When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes?

Abstract

This article is part of a series on enhancing the value of care in gastroenterology and hepatology. Each article in this series examines specific clinical scenarios in which the value of care can be improved over a range of sub-specialties in the field.David A. Katzka, MD, Guest Special Section Editor Hereditary colorectal cancer (CRC) syndromes account for 5%–10% of all CRC cases. Identification of mutation carriers and their families offers potential to provide life-saving cancer surveillance and prevention strategies, and represents an opportunity to deliver high-value care. Potential detection strategies include (1) screening all individuals with CRC for Lynch syndrome (LS), (2) careful evaluation of individuals with high adenoma burden or unusual polyps, and (3) identifying individuals with high-risk personal and/or familial history of cancer. LS is the most common inherited predisposition to CRC, caused by a mutation in 1 of the 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM, a promoter for the MSH2 gene. LS confers 15%–82% lifetime risk of CRC; up to 60% risk of endometrial cancer; and increased risks for ovarian, gastric, small bowel, brain, hepatobiliary, urinary tract, sebaceous gland, and pancreatic cancer.1Kohlmann W. Gruber S.B. Lynch syndrome.in: Pagon R.A. Adam M.P. Ardinger H.H. GeneReviews(R). University of Washington, Seattle (WA)1993Google Scholar Many, but not all, families with LS have multiple family members across multiple generations impacted by LS cancers because inheritance is autosomal-dominant. Preventive interventions, such as frequent surveillance colonoscopy or prophylactic hysterectomy, may improve outcomes.2de Vos tot Nederveen Cappel W.H. Jarvinen H.J. Lynch P.M. et al.Colorectal surveillance in Lynch syndrome families.Fam Cancer. 2013; 12: 261-265Google Scholar Readily available clinical tests can identify suggestive molecular “signs” within LS cancers, including failure to express ≥1 DNA mismatch repair proteins as measured by immunohistochemistry, and presence of high-frequency microsatellite instability.3Giardiello F.M. Allen J.I. Axilbund J.E. et al.Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.Am J Gastroenterol. 2014; 109: 1159-1179Google Scholar Both features are easily assessed with clinically available tests. Screening all patients with CRC for either abnormal absence of DNA mismatch repair protein expression or microsatellite instability is referred to as “universal screening,” and has been shown to maximize sensitivity for identifying individuals with LS compared with selection based on age at presentation and/or family cancer history.4Moreira L. Balaguer F. Lindor N. et al.Identification of Lynch syndrome among patients with colorectal cancer.JAMA. 2012; 308: 1555-1565Google Scholar The American Gastroenterological Association, National Comprehensive Cancer Network, and others have recommended universal screening for all newly diagnosed patients with CRC for LS, regardless of age at presentation or cancer family history.3Giardiello F.M. Allen J.I. Axilbund J.E. et al.Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.Am J Gastroenterol. 2014; 109: 1159-1179Google Scholar, 5Evaluation of Genomic Applications in P, Prevention Working GRecommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?.Genet Med. 2009; 11: 15-20Google Scholar Recommendations are supported by evidence that universal screening, coupled with mutation testing and surveillance in the index patient and relatives, has potential to reduce CRC morbidity and mortality.6Palomaki G.E. McClain M.R. Melillo S. et al.EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome.Genet Med. 2009; 11: 42-65Google Scholar Moreover, subsequent analyses have suggested this strategy is cost-effective.7Ladabaum 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: 69-79Google Scholar Several polyposis syndromes that present with high adenoma burden or unusual polyps are associated with high CRC risk (Table 1).8Syngal S. Brand R.E. Church J.M. et al.ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110 (quiz 263): 223-262Google Scholar Because patients with these conditions may be offered frequent surveillance colonoscopy and even prophylactic colectomy if cancer or an unmanageable polyp burden is present, identification offers potential to improve CRC outcomes. Work-up should be triggered based on presence of >10 adenomas, multiple hamartomatous polyps, or suggestive extracolonic manifestations (Table 1), and should include a careful assessment of number and type of polyps, and detailed family history.9Provenzale D. Gupta S. Ahnen D.J. et al.Genetic/familial high-risk assessment: colorectal version 1.2016, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2016; 14: 1010-1030Google Scholar Those with concerning features (eg, >20 adenomas, hamartomatous polyps, or >10 adenomas plus any concerning extracolonic manifestation and/or family history of cancer) should move on to referral to a genetics specialist and be considered for genetic testing.Table 1Clinical Features and Lifetime CRC Risk Associated With >10 Adenomas or Hamartomatous PolypsSyndromeGenesClinical featuresLifetime CRC riskFamilial adenomatous polyposisAPCAdenomas, thyroid cancer, desmoid tumors, duodenal adenomas, mandibular osteomas, and congenital hypertrophic pigmentary lesions of the retina100%13Jasperson K.W. Patel S.G. Ahnen D.J. APC-associated polyposis conditions.in: Pagon R.A. Adam M.P. Ardinger H.H. GeneReviews(R). University of Washington, Seattle (WA)1993Google ScholarMYH-associated polyposisMUTYH (biallelic)Adenomas, thyroid cancer, colorectal cancer43%–100%14Nielsen M, Lynch H, Infante E, et al. MUTYH-associated polyposis. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews(R). Seattle (WA): 1993.Google ScholarPeutz-JeghersSTK11Mucocutaneous melanin spots, hamartomas, breast, gastrointestinal, pancreatic, ovarian sex cord tumors with annular tubules, testicular large calcifying Sertoli cell tumors39%15McGarrity TJ, Amos CI, Baker MJ. Peutz-Jeghers syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews(R). Seattle (WA): 1993.Google ScholarCowden/PTEN hamartomaPTENHamartomas, dermatologic lesions (trichilemmomas, and papillomatous papules), macrocephaly, breast, thyroid, and endometrial cancers9%16Eng C. PTEN hamartoma tumor syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews(R). Seattle (WA): 1993.Google ScholarJuvenile polyposisBMPR1A, SMAD4Hamartomas, colon cancer, some with SMAD4 have hemorrhagic hereditary telangiectasia50%17Larsen Haidle J. Howe J.R. Juvenile polyposis syndrome.in: Pagon R.A. Adam M.P. Ardinger H.H. GeneReviews(R). University of Washington, Seattle (WA)1993Google ScholarCRC, colorectal cancer. Open table in a new tab CRC, colorectal cancer. Potential high-risk history includes early age onset of CRC or endometrial cancer (younger than 50 years of age), presence of multiple CRCs or other LS cancers, history of multiple family members with CRC or LS cancers (especially young onset), or known hereditary syndrome in the family. For identifying individuals at risk for LS, probability models, such as PREMM5 (http://premm.dfci.harvard.edu/), based on personal and family history have been developed.10Kastrinos 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: 2165-2172Google Scholar Consensus guidelines recommend genetic evaluation for those with a ≥5% model-predicted chance of having LS, personal or familial history of young-onset CRC, and/or when multiple family members are affected by cancer. Risk assessment and referral for hereditary CRC syndromes in usual practice is underutilized. Furthermore, physicians have difficulty in obtaining an accurate family history and recognizing potential hereditary CRC syndromes.11Grover S. Stoffel E.M. Bussone L. et al.Physician assessment of family cancer history and referral for genetic evaluation in colorectal cancer patients.Clin Gastroenterol Hepatol. 2004; 2: 813-819Google Scholar Implementation of universal screening for LS has been slow.12Beamer L.C. Grant M.L. Espenschied C.R. et al.Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results.J Clin Oncol. 2012; 30: 1058-1063Google Scholar Because gastroenterologists are at the forefront of CRC diagnosis and prevention, they are uniquely positioned to recognize individuals at increased risk based on phenotype and family history, but must develop and implement standardized protocols to ensure assessment. One approach recommended by the National Colorectal Cancer Roundtable is to implement a simple 3-question tool for identifying individuals at potentially increased risk meriting more detailed assessment of personal and family history that includes the following 3 questions18Kastrinos F. Allen J.I. Stockwell D.H. et al.Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy.Am J Gastroenterol. 2009; 104: 1508-1518Google Scholar:1.Do you have a first degree relative with CRC or LS-related cancer diagnosed before age 50?2.Have you had CRC or polyps diagnosed before age 50?3.Do you have ≥3 relatives with CRC? We recommend 3 strategies for finding individuals with hereditary CRC syndromes: (1) screening all individuals with CRC for LS, (2) careful evaluation of individuals with high adenoma burden or unusual polyps, and (3) identifying individuals with high-risk personal and/or familial history of cancer. Finding individuals and families with hereditary CRC syndromes presents an underutilized opportunity for delivery of high-value care.