Familial Cancer

, Volume 12, Issue 2, pp 229–240

Cancer risk in Lynch Syndrome

Original Article


Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by inactivating mutations in DNA mismatch repair genes. It accounts for 2–4 % of all incident colorectal cancers. Mutation carriers are at risk of early onset colorectal cancer, endometrial cancer, and a spectrum of other tumours. Accurate estimation of cancer risk for mutation carriers is essential for counselling, and establishing appropriate screening guidelines. This study reviews the current data on cancer risk, and emerging risk reduction strategies.


Lynch Syndrome Hereditary nonpolyposis colorectal cancer (HNPCC) DNA mismatch repair Familial relative risk Risk reduction Statistical bias 



Hereditary non-polyposis colorectal cancer


Mismatch repair


International Collaborative Group on HNPCC


Colorectal cancer


Central nervous system


  1. 1.
    Barnetson RA, Tenesa A, Farrington SM et al (2006) Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354(26):2751–2763PubMedCrossRefGoogle Scholar
  2. 2.
    Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348(10):919–932PubMedCrossRefGoogle Scholar
  3. 3.
    Lynch HT, Smyrk T (1996) Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78(6):1149–1167PubMedCrossRefGoogle Scholar
  4. 4.
    Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116(6):1453–1456PubMedCrossRefGoogle Scholar
  5. 5.
    Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The International Collaborative Group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34(5):424–425PubMedCrossRefGoogle Scholar
  6. 6.
    Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96(4):261–268PubMedCrossRefGoogle Scholar
  7. 7.
    Plaschke J, Engel C, Kruger S et al (2004) Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 22(22):4486–4494PubMedCrossRefGoogle Scholar
  8. 8.
    Dunlop MG, Farrington SM, Carothers AD et al (1997) Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6(1):105–110PubMedCrossRefGoogle Scholar
  9. 9.
    Hampel H, Stephens JA, Pukkala E et al (2005) Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 129(2):415–421PubMedGoogle Scholar
  10. 10.
    Barrow E, Alduaij W, Robinson L, Shenton A, Clancy T, Lalloo F, Hill J, Evans DG (2008) Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations. Clin Genet 74(3):233–242Google Scholar
  11. 11.
    Barrow E, Robinson L, Alduaij W et al (2009) Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 75(2):141–149PubMedCrossRefGoogle Scholar
  12. 12.
    Quehenberger F, Vasen HF, van Houwelingen HC (2005) Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 42(6):491–496PubMedCrossRefGoogle Scholar
  13. 13.
    Jenkins MA, Baglietto L, Dowty JG et al (2006) Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol 4(4):489–498PubMedCrossRefGoogle Scholar
  14. 14.
    Choi YH, Cotterchio M, McKeown-Eyssen G et al (2009) Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario. Hered Cancer Clin Pract 7(1):14PubMedCrossRefGoogle Scholar
  15. 15.
    Kastrinos F, Mukherjee B, Tayob N et al (2009) Risk of pancreatic cancer in families with Lynch syndrome. JAMA 302(16):1790–1795PubMedCrossRefGoogle Scholar
  16. 16.
    Baglietto L, Lindor NM, Dowty JG et al (2010) Risks of Lynch Syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 102(3):193–201PubMedCrossRefGoogle Scholar
  17. 17.
    Stoffel E, Mukherjee B, Raymond VM et al (2009) Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 137(5):1621–1627PubMedCrossRefGoogle Scholar
  18. 18.
    Alarcon F, Lasset C, Carayol J et al (2007) Estimating cancer risk in HNPCC by the GRL method. EJHG 15(8):831–836PubMedCrossRefGoogle Scholar
  19. 19.
    Bonadona V, Bonaiti B, Olschwang S et al (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305(22):2304–2310PubMedCrossRefGoogle Scholar
  20. 20.
    Aarnio M, Sankila R, Pukkala E et al (1999) Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81(2):214–218PubMedCrossRefGoogle Scholar
  21. 21.
    Vasen HF, Stormorken A, Menko FH et al (2001) MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 19(20):4074–4080PubMedGoogle Scholar
  22. 22.
