Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer

TLDR

Hereditary nonpolyposis colorectal cancer is linked to a locus on chromosome 2p, with tumors showing microsatellite instability. Chromosome microdissection and marker mapping defined a 0.8 Mb interval on 2p16, within which a mutS‑homolog gene was identified and sequenced to screen for germline mutations. Somatic and germline mutations in this mutS‑homolog were found in RER+ tumor cells, implicating it as the HNPCC gene.

Abstract

Recent studies have shown that a locus responsible for hereditary nonpolyposis colorectal cancer (HNPCC) is on chromosome 2p and that tumors developing in these patients contain alterations in microsatellite sequences (RER+ phenotype). We have used chromosome microdissection to obtain highly polymorphic markers from chromosome 2p16. These and other markers were ordered in a panel of somatic cell hybrids and used to define a 0.8 Mb interval containing the HNPCC locus. Candidate genes were then mapped, and one was found to lie within the 0.8 Mb interval. We identified this candidate by virtue of its homology to mutS mismatch repair genes. cDNA clones were obtained and the sequence used to detect germline mutations, including those producing termination codons, in HNPCC kindreds. Somatic as well as germline mutations of the gene were identified in RER+ tumor cells. This mutS homolog is therefore likely to be responsible for HNPCC.