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MSH6 and MSH3 Are Rarely Involved in Genetic Predisposition to Nonpolypotic Colon Cancer¹

Division of Human Cancer Genetics, Ohio State University, Columbus, Ohio 43210 [J. H., R. B. C., C. K. J., M. W. S., S. K. R., J. E. M., X. G., F. A. W., P. P.]; Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Finland [S. A. K.]; Karolinska Institute, S-17176 Stockholm, Sweden [T. L., A. L.]; Department of Surgery, Jyväskylä Central Hospital, FIN-40620 Jyväskylä, Finland [J-P. M.]; Second Department of Surgery, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland [H. J. J.]; Department of Oncology, University Hospital, S-90185 Umeå, Sweden [H. G.]; and Rigshospitalet and Danish Hereditary Nonpolyposis Colon Cancer Registry, DK-2100 Copenhagen, Denmark [M. L. B.]

A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)₈ tract in tumors, previously 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-mutation negative families with nonpolypotic colon cancer.

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