The International Mismatch Repair Consortium

  • Mark A. Jenkins
  • Jeanette C. Reece
  • Aung K. Win


The International Mismatch Repair Consortium (IMRC) is a collaboration of clinicians and scientists who have agreed to pool and analyse data on Lynch syndrome, a genetic predisposition to cancer caused by germline mutations in DNA mismatch repair genes or EPCAM deletion, with the rationale that research on this hereditary syndrome will benefit from large datasets from many countries. As of October 2017, the IMRC includes approximately 273 members from 122 centres/clinics in 29 countries throughout Africa, Asia, Australasia, Europe, and North and South America, who are involved in research or treatment of people with Lynch syndrome and their families. To date, there are six research projects registered at the IMRC: cancer risks for Lynch syndrome, classification of mismatch repair variants, genetic testing and screening practices, environmental and lifestyle modifiers of cancer risk, inherited methylation and cancer risks for family members of constitutional mismatch repair deficiency (CMMR-D) patients. The most significant project, in terms of data accrued, is the study of cancer risks for Lynch syndrome which mainly asks whether age-specific cumulative risk (penetrance) of cancers differs by country or geographic region. As of October 2017, almost 6200 pedigrees from investigators from approximately 24 countries have been submitted for penetrance analysis – see


Colorectal cancer Lynch syndrome Penetrance MLH1 MSH2 MSH6 PMS2 EPCAM International Risk factors Cohort Family history 



The National Health and Medical Research Council, Australia, has supported this research via a project grant and via research fellowships. We thank all researchers, clinicians and genetic counsellors at participating centres who have given their time and resources and the Lynch syndrome families.


