HIGH-FREQUENCY OF BETA-CATENIN (CTNNB1) MUTATIONS IN THE COLON TUMORSINDUCED BY 2 HETEROCYCLIC AMINES IN THE F344 RAT

Activating mutations in the beta-catenin (CTNNB1) gene corresponding t o N-terminal phosphorylation sites in the protein have been implicated in the development of human colon cancer. To determine the possible i nvolvement of such mutations during chemically induced colon carcinoge nesis, we examined the corresponding region of Ctnnb1 in colon tumors induced in the F344 rat by two cooked meat heterocyclic amines, 2-amin o-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP). All of the colon tumors induced by 2-amino-3-m ethylimidazo[4,5-f]quinoline that were examined (5 of 5) and 4 of 7 Ph IP-induced colon tumors had mutations within or flanking codons corres ponding to important phosphorylation sites in beta-catenin. None of th e colon tumors bearing Ctnnb1 mutations had genetic changes in the Apc gene, and those that contained wild-type Ctnnb1 were known from our p revious work to contain ripe mutations. The results provide evidence f or a major role of the beta-catenin/Apc pathway in the development of heterocyclic amine-induced colon tumors and give further weight to the view that regulation of beta-catenin is critical to the tumor suppres sive effects of Ape during colon carcinogenesis. In contrast, Ctnnb1 m utations were completely absent in 23 PhIP-induced mammary tumors, in accordance with recent work showing that human breast carcinomas lack mutations in CTNNB1.