Journal Article

Deficient DNA mismatch repair: a common etiologic factor for colon cancer

Päivi Peltomäki

in Human Molecular Genetics

Volume 10, issue 7, pages 735-740
Published in print April 2001 | ISSN: 0964-6906
Published online April 2001 | e-ISSN: 1460-2083 | DOI:
Deficient DNA mismatch repair: a common etiologic factor for colon cancer

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Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR). Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 (∼50%), MSH2 (∼40%) and MSH6 (∼10%). Genetically predisposed individuals carry a defective copy of an MMR gene in every cell. Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer. Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in ~15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR. Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis. Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.

Journal Article.  4872 words.  Illustrated.

Subjects: Genetics and Genomics

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