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Current clinical topics of Lynch syndrome

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Abstract

Lynch syndrome (LS) is one of the most common genetic cancer syndromes, occurring at a rate of 1 per 250–1000 in the general population. This autosomal dominant disease is caused by a germline variant in one of the four mismatch repair genes, MSH2, MLH1, MSH6, PMS2, or the EPCAM gene. LS develops at early ages in colorectal cancer (CRC), endometrial cancer, and various other associated tumors. Accurate diagnosis of LS and utilization of various risk-reduction strategies such as surveillance, prophylactic surgery, and chemoprevention could improve clinical outcomes. The efficacy of surveillance has only been proven for CRC; however, specialists have proposed surveillance for other LS associated tumors. Universal screening for tumor tissue using microsatellite instability testing or the mismatch repair protein immunochemistry in all CRC or endometrial cancers is recommended not only as a diagnostic tool for LS, but also as a predictive, prognostic, and therapeutic marker. Next-generation sequencing methods have revealed several conditions with phenotypes similar to LS, such as Lynch-like syndrome, constitutional mismatch repair deficiency syndrome, and polymerase proofreading-associated polyposis. Distinguishing LS from these similar conditions is clinically important, since clinical management for patients differs according to the conditions. Recently, immune checkpoint inhibitors have been shown to be a promising treatment against mismatch repair-deficient (dMMR) solid tumors. The efficacy of immune-checkpoint inhibitors in LS-associated tumors has been shown to be similar to that in sporadic dMMR tumors. This review discusses current clinical topics related to LS screening, diagnosis, surveillance, and therapy.

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References

  1. Warthin AS (1913) Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch Int Med 12:546–555

    Article  Google Scholar 

  2. Lynch HT, Shaw MW, Magnuson CW et al (1966) Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 117:206–212

    Article  CAS  PubMed  Google Scholar 

  3. Kohlmann W, Gruber SB (2004) Lynch syndrome. Gene Reviews. AVAILABLE via DIALOG. https://www.ncbi.nlm.nih.gov/books/NBK1211/. Accessed Apr 2018

  4. InSiGHT (2018) Available via DIALOG. https://www.insight-group.org/. Accessed Apr 2018

  5. Chika N, Eguchi H, Kumamoto K et al (2017) Prevalence of LS and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population. Jpn J Clin Oncol 47:108–117

    Article  PubMed  Google Scholar 

  6. Jensen LH, Bojesen A, Byriel L et al (2013) Implementing population-based screening for Lynch syndrome. J Clin Oncol 31(Suppl):abstr 6600. https://meetinglibrary.asco.org/record/84519/poster. Accessed Apr 2018

  7. Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for LS among patients with colorectal cancer. J Clin Oncol 26:5783–5788

    Article  PubMed  PubMed Central  Google Scholar 

  8. Moreira L, Balaguer F, Lindor N et al (2012) Identification of Lynch syndrome among patients with colorectal cancer. JAMA 308:1555–1565

    Article  CAS  PubMed  Google Scholar 

  9. Peltomäki P (2016) Update on Lynch syndrome genomics. Fam Cancer 15:385–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ligtenberg MJ, Kuiper RP, Chan TL et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41:112–117

    Article  CAS  PubMed  Google Scholar 

  11. Ishida H, Yamaguchi T, Tanakaya K et al (2018) Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (Translated Version). J Anus Rectum Colon (JARC). http://journal-arc.jp/pdf/002s10001.pdf. Accessed Apr 2018

  12. Umar A, Boland CR, Terdiman JP et al (2004) Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    Article  CAS  PubMed  Google Scholar 

  13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines). Genetic/Familial High-Risk Assessment: Colorectal Version 3.2017. http://www.nccn.org. Accessed Feb 2018

  14. Giardiello FM, Allen JI, Axilbund JE et al (2014) Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 147:502–526

    Article  PubMed  Google Scholar 

  15. Yamaguchi T, Furukawa Y, Nakamura Y et al (2014) Comparison of clinical features between suspected familial colorectal cancer type X and LS in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum. Jpn J Clin Oncol 45:153–159

    Article  PubMed  Google Scholar 

  16. Tanakaya K, Yamaguchi T, Ishikawa H et al (2016) Causes of cancer death among first-degree relatives in Japanese families with Lynch syndrome. Anticancer Res 36:1985–1989

    PubMed  Google Scholar 

  17. Vasen HF, Mecklin JP, Khan PM et al (1991) The International Collaborative Group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425

    Article  CAS  PubMed  Google Scholar 

  18. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009) 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 11:35–41

    Article  Google Scholar 

  19. Ishikubo T, Nishimura Y, Yamaguchi K et al (2004) The clinical features of rectal cancers with high-frequency microsatellite instability (MSI-H) in Japanese males. Cancer Lett 216:55–62

    Article  CAS  PubMed  Google Scholar 

  20. Asaka S, Arai Y, Nishimura Y et al (2009) Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes’ A to Dukes’ B. Carcinogenesis 30:494–499

    Article  CAS  PubMed  Google Scholar 

  21. Koinuma K, Shitoh K, Miyakura Y et al (2004) Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 108:237–242

    Article  CAS  PubMed  Google Scholar 

  22. McGivern A, Wynter CV, Whitehall VL et al (2004) Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non–polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3:101–110

    Article  CAS  PubMed  Google Scholar 

  23. Long GV, Wilmott JS, Capper D et al (2013) Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol 37:61–65

    Article  PubMed  Google Scholar 

  24. Kawaguchi M, Yanokura M, Banno K et al (2009) Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer. Int J Oncol 34:1541–1547

