It has recently been shown that hereditary nonpolyposis colorectal cancer (HNPCC) is caused by hereditable defects in DNA mismatch repair genes. However, the fraction of HNPCC due to defects in any one repair gene and the nature of these mutations are not known. We analyzed 29 HNPCC kindreds for mutations in the prototype DNA mismatch repair gene hMSH2 by a combination of linkage analysis, polymerase chain reaction-based screening, and sequencing of the coding region. The complete intron/exon structure of the gene was ascertained to facilitate this analysis. The results suggest that at least 40% of classic HNPCC kindreds are associated with germline mutations in hMSH2 and that most of these mutations produce drastic alterations in the predicted protein product.


Supported by grants from the Clayton Fund, the Academy of Finland, The Finnish cancer Societies, the Sigrid Juselius Foundation, the Folkhalsan Institute of Genetics, the Nebraska Health Department, the Council for Tobacco Research, and NIH grants CA35494, CA47527, CA57345, CA62924, and CA09326.

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