Effective Identification of Lynch Syndrome in Gastroenterology Practice
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Purpose of review
Identification of Lynch syndrome is important from an individual patient and public health standpoint. As paradigms for Lynch syndrome diagnosis have shifted in recent years, this review will discuss rationale and limitations for current strategies as well as provide an overview of future directions in the field.
In recent years, the use of clinical criteria and risk scores for identification of Lynch syndrome has been augmented by universal testing of all newly diagnosed colorectal cancers with molecular methods to screen for mismatch repair deficiency with high sensitivity and specificity. Studies of implementation and outcomes of universal testing in clinical practice have demonstrated significant heterogeneity that results in suboptimal uptake and contributes to disparities in diagnosis. Emerging technologies, such as next-generation sequencing, hold significant promise as a screening strategy for Lynch syndrome.
Universal testing for Lynch syndrome is being performed with increasing frequency, although real-world outcomes have demonstrated room for improvement. Future directions in Lynch syndrome diagnosis will involve optimization of universal testing workflow and application of new genetics technologies.
KeywordsLynch syndrome Amsterdam Criteria Bethesda Guidelines PREMM Model Universal Tumor Screening
Support was provided in part by NIH R01 CA220329 (SSK) and grant MRSG-13-144-01-CPHPS from the American Cancer Society (JMW).
Compliance with ethical standards
Conflict of interest
Charles Muller and Lindsay Matthews declare no conflict of interest. Sonia Kupfer reports non-financial support from Myriad Genetics for collaborative research, outside the submitted work. Jennifer Weiss reports grants from American Cancer Society, during the conduct of the study; personal fees from American College of Physicians as an Editor of MKSAP 18 Board Basics Gastroenterology and Hepatology Section, outside the submitted work.
Human and animal rights and informed consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 6.• National Comprehensive Cancer Network. Genetic/familial high-risk assessment: Colorectal (Version 1.2018). Accessed August 27, 2019. Accessible at https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. The NCCN guidelines provide expert opinion on the evaluation and management of Lynch syndrome. These guidelines are updated annually
- 8.• Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, 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;109:1159–79 Multi-society task force guidelines on genetic evaluation and management of Lynch syndrome with evidence-based recommendations. PubMedCrossRefPubMedCentralGoogle Scholar
- 12.United Stated Department of Health and Human Services Healthy People 2020. In: Genomics. Accessed August 1, 2019. Accessible at https://www.healthypeople.gov/2020/topics-objectives/topic/genomics.
- 18.Balmana J, Balaguer F, Castellvi-Bel S, Steyerberg EW, Andreu M, Llor X, et al. Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients. J Med Genet. 2008;45:557–63.PubMedCrossRefPubMedCentralGoogle Scholar
- 22.Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–57.Google Scholar
- 25.Lamberti C, Kruse R, Ruelfs C, Caspari R, Wang Y, Jungck M, et al. Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer. Gut. 1999;44:839–43.PubMedPubMedCentralCrossRefGoogle Scholar
- 26.Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005;293:1986–94.PubMedCrossRefPubMedCentralGoogle Scholar
- 27.Terdiman JP, Gum JR Jr, Conrad PG, Miller GA, Weinberg V, Crawley SC, et al. Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology. 2001;120:21–30.PubMedCrossRefPubMedCentralGoogle Scholar
- 33.Guivatchian T, Koeppe ES, Baker JR, Moisa C, Demerath M, Foor-Pessin C, 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.PubMedCrossRefPubMedCentralGoogle Scholar
