Predominant germ-line mutation of the hMSH2 gene in Japanese hereditary non-polyposis colorectal cancer kindreds

By means of PCR-SSCP and direct sequencing, we detected 12 germ-line mutati ons of hMSH2 or hMLH1 in 37 Japanese hereditary non-polyposis colorectal ca ncer (HNPCC) kindreds, of whom 15 satisfied the Amsterdam and 22 the Japane se criteriai. The germ-line mutation detection rate of hMSH2 was much highe r than that of hMLH1 (11/37 vs. 1/37). The total mutation detection rate of hMSH2 and hMLH1 in the Amsterdam criteria group was significantly higher t han that in the Japanese criteria group (9/15 vs. 3/22). Furthermore, the m ean age of the HNPCC patients in the mutation-positive group was tower than that in the mutation-negative one; the rates of both vertical transmission and multiplicity of tumors in the mutation-positive group were higher than those in the mutation-negative one. In addition, the number of patients wi th microsatellite instability-positive cancers in the mutation-positive gro up was higher than that in the mutation-negative one. Our results suggest: firstly that the hMSH2 gene plays a much more important role than hMLH1 in the carcinogenesis of Japanese HNPCC patients, secondly that the rate of hM SH2 and hMLH1 mutations is high in the kindreds satisfying the Amsterdam cr iteria and thirdly that both the clinical phenotypes (early onset, vertical transmission and multiplicity of tumors) and the microsatellite instabilit y status are important for the genetic screening of HNPCC. (C) 1999 Wiley-L iss, Inc.