FREQUENT MICROSATELLITE INSTABILITIES AND ANALYSES OF THE RELATED GENES IN FAMILIAL GASTRIC CANCERS

Microsatellite instability or replication error seems to be related to defective DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2, which have been identified as causative genes of hereditary non polyposis colorectal cancers (HNPCC). Recently, it was reported that m utations at the simple repeated sequences in the transforming growth f actor-beta type II receptor (TGF-beta RII) gene occurred in replicatio n error-positive colorectal cancers. To determine genetic alterations in familial gastric cancers (FGC), we examined replication error using eight microsatellite DNA markers, and screened mutations in the hMSH2 , hMLH1 and TGF-beta RII genes in six cases from four FGC kindreds. Mo reover, hMTHI, a human homolog of the bacterial mutT gene, was also sc reened. Four of six (67%) cancers showed the replication error-positiv e phenotype, indicating that microsatellite instability is highly asso ciated with not only HNPCC, but also FGC. No germline mutation was fou nd in the whole coding sequences of hMSH2 and hMTH1, or in the conserv ative regions of hMLH1 in any patient, while one cancer DNA showed a s omatic mutation at codon 682 (threonine to alanine) in hMSH2. No alter ation was found at the small repeated sequences in TGF-beta RII in FGC tumor DNA. These results indicate that the carcinogenetic process of FGC may be different from that of HNPCC.