can be limited for extensive discussions about personal and family history. Implementation of short surveys, robust universal tumor testing protocols, educational efforts, and a team approach can help to overcome many barriers. There remain areas of uncertainty such as which genes should be included on panel tests, cancer risk estimates for less penetrant genes, interpretation of variants of uncertain significance, as well as lack of access and genetic counseling resources.


Guarantor of the article: Sonia S. Kupfer, MD.

Specific author contributions: S.S.K. and C.A.B. both contributed equally to drafting and review of this manuscript.

Financial support: None to report.

Potential competing interests: S.S.K. has performed research with Myriad Genetics but has not received direct financial compensation.


1. Pearlman R, Frankel WL, Swanson B, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 2017;3:464–71.
2. Stoffel EM, Koeppe E, Everett J, et al. Germline genetic features of young individuals with colorectal cancer. Gastroenterology 2018;154:897–905 e1.
3. Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol 2017;35:1086–95.
4. Kastrinos F, Uno H, Ukaegbu C, et al. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome. J Clin Oncol 2017;35:2165–72.
5. Luba DG, DiSario JA, Rock C, et al. Community practice implementation of a self-administered version of PREMM1, 2, 6 to assess risk for Lynch syndrome. Clin Gastroenterol Hepatol 2018;16:49–58.
6. Kastrinos F, Allen JI, Stockwell DH, et al. Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. Am J Gastroenterol 2009;104:1508–18.
7. Guivatchian T, Koeppe ES, Baker JR, et al. Family history in colonoscopy patients: Feasibility and performance of electronic and paper-based surveys for colorectal cancer risk assessment in the outpatient setting. Gastrointest Endosc 2017;86:684–91.
8. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the US multi-society Task Force on colorectal cancer. Gastroenterology 2014;147:502–26.
9. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110:223–62; quiz 63.
10. Muller C, Lee SM, Barge W, et al. Low referral rate for genetic testing in racially and ethnically diverse patients despite universal colorectal cancer screening. Clin Gastroenterol Hepatol 2018;16:1911–8.e2.
11. Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: A cost-effectiveness analysis. Ann Intern Med 2011;155:69–79.
12. Gupta S, Provenzale D, Regenbogen SE, et al. NCCN guidelines insights: Genetic/familial high-risk assessment: Colorectal, version 3.2017. J Natl Compr Canc Netw 2017;15:1465–75.
13. Plesec T, Brown K, Allen C, et al. Clinicopathological features of a kindred with SCG5-GREM1-associated hereditary mixed polyposis syndrome. Hum Pathol 2017;60:75–81.
14. Heald B, Mester J, Rybicki L, et al. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology 2010;139:1927–33.
15. Grover S, Kastrinos F, Steyerberg EW, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA 2012;308:485–92.
16. Stanich PP, Pearlman R, Hinton A, et al. Prevalence of germline mutations in polyposis and colorectal cancer-associated genes in patients with multiple colorectal polyps. Clin Gastroenterol Hepatol 2018. [Epub ahead of print December 14, 2018.]
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