[Human mismatch repair genes and HNPCC].

Hereditary nonpolyposis colorectal cancer (HNPCC) is a major cancer susceptibility syndrome known to be caused by the inheritance of mutations in DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2. Germline mutations in the hMSH2 and hMLH1 genes were detected in 9 and 11 Japanese or Korean HNPCC kindreds, respectively. These data establish a basis for the presymptomatic diagnosis of HNPCC patients. To determine the relation between the mutation of the TGF-beta type II receptor gene and genomic instability in the tumorigenesis of HNPCC, we screened genomic DNA of tumors from HNPCC patients. Seventeen of the 24 (71%) genomic instability-positive HNPCC tumors carried one or two A deletions in the (A)10 repeat, while none of the 14 genomic instability-negative tumors did. These deletions inactivate the receptor through a frameshift mutation and the resultant protein truncation. These data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.