FaCD Online Syndrome Fact Sheet

Last updated: 24 Oct 2012

Name: Lynch syndrome

Synonym: Hereditary Non-Polyposis Colorectal Cancer, HNPCC, Lynch syndromes 1 and 2 (= Cancer Family Syndrome), Hereditary Mismatch Repair Deficiency syndrome, HMRDS

Mode of Inheritance: AD

OMIM number: 114500   114400   120435   120436   600678   600259  


EPCAM/TACSTD1, mapped to 2p21
MLH1, mapped to 3p21.3
MSH2, mapped to 2p21-p22
MSH6, mapped to 2p16
PMS2, mapped to 7p22

Tumor features

adenomatous polyps in the small intestine
biliary tract cancer (incl. gallbladder)
colorectal adenomas
endometrial cancer
gastric cancer, intestinal type
gastrointestinal adenomas
gastrointestinal cancer
gastrointestinal polyps
glioblastoma (multiforme)
glioma of the brain
ovarian cancer (i.e. epithelial origin)
pancreatic adenocarcinoma
prostate cancer
renal pyelum cancer
sebaceous adenoma
sebaceous carcinoma
sebaceous epithelioma
ureter cancer

Tumor features (possible)

breast cancer
breast cancer, male
hemangiopericytoma, malignant
Hodgkin disease (Hodgkin's lymphoma)
laryngeal cancer
lung/bronchial cancer
malignant fibrous histiocytoma
melanoma, cutaneous
non-Hodgkin lymphoma
primitive neuroectodermal tumor (PNET)
testicular germ cell tumor
urinary bladder cancer
uterus, sarcoma of the


Lynch syndrome, the name referring to oncologist Henry Lynch who contributed greatly to our knowledge of this disorder, is an autosomal dominant disorder[1]. It is characterized by a 25-70% cumulative life-time risk of colorectal cancer, often with an early onset (average 40-50 years) and proximal location. Number of adenomatous colorectal polyps is generally small, <5-10. There is an increased risk to develop extra-colorectal cancer, including endometrial cancer, with a cumulative life-time risk of 25-70%, ovarian cancer (3-10%, possibly higher for MSH6), gastric cancer (2-4%), cancer of the small intestine (4-7%), upper urinary tract (1-12%), brain (1%?), hepatobiliary tract (?%), pancreas(3,7%[37]), brain and sebaceous glands (?%, see also the Muir-Torre variant of Lynch syndrome).[2-9,20].

With the exception of endometrial cancer, MSH2 mutation carriers appear to have a higher risk to develop extra-intestinal cancer than MLH1 and MSH6 mutation carriers[20]. For carriers of germline MSH6 mutations the age at diagnosis of endometrial cancer is lower and the age at diagnosis of colorectal cancer higher than for MLH1 and MSH2 mutation carriers[5-7,10,38]. Quehenberger et al[9] and Carayol et al[11] demonstrated a large overestimation of colorectal cancer risk in Lynch syndrome (20+% rather than 70-90%). A recent study suggested approximately 50% risk of colorectal cancer by the age of 70 years[21]. Tumor risk appears to be modified by a CA repeat in the IGF1 gene[24] and presence of CHEK2 1100delC[25]. Senter et al[26] recently published the first risk estimates for carriers of PMS2 mutations. For North America, cumulative cancer risk to age 70 years was estimated at 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. Survival in women with ovarian cancer caused by Lynch syndrome appears to be much better than in women with BRCA1/2 mutations[35].

Incidental cases of other tumor types have been reported in which tumor findings pointed to a causal role of the Lynch syndrome gene mutations: male and female breast cancer[29-32], testicular germ cell tumors[23], sarcoma[27,28], thyroid cancer[12], lymphoma[12,19], melanoma[22], lung cancer[34] and a cerebral primitive neuroectodermal tumor (PNET)[36]. There is no proof yet that Lynch syndrome families have a strongly increased risk to develop these tumor types. Their is evidence for an increased prostate cancer risk[23,40-43],

At the molecular level, Lynch syndrome is characterized by germline mutations in genes responsible for the repair of DNA replication errors, the mismatch repair (MMR) genes, in particular MLH1, MSH2, MSH6 and PMS2. Germline deletion of the 3' exons of TACSTD1/EPCAM can cause heritable somatic methylation and inactivation of MSH2 and thus Lynch syndrome[33] . De novo mutations are very rare[13,14]. Deficiency of MMR genes causes replication errors (mismatches) in repetitive DNA segments, known as microsatellites. Microsatellite instability (MSI) is not a unique feature of Lynch syndrome and therefore no proof of this syndrome, but occurs in different percentages in the majority of solid neoplasms[15].

