Familial Cancer

, Volume 18, Issue 2, pp 211–219 | Cite as

Recent advances in Lynch syndrome

  • Leah H. Biller
  • Sapna SyngalEmail author
  • Matthew B. Yurgelun


Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation, which in turn has implications on surveillance strategies for patients. Even the treatment of Lynch-associated cancers has changed with the addition of immunotherapy for advanced disease. This progress report aims to review some of the many advances in epidemiology, molecular pathogenesis, diagnosis, clinical phenotype, cancer surveillance, treatment, and chemo- and immune-prevention strategies in the Lynch syndrome field over the past 5 years.


Lynch syndrome Cancer genetics Hereditary cancer syndromes 



S. Syngal is a consultant for Myriad Genetics and has rights to an inventor portion of licensing revenues from PREMM5.


  1. 1.
    Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP (2015) Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer. Google Scholar
  2. 2.
    Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109):816–819CrossRefGoogle Scholar
  3. 3.
    Aaltonen LA, Peltomaki P, Leach FS et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260(5109):812–816CrossRefGoogle Scholar
  4. 4.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363(6429):558–561. CrossRefGoogle Scholar
  5. 5.
    Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352(18):1851–1860. CrossRefGoogle Scholar
  6. 6.
    Hampel H, Frankel W, Panescu J et al (2006) Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66(15):7810–7817. CrossRefGoogle Scholar
  7. 7.
    NCCN clinical practice guidelines in oncology: genetic/familial high risk assessment: colorectal. Version 1.2018. Published July 12, 2018. Accessed 1 Aug 2018
  8. 8.
    Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW (2015) ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. Google Scholar
  9. 9.
    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. Am J Gastroenterol 109(8):1159–1179. CrossRefGoogle Scholar
  10. 10.
    Balmana J, Balaguer F, Cervantes A, Arnold D (2013) Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol Off J Eur Soc Med Oncol 24(Suppl 6):vi73–80. Google Scholar
  11. 11.
    Vasen HFA, Blanco I, Aktan-Collan K et al (2013) Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62(6):812–823. CrossRefGoogle Scholar
  12. 12.
    Stoffel EM, Mangu PB, Gruber SB et al (2015) Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol 33(2):209–217. CrossRefGoogle Scholar
  13. 13.
    NCCN clinical practice guidelines in oncology: uterine neoplasm. Version 1.2019. Published October 17, 2018. Accessed 25 Oct 2018
  14. 14.
    SGO Clinical Practice Statement: Screening for Lynch Syndrome in Endometrial Cancer. Published March 2014. Accessed Oct 2018
  15. 15.
    Jarvinen 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(5):829–834CrossRefGoogle Scholar
  16. 16.
    Schmeler KM, Lynch HT, Chen L et al (2006) Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354(3):261–269. CrossRefGoogle Scholar
  17. 17.
    Burn J, Gerdes 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(9809):2081–2087. CrossRefGoogle Scholar
  18. 18.
    Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3):247–257. CrossRefGoogle Scholar
  19. 19.
    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(20):3219–3226. CrossRefGoogle Scholar
  20. 20.
    Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. Google Scholar
  21. 21.
    Yurgelun MB, Kulke MH, Fuchs CS et al (2017) Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol 35(10):1086–1095. CrossRefGoogle Scholar
  22. 22.
    Win AK, Jenkins MA, Dowty JG et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. Google Scholar
  23. 23.
    Ponti G, Castellsague E, Ruini C, Percesepe A, Tomasi A (2015) Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet 87(6):507–516. CrossRefGoogle Scholar
  24. 24.
    Haraldsdottir S, Rafnar T, Frankel WL et al. Comprehensive population-wide detection of Lynch syndrome in Iceland. ASCO Meet Abstr. 2016Google Scholar
  25. 25.
    Dominguez-Valentin M, Nilbert M, Wernhoff P et al (2013) Mutation spectrum in South American Lynch syndrome families. Hered Cancer Clin Pract. Google Scholar
  26. 26.
    Guindalini RSC, Win AK, Gulden C et al (2015) Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology. Google Scholar
  27. 27.
    Dymerska D, Gołębiewska K, Kuświk M et al (2017) New EPCAM founder deletion in Polish population. Clin Genet. Google Scholar
  28. 28.
    Haraldsdottir S, Rafnar T, Frankel WL et al (2017) Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun 8:1–11. CrossRefGoogle Scholar
  29. 29.
    Cancer Genom Atlas (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature. Google Scholar
  30. 30.
    Yurgelun MB, Goel A, Hornick JL et al (2012) Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res 5(4):574 LP–L582CrossRefGoogle Scholar
  31. 31.
    Ahadova A, Gallon R, Gebert J et al (2018) Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer 143(1):139–150. CrossRefGoogle Scholar
  32. 32.
    Kloor M, Huth C, Voigt AY et al (2012) Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol 13(6):598–606. CrossRefGoogle Scholar
  33. 33.
    Ahadova A, von Knebel Doeberitz M, Bläker H, Kloor M (2016) CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer 15(4):579–586. CrossRefGoogle Scholar
  34. 34.
    Moller P, Seppala T, Bernstein I et al (2017) Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 66(9):1657–1664. CrossRefGoogle Scholar
  35. 35.
