Mutation in the Mismatch Repair Gene Msh6 Causes Cancer Susceptibility

Abstract

Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by gene targeting. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1, 2, and 4 nucleotide insertion/deletion mismatches was unaffected. Mice that were homozygous for the mutation had a reduced life span. The mice developed a spectrum of tumors, the most predominant of which were gastrointestinal tumors and B- as well as T-cell lymphomas. The tumors did not show any microsatellite instability. We conclude that MSH6 mutations, like those in some other members of the family of mismatch repair genes, lead to cancer susceptibility, and germline mutations in this gene may be associated with a cancer predisposition syndrome that does not show microsatellite instability.

Mouse models for colorectal cancer

“…This observation has important implications because an involvement of MSH6 in HNPCC (Prolla et al, 1998) might not have been identi®ed if the RER+ phenotype is used as a diagnostic criterion. Families with germ line mutations in the MSH6 gene have been identi®ed Edelmann et al, 1997;Miyaki et al, 1997). Tumors that are similar to those observed in Msh67/7 mice were found in some HNPCC patients.…”

Progress and prospects: oligonucleotide-directed gene modification in mouse embryonic stem cells: a route to therapeutic application

“…41,[51][52][53][54][55] It has been postulated that mismatches that are poorly detected by the MMR system could be introduced into MMRproficient cell lines with a reasonable efficacy. 48 Indeed, ssODNs encoding complex mismatches, such as 3-or 4-nt substitutions and 4-nt insertions, led to detectable levels of gene alteration in wild-type ESCs, but frequencies were still rather low (B10 À6 ) and general rules for ssODN design could not be established.…”

Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer

“…8,9 The cellular state with an elevated mutation rate, that is, the 'mutator phenotype' , 10 has since then received attention as a cause for tumourigenesis. Indeed, tumours frequently arise in MMR gene-knockout mice 11,12 and the mutation rates in the MMR-defective mouse cells are known to be markedly increased. 11,13 Human cell lines with an acknowledged defect in the MMR genes also exhibit significantly elevated mutation rates.…”