Clinical criteria =Amsterdam criteria II)[16]:

  • a) the presence of at least 3 relatives with histologically verified
  • colorectal cancer,
  • endometrial cancer,
  • small bowel cancer,
  • ureter cancer or
  • renal pelvis cancer;
  • and one of these relatives should be a first-degree relative of the other two,
  • (b) at least 2 successive generations should be affected,
  • (c) at least one case of these cancers diagnosed before age 50 and
  • (d) exclusion (on clinical grounds) of Familial Adenomatous Polyposis.

Families that meet these criteria, but do not show signs of mismatch repair deficiency in their tumors are considered not to have Lynch syndrome. Some authors refer to these families as Familial Colorectal Cancer type X[17].

The Revised Bethesda guidelines try to incorporate insights based on the molecular studies of patients and families with colorectal cancer and other HNPCC associated tumors, and aim at providing clinicians with practical criteria to select patients and their families for tumor MSI testing[18]
  • CRC diagnosed in a patient aged <50 years
  • Presence of synchronous, metachronous colorectal or other Lynch syndrome-related tumours*, regardless of age
  • CRC with MSI-H phenotype diagnosed in a patient aged <60 years
  • Patient with CRC and a first-degree relative with a Lynch syndrome-related tumour, with one of the cancers diagnosed at age <50 years
  • Patient with CRC with two or more first-degree or second-degree relatives with a Lynch syndrome-related tumour, regardless of age

  • * = cancer of the colorectum, stomach, small intestine, pancreas, biliary tract, renal pyelum, ureter, ovarium, brain; sebeacous gland adenoma or carcinoma and keratoacanthoma


