MUTATION IN THE MISMATCH REPAIR GENE MSH6 CAUSES CANCER SUSCEPTIBILITY

Mice carrying a null mutation in the mismatch repair gene Msh6 were ge nerated by gene targeting. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared fr om these cells were defective for repair of single nucleotide mismatch es. 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 predomina nt of which were gastrointestinal tumors and B-as well as T-cell lymph omas. The tumors did not show any microsatellite instability. We concl ude that MSH6 mutations, like those in some other members bf the famil y of mismatch repair genes, lead to cancer susceptibility, and germlin e mutations in this gene may be associated with a cancer predispositio n syndrome that does not show microsatellite instability.