    Rodriguez-Soler M, Perez-Carbonell L, Guarinos C et al (2013) Risk of cancer in cases of suspected Lynch syndrome without germline mutation. Gastroenterology 144(5):924–926. CrossRefGoogle Scholar
  36. 36.
    Hemminger JA, Pearlman R, Haraldsdottir S et al (2018) Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome. Hum Pathol. Google Scholar
  37. 37.
    Sourrouille I, Coulet F, Lefevre JH et al (2013) Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer. Google Scholar
  38. 38.
    Haraldsdottir S, Hampel H, Tomsic J et al (2014) Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 147(6):1308–1316.e1. CrossRefGoogle Scholar
  39. 39.
    Hampel H, Pearlman R, Beightol M et al (2018) Assessment of tumor sequencing as a replacement for Lynch syndrome screening and current molecular tests for patients with colorectal cancer. JAMA Oncol 4(6):806–813. CrossRefGoogle Scholar
  40. 40.
    Luba DG, DiSario JA, Rock C et al (2018) Community practice implementation of a self-administered version of PREMM1,2,6 to assess risk for Lynch syndrome. Clin Gastroenterol Hepatol 16(1):49–58. CrossRefGoogle Scholar
  41. 41.
    Kastrinos F, Uno H, Ukaegbu C et al (2017) Development & validation of the PREMM5 model for comprehensive risk assessment of lynch syndrome. J Clin Oncol. Google Scholar
  42. 42.
    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(3):604 – 13.e20. CrossRefGoogle Scholar
  43. 43.
    Ring KL, Bruegl AS, Allen BA et al (2016) Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol 29(11):1381–1389. CrossRefGoogle Scholar
  44. 44.
    Pearlman R, WL F, Swanson B (2017) al et. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 3(4):464–471. CrossRefGoogle Scholar
  45. 45.
    Stoffel EM, Koeppe E, Everett J et al (2018) Germline genetic features of young individuals with colorectal cancer. Gastroenterology 154(4):897–905. CrossRefGoogle Scholar
  46. 46.
    Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME (2013) Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol. Google Scholar
  47. 47.
    Katona BW, Yurgelun MB, Garber JE et al (2018) A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med. Google Scholar
  48. 48.
    Kurian AW, Li Y, Hamilton AS et al (2017) Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer. J Clin Oncol 35(20):2232–2239. CrossRefGoogle Scholar
  49. 49.
    Latham Schwark A, Srinivasan P, Kemel Y et al (2018) Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. J Clin Oncol 36(18_suppl):LBA1509–LBA1509. CrossRefGoogle Scholar
  50. 50.
    Barrow E, Hill J, Evans DG (2013) Cancer risk in Lynch syndrome. Fam Cancer 12(2):229–240. CrossRefGoogle Scholar
  51. 51.
    Dowty JG, Win AK, Buchanan DD et al (2013) Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat 34(3):490–497. CrossRefGoogle Scholar
  52. 52.
    Møller P, Seppälä TT, Bernstein I et al (2018) Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 67(7):1306 LP–L1316CrossRefGoogle Scholar
  53. 53.
    Sanchez A, Navarro M, Ocaña T et al (2017) Colorectal cancer incidence in Lynch syndrome patients: first report of a Multicenter Nation-Wide Study. Gastroenterology 152(5):S552. CrossRefGoogle Scholar
  54. 54.
    ten Broeke SW, van der Klift HM, Tops CMJ et al. Cancer risks for PMS2 -associated Lynch syndrome. J Clin Oncol.
  55. 55.
    Engel C, Vasen HF, Seppala T et al (2018) No difference in colorectal cancer incidence or stage at detection by colonoscopy among 3 countries with different Lynch syndrome surveillance policies. Gastroenterology. Google Scholar
  56. 56.
    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(3):464–472. CrossRefGoogle Scholar
  57. 57.
    Saeterdal I, Bjorheim J, Lislerud K et al (2001) Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci USA 98(23):13255–13260. CrossRefGoogle Scholar
  58. 58.
    Sclafani F (2017) PD-1 inhibition in metastatic dMMR/MSI-H colorectal cancer. Lancet Oncol 18(9):1141–1142. CrossRefGoogle Scholar
  59. 59.
    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(8):773–779. CrossRefGoogle Scholar
  60. 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(9):1182–1191. CrossRefGoogle Scholar
  61. 61.
    Le DT, Uram JN, Wang H et al (2015) PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. CrossRefGoogle Scholar
  62. 62.
    Le DT, Durham JN, Smith KN et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349):409–413. CrossRefGoogle Scholar
  63. 63.
    Movahedi M, Bishop DT, Macrae F et al (2015) Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 study. J Clin Oncol 33(31):3591–3597. CrossRefGoogle Scholar
  64. 64.
    Spira A, Disis ML, Schiller JT et al (2016) Leveraging premalignant biology for immune-based cancer prevention. Proc Natl Acad Sci USA 113(39):10750–10758. CrossRefGoogle Scholar
  65. 65.
    Schwitalle Y, Kloor M, Eiermann S et al (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134(4):988–997. CrossRefGoogle Scholar
  66. 66.
    Majumder S, Shah R, Elias J et al (2018) A cancer vaccine approach for personalized treatment of Lynch syndrome.
  67. 67.
    Chang K, Taggart MW, Reyes-Uribe L et al (2018) Immune profiling of premalignant lesions in patients with Lynch syndrome. JAMA Oncol 4(8):1085–1092. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Leah H. Biller
    • 1
  • Sapna Syngal
    • 2
    • 3
    • 4
    Email author
  • Matthew B. Yurgelun
    • 2
    • 3
    • 4
  1. 1.Beth Israel Deaconess Medical CenterBostonUSA
  2. 2.Dana-Farber Cancer InstituteBostonUSA
  3. 3.Harvard Medical SchoolBostonUSA
  4. 4.Brigham & Women’s HospitalBostonUSA

Personalised recommendations