  1. 1.
    Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34(3):490–7. Scholar
  2. 2.
    Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet. 2005;42(6):491–6. Scholar
  3. 3.
    Bonadona V, Bonaiti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304–10. Scholar
  4. 4.
    Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193–201. Scholar
  5. 5.
    Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135(2):419–28.e1. Scholar
  6. 6.
    Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009;137(5):1621–7. Scholar
  7. 7.
    Choi Y-H, Cotterchio M, McKeown-Eyssen G, Neerav M, Bapat B, Boyd K, et al. Penetrance of colorectal cancer among MLH1/ MSH2 carriers participating in the colorectal cancer familial registry in Ontario. Hered Cancer Clin Prac. 2009;7:14.
  8. 8.
    Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 1997;6(1):105–10.CrossRefGoogle Scholar
  9. 9.
    Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129(2):415–21. Scholar
  10. 10.
    ten Broeke SW, Brohet RM, Tops CM, van der Klift HM, Velthuizen ME, Bernstein I, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015;33(4):319–25. Scholar
  11. 11.
    Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66(3):464–72.
  12. 12.
    Arnold S, Buchanan DD, Barker M, Jaskowski L, Walsh MD, Birney G, et al. Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. Hum Mutat. 2009;30(5):757–70. Scholar
  13. 13.
    Thompson BA, Goldgar DE, Paterson C, Clendenning M, Walters R, Arnold S, et al. A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. Hum Mutat. 2013;34(1):200–9. Scholar
  14. 14.
    Spurdle AB. Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models. Curr Opin Genet Dev. 2010;20(3):315–23. Scholar
  15. 15.
    Lindor N, Peterson G, Spurdle A, Thompson B, Goldgar D, Thibodeau S. Pancreatic cancer and a novel MSH2 germline alteration. Pancreas. 2011;40(7):1138–40. Scholar
  16. 16.
    Stuckless S, Parfrey PS, Woods MO, Cox J, Fitzgerald GW, Green JS, et al. The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam Cancer. 2007;6(1):1–12. Scholar
  17. 17.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917. Scholar
  18. 18.
    Le Marchand L. Combined influence of genetic and dietary factors on colorectal cancer incidence in Japanese Americans. J Natl Cancer Inst Monogr. 1999;26:101–5.CrossRefGoogle Scholar
  19. 19.
    Park JG, Park YJ, Wijnen JT, Vasen HF. Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. Int J Cancer. 1999;82(4):516–9. CrossRefGoogle Scholar
  20. 20.
    van Vliet CM, Dowty JG, van Vliet JL, Smith L, Mead LJ, Macrae FA, et al. Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes. Hum Mutat. ​2011;32(2):207–12.
  21. 21.
    Green J, O'Driscoll M, Barnes A, Maher ER, Bridge P, Shields K, et al. Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation. Dis Colon Rectum. 2002;45(9):1223–32. Scholar
  22. 22.
    Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000;118(5):829–34.CrossRefGoogle Scholar
  23. 23.
    Parry S, Win AK, Parry B, Macrae FA, Gurrin LC, Church JM, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut. 2011;60(7):950–7. Scholar
  24. 24.
    Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081–7. Scholar
  25. 25.
    Win AK, Dowty JG, English DR, Campbell PT, Young JP, Winship I, et al. Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes. Br J Cancer. 2011;105(1):162–9. Scholar
  26. 26.
    Botma A, Nagengast FM, Braem MGM, Hendriks JCM, Kleibeuker JH, Vasen HFA, et al. Body mass index increases risk of colorectal adenomas in men with Lynch syndrome: the GEOLynch cohort study. J Clin Oncol. 2010;28(28):4346–53. Scholar
  27. 27.
    Watson P, Ashwathnarayan R, Lynch HT, Roy HK. Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome). Arch Intern Med. 2004;164(22):2429–31. Scholar
  28. 28.
    Pande M, Lynch PM, Hopper JL, Jenkins MA, Gallinger S, Haile RW, et al. Smoking and colorectal cancer in Lynch syndrome: results from the Colon Cancer Family Registry and the University of Texas M.D. Anderson Cancer Center. Clin Cancer Res. 2010;16(4):1331–9. Scholar
  29. 29.
    Chau R, Dashti SG, Ait Ouakrim D, Buchanan DD, Clendenning M, Rosty C, et al. Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome. Int J Epidemiol. 2016;45(3):940–53. Scholar
  30. 30.
    Dashti SG, Buchanan DD, Jayasekara H, Ait Ouakrim D, Clendenning M, Rosty C, et al. Alcohol consumption and the risk of colorectal cancer for mismatch repair gene mutation carriers. Cancer Epidemiol Biomark Prev. 2017;26(3):366–75. Scholar
  31. 31.
    Ferlitsch M, Reinhart K, Pramhas S, Wiener C, Gal O, Bannert C, et al. Sex-specific prevalence of adenomas, advanced adenomas, and colorectal cancer in individuals undergoing screening colonoscopy. JAMA. 2011;306(12):1352–8. Scholar
  32. 32.
    Bauer CM, Ray AM, Halstead-Nussloch BA, Dekker RG, Raymond VM, Gruber SB, et al. Hereditary prostate cancer as a feature of Lynch syndrome. Fam Cancer. 2011;10(1):37–42. Scholar
  33. 33.
    Grindedal EM, Moller P, Eeles R, Stormorken AT, Bowitz-Lothe IM, Landro SM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomark Prev. 2009;18(9):2460–7. Scholar
  34. 34.
    Barrow PJ, Ingham S, O'Hara C, Green K, McIntyre I, Lalloo F, et al. The spectrum of urological malignancy in Lynch syndrome. Fam Cancer. 2013;12(1):57–63. Scholar
  35. 35.
    Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomark Prev. 2014;23(3):437–49. Scholar
  36. 36.
    Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res. 2013;15(2):R27. Scholar
  37. 37.
    Win AK, Lindor NM, Winship I, Tucker KM, Buchanan DD, Young JP, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013;105(4):274–9. Scholar
  38. 38.
    Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, et al. Risks of primary extracolonic cancers following colorectal cancer in Lynch syndrome. J Natl Cancer Inst. 2012;104(18):1363–72. Scholar
  39. 39.
    Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30(9):958–64. Scholar
  40. 40.
    Elston RC, Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21(6):523–42.CrossRefGoogle Scholar
  41. 41.
    Lange K, Weeks D, Boehnke M. Programs for pedigree analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol. 1988;5(6):471–2. Scholar
  42. 42.
    Bonaiti B, Bonadona V, Perdry H, Andrieu N, Bonaiti-Pellie C. Estimating penetrance from multiple case families with predisposing mutations: extension of the ‘genotype-restricted likelihood’ (GRL) method. Eur J Hum Genet. 2011;19(2):173–9. Scholar
  43. 43.
    Carayol J, Bonaiti-Pellie C. Estimating penetrance from family data using a retrospective likelihood when ascertainment depends on genotype and age of onset. Genet Epidemiol. 2004;27(2):109–17. Scholar
  44. 44.
    Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D. Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol. 2001;21(1):1–18. Scholar
  45. 45.
    Gong G, Hannon N, Whittemore AS. Estimating gene penetrance from family data. Genet Epidemiol. 2010;34(4):373–81. Scholar
  46. 46.
    Cannings C, Thompson EA, Skolnick MH. Probability functions on complex pedigrees. Adv Appl Probab. 1978;10(1):26–61. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Mark A. Jenkins
    • 1
    • 2
  • Jeanette C. Reece
    • 1
  • Aung K. Win
    • 1
    • 2
  1. 1.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, The University of MelbourneParkvilleAustralia
  2. 2.University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer CentreParkvilleAustralia

Personalised recommendations