DNA Mismatch Repair Gene Mutations in Human Cancer
Päivi Peltomäki
Department of Medical Genetics, University of Helsinki, Finland
Abstract
A new pathogenetic mechanism leading to cancer has been delineated in the past 3 years when human homologues of DNA mismatch repair (MMR) genes have been identified and shown to be involved in various types of cancer. Germline mutations of MMR genes cause susceptibility to a hereditary form of colon cancer, hereditary nonpolyposis colon cancer (HNPCC), which represents one of the most common syndromes associated with cancer predisposition in man. Tumors from HNPCC patients are hypermutable and show length variation at short tandem repeat sequences, a phenomenon referred to as microsatellite instability or replication errors. A similar abnormality is found in a proportion of sporadic tumors of the colorectum as well as a variety of other organs; acquired mutations in MMR genes or other endogenous or exogenous causes may underlie these cases. Genetic and biochemical characterization of the functions of normal and mutated MMR genes elucidates mechanisms of cancer development and provides tools for diagnostic applications. -- Environ Health Perspect 105(Suppl 4):775-780 (1997)
Key words: DNA mismatch repair, microsatellite instability, MSH2, MLH1, PMS1, PMS2, gene mutations, hereditary nonpolyposis colorectal cancer
This paper was prepared as background for the Workshop on Susceptibility to Environmental Hazards convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held 17-22 March 1996 in Espoo, Finland. Manuscript received at EHP 5 November 1996; accepted 18 November 1996.
Address correspondence to Dr. P. Peltomäki, P.O. Box 21 (Haartmaninkatu 3), FIN-00014, University of Helsinki, Helsinki, Finland. Telephone: 358-9-43461. Fax: 358-9-4346677. E-mail: paivi.peltomaki@helsinki.fi
Abbreviations used: ERCC2, excision repair cross complementing 2; GTBP, G/T mismatch binding protein; HNPCC, hereditary nonpolyposis colon cancer; MLH1, mutL homolog 1; MMR, DNA mismatch repair; MSH2, mutS homolog 2; PMS1, postmeiotic segregation increased 1; PMS2, postmeiotic segregation increased 2; RER, replication error; VSP, very short-patch pathway.
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Last Update: June 16, 1997