Frequent mutation of ss-catenin and APC genes in primary colorectal tumorsfrom patients with hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by defec tive DNA mismatch repair, which results in genetic instability of tumors; h owever, only a few target genes have been recognized. Our previous study de tected a low frequency of APC gene mutation (21%) in colorectal tumors from HNPCC patients, in contrast to a high frequency of APC gene alteration (>7 0%) in non-HNPCC tumors. Because both beta-catenin and ACP gene mutations h ave recently been shown to activate the same signaling pathway, we analyzed beta-catenin mutation in HNPCC tumors. A notable frequency of beta-catenin gene mutation (43%, 12 of 28) was found to occur in HNPCC colorectal tumor s. beta-Catenin mutations were not detected in tumors with APC mutations. A ll beta-catenin mutations detected in HNPCC tumors existed within the regul atory domain of beta-catenin. Immunohistochemical staining of tumors with t his mutation showed accumulation of beta-catenin protein in nuclei. These a nd previous data from our laboratory suggest that activation of the beta-ca tenin-Tef signaling pathway, through either beta-catenin or APC mutation, c ontributes to HNPCC colorectal carcinogenesis in similar to 65% of cases.