    CAS  PubMed  Google Scholar 

  25. Le DT, Uram JN, Wang H et al (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372:2509–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Win AK, Jenkins MA, Buchanan DD et al (2011) Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet 48:530–534

    Article  CAS  PubMed  Google Scholar 

  27. Ponti G, Castellsagué E, Ruini C et al (2015) Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet 87:507–516

    Article  CAS  PubMed  Google Scholar 

  28. Sumitsuji I, Sugano K, Matsui T et al (2003) Frequent genomic disorganisation of MLH1 in hereditary non-polyposis colorectal cancer (HNPCC) screened by RT-PCR on puromycin treated samples. J Med Genet 40:e30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Utsumi M, Tanakaya K, Mushiake Y et al (2017) Metachronous colorectal carcinoma with massive submucosal invasion detected by annual surveillance in a LS patient: a case report. World J Surg Oncol 15:140

    Article  PubMed  PubMed Central  Google Scholar 

  30. Furukawa Y (2013) Genetic changes of Japanese Lynch syndrome (in Japanese). Intestine 17:2–5

    Google Scholar 

  31. Pritchard CC, Smith C, Salipante SJ et al (2012) ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing. J Mol Diagn 14:357–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yurgelun MB, Allen B, Kaldate RR et al (2015) Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch Syndrome. Gastroenterology 149:604–613

    Article  CAS  PubMed  Google Scholar 

  33. Bradbury AR, Patrick-Miller L, Long J et al (2015) Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility. Genet Med 17:485–492

    Article  PubMed  Google Scholar 

  34. Bakry D, Aronson M, Durno C et al (2014) Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer 50:987–996

    Article  PubMed  Google Scholar 

  35. Carethers JM, Stoffel EM (2015) Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer. World J Gastroenterol 21:9253–9261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124:105–122

    Article  PubMed  Google Scholar 

  37. Rana Q, Syngal HS (2017) Biallelic mismatch repair deficiency: management and prevention of a devastating manifestation of the Lynch syndrome. Gastroenterology 152:1254–1257

    Article  Google Scholar 

  38. Adam R, Spier I, Zhao B et al (2016) Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet 99:337–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Durno C, Boland CR, Cohen S et al (2017) Recommendations on surveillance and management of biallelic mismatch repair deficiency (BMMRD) syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2017 152:1605–1614

    Article  PubMed  Google Scholar 

  40. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C et al (2013) Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology 144:926–932

    Article  CAS  PubMed  Google Scholar 

  41. Dillon JL, Gonzalez JL, DeMars L et al (2017) Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome. Hum Pathol 70:121–128

    Article  PubMed  Google Scholar 

  42. Vasen HF, Watson P, Mecklin JP et al (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456

    Article  CAS  PubMed  Google Scholar 

  43. Lindor NM, Rabe K, Petersen GM et al. (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293:1979–1985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Garre P, Martin L, Sanz J et al (2015) BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. Clin Genet 87:582–587

    Article  CAS  PubMed  Google Scholar 

  45. Dominguez-Valentin M, Therkildsen C, Da Silva S et al (2014) Familial colorectal cancer type X: genetic profiles and phenotypic features. Mod Pathol 28:30–36

    Article  PubMed  Google Scholar 

  46. Nejadtaghi M, Jafari H, Farrohki E et al (2017) Familial Colorectal Cancer Type X (FCCTX) and the correlation with various genes-A systematic review. Curr Probl Cancer 41:388–397

    Article  PubMed  Google Scholar 

  47. Palles C, Cazier JB, Howarth KM et al (2013) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45:136–144

    Article  CAS  PubMed  Google Scholar 

  48. Briggs S, Tomlinson I (2013) Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol 230:148–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Seshagiri S (2013) The burden of faulty proofreading in colon cancer. Nat Genet 45:121–122

    Article  CAS  PubMed  Google Scholar 

  50. Bourdais R, Rousseau B, Pujals A et al (2017) Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency. Crit Rev Oncol Hematol 113:242–248

    Article  PubMed  Google Scholar 

  51. Järvinen HJ, Aarnio M, Mustonen H et al (2000) Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829–834

    Article  PubMed  Google Scholar 

  52. Vasen HF, Blanco I, Aktan-Collan K et al (2013) Revised guidelines for the clinical management of LS (HNPCC): recommendations by a group of European experts. Gut 62:812–823

    Article  CAS  PubMed  Google Scholar 

  53. Parry S, Win AK, Parry B, et.al (2011) Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 60:950–957

    Article  PubMed  Google Scholar 

  54. Schmeler KM, Lynch HT, Chem LM et al (2006) Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354:261–269

    Article  CAS  PubMed  Google Scholar 

  55. Møller P, Seppälä T, Bernstein I et al (2017) Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. GUT 66:464–472

    Article  PubMed  Google Scholar 

  56. Burn J, Gardes AM, Macrae F et al (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378:2081–2087

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sargent DJ, Marsoni S, Monges G et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28:3219–3226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Goldstein J, Tran B, Ensor J et al (2014) Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol 25:1032–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Le DT, Durham JN, Smith KN et al (2017) Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Overman MJ, McDermott R, Leach JL et al (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18:1182–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Overman MJ, Lonardi S, Wong KYM et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36:773–779

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Kohji Tanakaya.

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Tanakaya, K. Current clinical topics of Lynch syndrome. Int J Clin Oncol 24, 1013–1019 (2019). https://doi.org/10.1007/s10147-018-1282-7

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