    Green J, O’Driscoll M, Barnes A et al (2002) 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 45(9):1223–1232PubMedCrossRefGoogle Scholar
  23. 23.
    Hendriks YM, Wagner A, Morreau H et al (2004) Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 127(1):17–25PubMedCrossRefGoogle Scholar
  24. 24.
    Ramsoekh D, Wagner A, van Leerdam ME et al (2009) Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hereditary cancer in clinical practice 7(1):17PubMedCrossRefGoogle Scholar
  25. 25.
    Talseth-Palmer BA, McPhillips M, Groombridge C, Spigelman A, Scott RJ (2010) MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 8(1):5PubMedCrossRefGoogle Scholar
  26. 26.
    van der Post RS, Kiemeney LA, Ligtenberg MJ et al (2010) Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 47(7):464–470PubMedCrossRefGoogle Scholar
  27. 27.
    Therkildsen C, Isinger-Ekstrand A, Ladelund S, Nissen A, Rambech E, Bernstein I, Nilbert M (2012) Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation. Fam Cancer 11(4):579–585Google Scholar
  28. 28.
    Lin KM, Shashidharan M, Thorson AG et al (1998) Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer. J Gastrointest Surg 2(1):67–71PubMedCrossRefGoogle Scholar
  29. 29.
    Aarnio M (2012) Clinicopathological features and management of cancers in lynch syndrome. Pathol Res Int 2012:350309Google Scholar
  30. 30.
    Fitzpatrick D, Gavin A, Middleton R, Catney D (2004) Cancer in Northern Ireland 1993–2001: a comprehensive report. In: Northern Ireland Cancer Registry B (ed) Northern IrelandGoogle Scholar
  31. 31.
    Stratton JF, Thompson D, Bobrow L et al (1999) The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study. Am J Hum Genet 65(6):1725–1732PubMedCrossRefGoogle Scholar
  32. 32.
    Watson P, Vasen HF, Mecklin JP et al (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123(2):444–449PubMedCrossRefGoogle Scholar
  33. 33.
    Capelle LG, Van Grieken NC, Lingsma HF et al (2010) Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenterology 138(2):487–492PubMedCrossRefGoogle Scholar
  34. 34.
    Koornstra JJ, Kleibeuker JH, Vasen HF (2008) Small-bowel cancer in Lynch syndrome: is it time for surveillance? Lancet Oncol 9(9):901–905PubMedCrossRefGoogle Scholar
  35. 35.
    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):2081–2087PubMedCrossRefGoogle Scholar
  36. 36.
    Win AK, Young JP, Lindor NM et al (2012) 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 30(9):958–964PubMedCrossRefGoogle Scholar
  37. 37.
    Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J (1996) Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 77(9):1836–1843PubMedCrossRefGoogle Scholar
  38. 38.
    de Leeuw WJ, van Puijenbroek M, Tollenaar RA, Cornelisse CJ, Vasen HF, Morreau H (2002) Correspondence re: A. Muller et al., Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res 62:1014–1019. Cancer Res 2003 63(5):1148–1149Google Scholar
  39. 39.
    Muller A, Edmonston TB, Corao DA et al (2002) Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res 62(4):1014–1019PubMedGoogle Scholar
  40. 40.
    Scott RJ, McPhillips M, Meldrum CJ et al (2001) Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68(1):118–127PubMedCrossRefGoogle Scholar
  41. 41.
    Vasen HF, Morreau H, Nortier JW (2001) Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet 68(6):1533–1535PubMedCrossRefGoogle Scholar
  42. 42.
    Grandval P, Barouk-Simonet E, Bronner M, Buisine MP, Moretta J, Tinat J, Olschwang S (2012) Is the controversy on breast cancer as part of the Lynch-related tumor spectrum still open? Fam Cancer 11(4):681–683Google Scholar
  43. 43.
    de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G et al (2002) Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum 45(12):1588–1594PubMedCrossRefGoogle Scholar
  44. 44.
    de Jong AE, Hendriks YM, Kleibeuker JH et al (2006) Decrease in mortality in Lynch syndrome families because of surveillance. Gastroenterology 130(3):665–671PubMedCrossRefGoogle Scholar
  45. 45.
    Jarvinen HJ, Mecklin JP, Sistonen P (1995) Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 108(5):1405–1411PubMedCrossRefGoogle Scholar
  46. 46.
    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):829–834PubMedCrossRefGoogle Scholar
  47. 47.
