To clarify the roles of the adenomatous polyposis coli (APC) and beta-catenin genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesis, we searched for their mutations in 14 HNPCC adenomas with microsatellite instability (MSI). Seven (50%) adenomas exhibited somatic APC mutations, five of which were frameshift mutations and the other two nonsense ones. However, the APC mutational spectrum of these adenomas was similar to that of sporadic colorectal tumors. Two adenomas (14.3%) with undetectable APC alterations showed missense mutations at codon 45 (TCT to TTT or to CCT) in beta-catenin. The MSI frequency in adenomas with beta-catenin mutations was significantly higher than that with APCones (P<0.001), indicating that mutations of beta-catenin rather than APC are strongly associated with MSI. These data suggest that adenomas with beta-catenin activating mutations and some with APC inactivating mutations may be precursors of HNPCC colorectal cancers.