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Hereditary non polyposis colorectal carcinoma (HNPCC Syndrome)

Written2001-09Pierre Laurent-Puig
Laboratoire de Toxicologie Moléculaire U490, 45 rue des Saints Pöres, 75006 Paris, France

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Identity

Other namesLynch syndrome
Atlas_Id 10049
Genes implicated inEPCAM  MLH1  MSH2  MSH6  PMS1  PMS2  TGFBR2  
Inheritance autosomal dominant ; frequency is about 1 to 2/1000 inhabitants; founder effect has been found in finnish population

Clinics

Phenotype and clinics Hereditary non polyposis colorectal carcinoma is an autosomal dominantly inherited predisposition to develop colorectal cancer, endometrial carcinoma and ovary carcinoma, urinary tract carcinomas, stomach, small bowel and biliary tract carcinoma, and brain tumors. Colorectal carcinoma is characterized by early age at onset, predominantly right sided with an excess of synchrounous and metachronous tumors.
Neoplastic risk The risk of colorectal cancer in HNPCC patients is estimates up to 75% by age 75. The average age of diagnosis is 45 years for colorectal cancer. It is interesting to note that the risk of colorectal cancer for women was less that observed for men and average age of diagnosis was delayed. The risk of uterine cancer in HNPCC female is estimated up to 40% and the risk of ovarian cancer is less than 10%. The risk of metachronous colorectal cancer, when limited resection of colon was performed, is estimated to 30%
Treatment Full coloscopy to the caecum is recommended every two years beginning at age 25 years or 5 years before the first cancer. Annual screening for uterine cancer is recommended beginning at the age 35 years. The method of screening include transvaginal ultrasound and hysteroscopy
Prognosis Coloscopy screening at 3 year intervals more than halves the risk of colorectal cancer, prevents colorectal cancer deaths, and decreases overall mortality by about 65% in HNPCC families

Genes involved and Proteins

Note different genes can be respnsible for Lynch syndrome:
  • hMSH2 (mutS (E. coli) homolog 2 (colon cancer, nonpolyposis type 1)) located in 2p22-p21
  • hMLH1 (mutL (E. coli) homolog 1 (colon cancer, nonpolyposis type 2)) located in 3p21.3
  • hMSH6 (mutS (E. coli) homolog 6) located in 2p16
  • PMS2 (postmeiotic segregation increased (S. cerevisiae) 2) located in 7p22
  • PMS1 (postmeiotic segregation increased (S. cerevisiae) 1) located in 2q31.1
  • TGFBR2 (transforming growth factor, beta receptor II (70-80kD)) located in 3p22
  • Protein
    Localisation nuclear
    Function These protein works on DNA mismatch repair pathways. hMSH21 et hMLH1 are similar to MutS andt MutL in Echerichia Coli. These two proteins participated to the recognition of DNA mismatch during DNA replication. They formed complex with hMSH3, hMSH6 and PMS2 allowing the mismatch repair
    Mutations
    Germinal Yes; no mutations hot spot
    Somatic Yes; extinction of hMLH1 by promoter hypermethylation

    Bibliography

    Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease.
    Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomäki P, Chadwick RB, Kääriäinen H, Eskelinen M, Järvinen H, Mecklin JP, de la Chapelle A
    The New England journal of medicine. 1998 ; 338 (21) : 1481-1487.
    PMID 9593786
     
    Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer.
    Järvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomäki P, De La Chapelle A, Mecklin JP
    Gastroenterology. 2000 ; 118 (5) : 829-834.
    PMID 10784581
     
    Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer.
    Peltomä P, Vasen HF
    Gastroenterology. 1997 ; 113 (4) : 1146-1158.
    PMID 9322509
     
    Population-based molecular detection of hereditary nonpolyposis colorectal cancer.
    Salovaara R, Loukola A, Kristo P, Kääriäinen H, Ahtola H, Eskelinen M, Härkönen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Järvinen H, Mecklin JP, Aaltonen LA, de la Chapelle A
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000 ; 18 (11) : 2193-2200.
    PMID 10829038
     

    Citation

    This paper should be referenced as such :
    Laurent-Puig, P
    Hereditary non polyposis colorectal carcinoma (HNPCC syndrome)
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(1):56-57.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/HNPCCLynchID10049.html


    External links

    OMIM120435
    OMIM609310
    OMIM613244
    OMIM614337
    OrphanetHereditary mixed polyposis syndrome
    MeSHD003123  
    MedGenD003123  
    UMLS-  
    ICD-10D12.6  
    AssociationLe syndrome HNPCC
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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