- 39.•• Kastrinos F, Uno H, Ukaegbu C, Alvero C, McFarland A, Yurgelun MB, et al. Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome. J Clin Oncol. 2017;35:2165–72 Validation of PREMM5 model for identification of Lynch syndrome risk using data from over 18,000 tested individuals and validated in over 1,000 individuals. PubMedPubMedCentralCrossRefGoogle Scholar
- 43.Kastrinos F, Steyerberg EW. Family matters in lynch syndrome. J Natl Cancer Inst. 2015;107.Google Scholar
- 46.Parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet. 2012;49:151–7.PubMedCrossRefPubMedCentralGoogle Scholar
- 48.Pearlman R, Hampel H, de la Chepelle A, Goldberg R, Ciombor K, Arnold M, et al. Ohio colorectal cancer prevention initiative. Familial Cancer. 2017;16:S48.Google Scholar
- 50.Beamer LC, Grant ML, Espenschied CR, Blazer KR, Hampel HL, Weitzel JN, 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;30:1058–63.PubMedPubMedCentralCrossRefGoogle Scholar
- 56.Cavazza A, Radia C, Harlow C, Monahan KJ. Experience of the implementation and outcomes of universal testing for Lynch syndrome in the United Kingdom. Color Dis. 2019;21:760–6.Google Scholar
- 57.Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11:35–41.CrossRefGoogle Scholar
- 58.Li D, Hoodfar E, Jiang SF, Udaltsova N, Pham NP, Jodesty Y, et al. Comparison of Universal Versus Age-Restricted Screening of Colorectal Tumors for Lynch Syndrome Using Mismatch Repair Immunohistochemistry: A Cohort Study. Ann Intern Med. 2019.Google Scholar
- 59.Bellcross CA, Bedrosian SR, Daniels E, Duquette D, Hampel H, Jasperson K, et al. Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting. Genet Med. 2012;14:152–62.PubMedCrossRefPubMedCentralGoogle Scholar
- 63.•• Ladabaum U, Wang G, Terdiman J, Blanco A, Kuppermann M, Boland CR, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med. 2011;155:69–79 This paper examines the cost-effectiveness of universal tumor screening for Lynch syndrome. PubMedPubMedCentralCrossRefGoogle Scholar
- 65.Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, et al. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484–93.PubMedCrossRefPubMedCentralGoogle Scholar
- 66.• Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. American College of Gastroenterology. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110:223–62 American College of Gastroenterology guidelines on evaluation of hereditary gastrointestinal cancer syndromes including Lynch syndrome. PubMedPubMedCentralCrossRefGoogle Scholar
- 68.Karlitz JJ, Hsieh MC, Liu Y, Blanton C, Schmidt B, Jessup JM, et al. Population-Based Lynch Syndrome Screening by Microsatellite Instability in Patients ≤50: Prevalence, Testing Determinants, and Result Availability Prior to Colon Surgery. Am J Gastroenterol. 2015;110:948–55.PubMedCrossRefPubMedCentralGoogle Scholar
- 70.Jain A, Shafer L, Rothenmund H, Kim CA, Samadder J, Gupta S, et al. Suboptimal Adherence in Clinical Practice to Guidelines Recommendation to Screen for Lynch Syndrome. Dig Dis Sci. 2019.Google Scholar
- 84.Pritchard CC, Salipante SJ, Koehler K, Smith C, Scroggins S, Wood B, et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn. 2014;16:56–67.PubMedPubMedCentralCrossRefGoogle Scholar
- 85.Christakis AG, Papke DJ, Nowak JA, Yurgelun MB, Agoston AT, Lindeman NI, et al. Targeted Cancer Next-Generation Sequencing as a Primary Screening Tool for Microsatellite Instability and Lynch Syndrome in Upper Gastrointestinal Tract Cancers. Cancer Epidemiol Biomark Prev. 2019;28:1246–51.CrossRefGoogle Scholar
- 87.Colon Cancer Genetics Group. University of Edinburgh and MRC Human genetics Unit, Edinburgh. Prediction of DNA mismatch repair gene mutation status in incident colorectal cancer cases. Accessed August 16, 2019. Accessible at http://hnpccpredict.hgu.mrc.ac.uk/.
- 88.BayesMendel Lab. Harvard University. MMRpro. Accessed August 16, 2019. Accessible at https://projects.iq.harvard.edu/bayesmendel/mmrpro.
- 89.Dana-Farber Cancer Institute. PREMM. Lynch syndrome prediction model. MLH1, MSH2, MSH6, PMS2, and EPCAM gene mutations. Accessed August 16, 2019. Accessible at https://premm.dfci.harvard.edu/.