Clinical, anamnestic, molecular and genetic criteria for Lynch syndrome

Lynch syndrome is the most common cancer-prone syndrome associated with a high risk of colorectal cancer (CRC), neoplasms of the upper gastrointestinal system, the urinary tract, the female reproductive system, brain tumours and others. The only known form of hereditary endometrial cancer is also diagnosed as part of Lynch syndrome. One or more pathogenic germline mutations in one of the mismatch repair (MMR) genes are the cause of Lynch syndrome. Mapping of MMR genes and the discovery of microsatellite instability (MSI) have given rise to the possibility of using these clue characteristics of the pathogenic process for the elaboration of a screening test for Lynch syndrome. Being highly accurate and superior to all previously developed clinical criteria and guidelines, MSI-testing along with the assessment of the expression patterns of MMR proteins by immunohistochemistry has taken the leading role in the early diagnosis of Lynch syndrome. This article focuses on a brief review about the main evolutionary stages of clinical, anamnestic, molecular and genetic criteria for Lynch syndrome together with the results of our own research on the accuracy of the Amsterdam criteria, the Bethesda guidelines and MSI-diagnostics in the determination of the indications for MMR-genotyping in colorectal cancer patients suspected for Lynch syndrome.

1. Nagy R., Sweet K., Eng C. Highly penetrant hereditary cancer syndromes. Oncogene 2004;23(38):6445–70. DOI: 10.1038/sj.onc.1207714.

2. Giardiello 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. Gastroenterology 2014;147(2):502–26. DOI: 10.1053/j.gastro.2014.04.001.

3. Lynch H.T., de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348(10):919–32. DOI: 10.1056/NEJMra012242.

4. Hampel H., Frankel W.L., Martin E. et al. Screening for the Lynch syndrome (hereditary non-polyposis colorectal cancer). N Engl J Med 2005;352(18):1851–60. DOI: 10.1200/JCO.2008.17.5950.

5. Barnetson R.A., Tenesa A., Farrington S.M. et al. Identification and survival of carriers of mutations in DNA mismatchrepair genes in colon cancer. N Engl J Med 2006;354(26):2751–63. DOI: 10.1056/NEJMoa053493.

6. Engel C., Loeffler M., Steinke V. et al. Risks of less common cancers in proven mutation carriers with lynch syndrome J Clin Oncol 2012;30(35):4409–15. DOI: 10.1200/JCO.2012.43.2278.

7. Hitchins M.P., Ward R.L. Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet 2009;46(12):793–802. DOI: 10.1136/jmg.2009.068122.

8. American Society of clinical oncology. Hereditary Colorectal Cancer Syndromes Endorsement of the Familial Risk– Colorectal Cancer ESMO Guideline Available at: www.asco.org/endorsements/HereditaryCRC.

9. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf.

10. American College of Medical Genetics and Genomics. Available at: https://www.acmg.net/.

11. Kohlmann W., Gruber S.B. Lynch syndrome. Gene Reviews at GeneTests: Medical Genetics Information Resourse. University of Washington, Seattle 1993–2014. Available at: http://www.genetests.org.

12. Jasperson K.W., Tuohy T.M., Neklason D.W. et al. Hereditary and familial colon cancer. Gastroenterology 2010;138(6):2044–58. DOI: 10.1053/j.gastro.2010.01.054.

13. Kastrinos F., Stoffel E.M. History, Genetics, and strategies for cancer prevention in Lynch syndrome. Clin Gastroenterol Hepatol 2014;12(5):715–27. DOI: 10.1016/j.cgh.2013.06.031.

14. Schwark A.L., Srinivasan P., Kemel Y. et al. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. J Clin Oncol 36(18_ suppl):LBA1509.

15. Vasen H.F., Mecklin J.P., Watson P. et al. Surveillance in hereditary non-polyposis colorectal cancer: an international cooperative study of 165 families. The International Collaborative Group on HNPCC. Dis Colon Rectum 1993;36:1–4. DOI: 10.1007/BF02050292.

16. Vasen H.F., Watson P., Mecklin J.P., Lynch H.T. New clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–6. DOI: 10.1016/S00165085(99)70510-X.

17. Boland C.R., Thibodeau S.N., Hamilton S.R. 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.

18. Umar A., Boland C.R., Terdiman J.P. et al. Revised bethesda guidelines for hereditary non-polyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261– 8. DOI: 10.1093/jnci/djh281.

19. Hampel H., Frankel W.L., Martin E. et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26(35):5783–8. DOI: 10.1200/JCO.2008.17.5950.

20. Vasen H.F. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol 2000;18(21 Suppl):81S–92S.

21. Raedle J., Trojan A., Brieger J. et al. Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. Ann Intern Med 2001;135(8 Pt 1):566–76. DOI: 10.7326/0003-4819135-8_part_1-200110160-00007.

22. Piñol V., Castells A., Andreu M. et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary non-polyposis colorectal cancer. JAMA 2005;293(16):1986–94. DOI: 10.1001/jama.293.16.1986.

23. Chen S., Wang W., Lee S. et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006;296:1479–87. DOI: 10.1001/jama.296.12.1479.

24. Kastrinos F., Steyerberg E.W., Balmana J. et al. Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer. Gut 2013;62:272–9. DOI: 10.1136/gutjnl-2011-301265.

25. Kastrinos F., Steyerberg E.W., Mercado R. et al. The PREMM1,2,6 model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 2011;140:73–81. DOI: 10.1053/j.gastro.2010.08.021.

26. Green R.C., Parfrey P.S., Woods M.O., Younghusband H.B. Prediction of Lynch syndrome in consecutive patients with colorectal cancer. J Natl Cancer Inst 2009;101:331–40. DOI: 10.1093/jnci/djn499.

27. Cohen S.A., Pritchard C.C., Jarvik G.P. Lynch syndrome: from screening to diagnosis to treatment in the era of modern molecular oncology. Annu Rev Genom Hum Genet 2019;20:293–307. DOI: 10.1146/annurev-genom-083118-015406.

28. Tiwari A.K., Roy H.K., Lynch H.T. Lynch syndrome in the 21st century: clinical perspectives. QJM 2016;109(3):151–8. DOI: 10.1093/qjmed/hcv137.

29. Pearlman R., Markow M., Knight D. et al. Two-stain immunohistochemical screening for Lynch syndrome in colorectal cancer may fail to detect mismatch repair deficiency. Mod Pathol 2018;31:1891–900. DOI: 10.1038/s41379-018-0058-y.

30. 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. DOI: 10.1097/GIM.0b013e31818fa2ff.

31. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls.

32. Salipante S.J., Scroggins S.M., Hampel H.L. et al. Microsatellite instability detection by next generation sequencing. Clin Chem 2014;60(9):1192–9.

33. Moreira L., Balaguer F., Lindor N. et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012;308(15):1555–65.