MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer

A set of 90 nonpolypotic colon cancer families in which germ-fine mutations of MSH2 and MLH1 had been excluded were screened for mutations in two addi tional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and no t fulfilling the Amsterdam I criteria, showing early and late onset colorec tal land other) cancers, and having microsatellite stable and unstable tumo rs were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly s maller, families). Whereas MSH3 was not involved in any family, a large Ams terdam-positive, late-onset family showed a novel germ-line mutation in MSH 6 (deletion of CT at nucleotide 3052 in exon 4), The mutation was identifie d through genetic linkage (multipoint lod score 2.4) and subsequent sequenc ing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon i n families with frameshift mutations in the (C)(8) tract in tumors, previou sly suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutat ion negative families with nonpolypotic colon cancer.