To clarify the roles of the adenomatous polyposis coli (APC) and beta -cate
nin genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesi
s, we searched for their mutations in 14 HNPCC adenomas with microsatellite
instability (MSI). Seven (50%) adenomas exhibited somatic APC mutations, f
ive of which were frameshift mutations and the other two nonsense ones. How
ever, the APC mutational spectrum of these adenomas was similar to that of
sporadic colorectal tumors. Two adenomas (14.3%) with undetectable APC alte
rations showed missense mutations at codon 45 (TCT to TTT or to CCT) in bet
a -catenin. The MSI frequency in adenomas with beta -catenin mutations was
significantly higher than that with APCones (P < 0.001), indicating that mu
tations of <beta>-catenin rather than APC are strongly associated with MSI.
These data suggest that adenomas with beta -catenin activating mutations a
nd some with APC inactivating mutations may be precursors of HNPCC colorect
al cancers. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.