beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway

Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in beta-catenin (encoded by CTNNB1) that result in dec reased phosphorylation by GSK-3 beta and increased signaling through the Tc f/Lef transcription factors. To investigate the relationship between CTNNB1 mutations and underlying pathways of genomic instability, we examined 80 c olorectal cancers stratified by the presence or absence of microsatellite i nstability (MSI). CTNNB1 mutations were identified in 13 (25%) of 53 cancer s with high frequency MSI (MSI-H), including 12 point mutations at exon 3 p hosphorylation sites (codons 41 and 45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations were identified in 27 microsatellit e stable or low frequency MSI (MSI-L) tolorectal cancers (P < 0.01), In con trast, CTNNB1 mutations were identified in 3 of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting a more generalized invol vement in these tumors. Only six (46%) of the endometrial carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK-3 beta, and o nly one of these was at either codon 41 or 45, All point mutations in MSI-E I cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were transversions (P < 0.01), The differences in the mutation profiles suggest that there may be molecular fingerprints of CTNNB1 mutations, determined by biological factors related to both tumor type and underlying pathways of g enomic instability.