    Stupart DA, Goldberg PA, Algar U, Ramesar R (2009) Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis 11(2):126–130PubMedCrossRefGoogle Scholar
  48. 48.
    Vasen HF, Abdirahman M, Brohet R et al (2010) One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology 138(7):2300–2306PubMedCrossRefGoogle Scholar
  49. 49.
    Dunlop MG (2002) Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 51(Suppl 5):V21–V27PubMedCrossRefGoogle Scholar
  50. 50.
    Lindor NM, Petersen GM, Hadley DW et al (2006) Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 296(12):1507–1517PubMedCrossRefGoogle Scholar
  51. 51.
    Vasen HF, Moslein G, Alonso A et al (2007) Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44(6):353–362PubMedCrossRefGoogle Scholar
  52. 52.
    Ersig AL, Williams JK, Hadley DW, Koehly LM (2009) Communication, encouragement, and cancer screening in families with and without mutations for hereditary nonpolyposis colorectal cancer: a pilot study. Genet Med 11(10):728–734PubMedCrossRefGoogle Scholar
  53. 53.
    Thorson AG, Knezetic JA, Lynch HT (1999) A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome). Dis Colon Rectum 42(1):1–9PubMedCrossRefGoogle Scholar
  54. 54.
    Renkonen-Sinisalo L, Butzow R, Leminen A, Lehtovirta P, Mecklin JP, Jarvinen HJ (2007) Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer 120(4):821–824PubMedCrossRefGoogle Scholar
  55. 55.
    Rijcken FE, Mourits MJ, Kleibeuker JH, Hollema H, van der Zee AG (2003) Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 91(1):74–80PubMedCrossRefGoogle Scholar
  56. 56.
    Dove-Edwin I, Boks D, Goff S et al (2002) The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 94(6):1708–1712PubMedCrossRefGoogle Scholar
  57. 57.
    Manchanda R, Saridogan E, Abdelraheim A, Johnson M, Rosenthal AN, Benjamin E, Brunell C, Side L, Gessler S, Jacobs I, Menon U (2012) Annual outpatient hysteroscopy and endometrial sampling (OHES) in HNPCC/Lynch syndrome (LS). Arch Gynecol Obstet 286(6):1555–1562Google Scholar
  58. 58.
    Renkonen-Sinisalo L, Sipponen P, Aarnio M et al (2002) No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol 37(5):574–577PubMedCrossRefGoogle Scholar
  59. 59.
    Myrhoj T, Andersen MB, Bernstein I (2008) Screening for urinary tract cancer with urine cytology in Lynch syndrome and familial colorectal cancer. Fam Cancer 7(4):303–307PubMedCrossRefGoogle Scholar
  60. 60.
    Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ (1995) Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64(6):430–433PubMedCrossRefGoogle Scholar
  61. 61.
    Natarajan N, Watson P, Silva-Lopez E, Lynch HT (2010) Comparison of extended colectomy and limited resection in patients with Lynch syndrome. Dis Colon Rectum 53(1):77–82PubMedCrossRefGoogle Scholar
  62. 62.
    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(7):950–957PubMedCrossRefGoogle Scholar
  63. 63.
    Newton KF, Green K, Walsh S, Lalloo F, Hill J, Evans DGR (2012) Metachronous colorectal cancer risk in patients with a moderate family history. Colorectal Dis. Accepted Article. doi:10.1111/codi.12005
  64. 64.
    Stupart DA, Goldberg PA, Baigrie RJ, Algar U, Ramesar R (2011) Surgery for colonic cancer in HNPCC: total vs segmental colectomy. Colorectal Dis 13(12):1395–1399PubMedCrossRefGoogle Scholar
  65. 65.
    de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P et al (2003) Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut Dec 52(12):1752–1755CrossRefGoogle Scholar
  66. 66.
    Haanstra JF, de Vos Tot Nederveen Cappel WH, Gopie JP et al (2012) Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy. Dis Colon Rectum 55(6):653–659PubMedCrossRefGoogle Scholar
  67. 67.
    Schmeler KM, Lynch HT, Chen LM et al (2006) Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354(3):261–269PubMedCrossRefGoogle Scholar
  68. 68.
    Cuzick J, Otto F, Baron JA et al (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 10(5):501–507PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of General SurgeryUniversity of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal InfirmaryManchesterUK
  2. 2.Genetic MedicineThe University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary’s HospitalManchesterUK

Personalised recommendations