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  

Genes

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
astrocytoma
biliary tract cancer (incl. gallbladder)
colorectal adenomas
endometrial cancer
ependymoma
gastric cancer, intestinal type
gastrointestinal adenomas
gastrointestinal cancer
gastrointestinal polyps
glioblastoma (multiforme)
glioma of the brain
keratoacanthoma
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
chondrosarcoma
gliosarcoma
hemangiopericytoma, malignant
Hodgkin disease (Hodgkin's lymphoma)
laryngeal cancer
leiomyosarcoma
liposarcoma
lung/bronchial cancer
malignant fibrous histiocytoma
melanoma, cutaneous
non-Hodgkin lymphoma
osteosarcoma
primitive neuroectodermal tumor (PNET)
sarcoma
testicular germ cell tumor
urinary bladder cancer
uterus, sarcoma of the

Comment

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

Links

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

References

[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.
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[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.
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[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.
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[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.
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[43] Grindedal Eli Marie et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer epidemiology, biomarkers & prevention.