International Society for Gastrointestinal Hereditary Tumours (InSiGHT) 18 1 08


[1] Douglas JA, Gruber SB, Meister KA, Bonner J, Watson P, Krush AJ, Lynch HT. History and molecular genetics of Lynch syndrome in family G: a century later. JAMA : the journal of the American Medical Association 2005; 294(17):2195-202.
[2] Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW, Vogelstein B. Cancer risk associated with germline DNA mismatch repair gene mutations. Human molecular genetics 1997; 6(1):105-10.
[3] Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomäki P, Mecklin JP, Järvinen HJ. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International journal of cancer. Journal international du cancer 1999; 81(2):214-8.
[4] Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard ML, Mohr J, Fodde R, Khan PM. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996; 110(4):1020-7.
[5] Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, Taal BG, Moller P, Wijnen JT. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2001; 19(20):4074-80.
[6] Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, Sandkuijl L, Møller P, Genuardi M, Van Houwelingen H, Tops C, Van Puijenbroek M, Verkuijlen P, Kenter G, Van Mil A, Meijers-Heijboer H, Tan GB, Breuning MH, Fodde R, Wijnen JT, Bröcker-Vriends AH, Vasen H. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 2004; 127(1):17-25.
[7] Plaschke J, Engel C, Krüger S, Holinski-Feder E, Pagenstecher C, Mangold E, Moeslein G, Schulmann K, Gebert J, von Knebel Doeberitz M, Rüschoff J, Loeffler M, Schackert HK. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2004; 22(22):4486-94.
[8] Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP, de la Chapelle A. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005; 129(2):415-21.
[9] 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. Journal of medical genetics 2005; 42(6):491-6.
[10] Buttin BM, Powell MA, Mutch DG, Babb SA, Huettner PC, Edmonston TB, Herzog TJ, Rader JS, Gibb RK, Whelan AJ, Goodfellow PJ. Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history. American journal of human genetics 2004; 74(6):1262-9.
[11] Carayol J, Khlat M, Maccario J, Bonaïti-Pellié C. Hereditary non-polyposis colorectal cancer: current risks of colorectal cancer largely overestimated. Journal of medical genetics 2002; 39(5):335-9.
[12] Stulp R, Herkert A, Karrenbeld A, Sijmons RH. Thyroid cancer in Lynch syndrome. Case report and review of the expanding syndrome tumour spectrum. Hereditary cancer in clinical practice 2008; 6(1):15-21
[13] Kraus C, Kastl S, Günther K, Klessinger S, Hohenberger W, Ballhausen WG. A proven de novo germline mutation in HNPCC. Journal of medical genetics 1999; 36(12):919-21.
[14] Stulp RP, Vos YJ, Mol B, Karrenbeld A, de Raad M, van der Mijle HJ, Sijmons RH. First report of a de novo germline mutation in the MLH1 gene. World journal of gastroenterology : WJG 2006; 12(5):809-11.
[15] Lawes DA, SenGupta S, Boulos PB. The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2003; 29(3):201-12.
[16] Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999; 116(6):1453-6.
[17] Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA : the journal of the American Medical Association 2005; 293(16):1979-85.
[18] Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. Journal of the National Cancer Institute 2004; 96(4):261-8.
[19] Pineda M, Castellsagué E, Musulén E, Llort G, Frebourg T, Baert-Desurmont S, González S, Capellá G, Blanco I. Non-Hodgkin lymphoma related to hereditary nonpolyposis colorectal cancer in a patient with a novel heterozygous complex deletion in the MSH2 gene. Genes, chromosomes & cancer 2008; 47(4):326-32.
[20] Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Järvinen HJ, Myrhøj T, Sunde L, Wijnen JT, Lynch HT. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. International journal of cancer 2008; 123(2):444-9.
[21] Barrow E, Alduaij W, Robinson L, Shenton A, Clancy T, Lalloo F, Hill J, Evans D. Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations. Clinical genetics 2008; .
[22] Ponti G, Losi L, Pellacani G, Wannesson L, Cesinaro AM, Venesio T, Petti C, Seidenari S. Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer. The British journal of dermatology 2008; 159(1):162-8.
[23] Rouprêt M, Yates DR, Comperat E, Cussenot O. Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum. European urology 2008; epub ahead of print.
[24] Reeves SG, Rich D, Meldrum CJ, Colyvas K, Kurzawski G, Suchy J, Lubinski J, Scott RJ. IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer. International journal of cancer. Journal international du cancer 2008; 123(6):1339-43.
[25] Wasielewski M, Vasen H, Wijnen J, Hooning M, Dooijes D, Tops C, Klijn JG, Meijers-Heijboer H, Schutte M. CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer. Clinical cancer research 2008; 14(15):4989-94.
[26] Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008; 135(2):419-28.
[27] Sijmons R, Hofstra R, Hollema H, Mensink R, van der Hout A, Hoekstra H, Kleibeuker J, Molenaar W, Wijnen J, Fodde R, Vasen H, Buys C. Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer. Genes Chromosomes Cancer. 2000 Dec;29(4):353-5.
[28] Nilbert M, Therkildsen C, Nissen A, Akerman M, Bernstein I. Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum. Fam Cancer. 2009 Jan 8. [Epub ahead of print]
[29] Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J. Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 1996 May 1;77(9):1836-43
[30] Boyd J, Rhei E, Federici MG, Borgen PI, Watson P, Franklin B, Karr B, Lynch J, Lemon SJ, Lynch HT. Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 1999; 53(1):87-91.
[31] Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, du Sart D, Tucker K, Kirk J. Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet. 2001 Jan;68(1):118-127
[32] de Leeuw WJ, van Puijenbroek M, Tollenaar RA, Cornelisse CJ, Vasen HF, Morreau H. Correspondence re: A. Müller et al., Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res. 2002;62: 1014-1019.
[33] Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1.Nat Genet. 2009 Jan;41(1):112-7
[34] Canney A, Sheahan K, Keegan D, Tolan M, Hyland J, Green A. Synchronous lung tumours in a patient with metachronous colorectal carcinoma and a germline MSH2 mutation. J Clin Pathol. 2009 May;62(5):471-3.
[35] Grindedal EM, Renkonen-Sinisalo L Dr, Vasen H, Evans G, Sala P, Blanco I, Gronwald J, Apold J, Eccles DM, Sánchez AA, Sampson J, Järvinen HJ, Bertario L, Crawford GC, Stormorken AT, Maehle L, Møller P. Survival in women with MMR mutations and ovarian cancer; A multicentre study in Lynch Syndrome kindreds. J Med Genet. 2009 Jul 26. [Epub ahead of print]
[36] Jeans AF, Frayling I, Jasani B, Side L, Blesing C, Ansorge O. Cerebral primitive neuroectodermal tumor in an adult with a heterozygous MSH2 mutation. Nat Rev Clin Oncol. 2009 May;6(5):295-9.
[37] Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009 Oct 28;302(16):1790-5.
[38] Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH; Dutch Lynch Syndrome Study Group, Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, Macrae F, Antill Y, Winship IM, Giles GG, Goldblatt J, Parry S, Suthers G, Leggett B, Butz M, Aronson M, Poynter JN, Baron JA, Le Marchand L, Haile R, Gallinger S, Hopper JL, Potter J, de la Chapelle A, Vasen HF, Dunlop MG, Thibodeau SN, Jenkins MA. Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers. J Natl Cancer Inst. 2009 Dec 22. [Epub ahead of print]
[39] Koornstra JJ, Mourits MJ, Sijmons RH, Leliveld AM, Hollema H, Kleibeuker JH. Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol. 2009 Apr;10(4):400-8.
[40] Barrow PJ, Ingham S, O'Hara C, Green K, McIntyre I, Lalloo F, Hill J, Evans DG. The spectrum of urological malignancy in Lynch syndrome. Fam Cancer. 2012 Oct 11. [Epub ahead of print]
[41] Bauer CM, Ray AM, Halstead-Nussloch BA, Dekker RG, Raymond VM, Gruber SB, Cooney KA. Hereditary prostate cancer as a feature of Lynch syndrome. Fam Cancer. 2011 Mar;10(1):37-42.
[42] Win Aung Ko et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. Journal of the National Cancer Institute 2012; 104:1363-72.
[43] Grindedal Eli Marie et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer epidemiology, biomarkers & prevention.