CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1

beta -Catenin plays a key role in the Wnt signaling pathway, and mutations of CTNNB1, the gene that encodes beta -catenin, have been identified in abo ut one-fourth of human hepatocellular carcinomas from regions of low aflato xin B1 exposure. In this study 62 hepatocellular carcinomas (HCCs) from peo ple highly exposed to aflatoxin B1 in Guangxi, People's Republic of China, were laser-capture microdissected and examined for CTNNB1 mutations. In add ition, 41 of the HCCs were evaluated for the presence of the beta -catenin protein by immunohistochemical methods. Twenty of the HCCs showed positive results for beta -catenin, with strong membrane staining, while adjacent no n-neoplastic liver tissue lacked or showed only weak membrane staining. One HCC, in which a CTNNB1 mutation was not detected, showed nuclear staining for the beta -catenin protein. Mutations of CTNNB1 were identified in five HCCs. These consisted of four point mutations in the glycogen serine kinase -3 beta phosphorylation region of codons 32-45 and one deletion of codons 3 2-38. These mutations were similar to those previously reported for human H CC, although at a lower frequency. A signature mutation profile associated with aflatoxin B1 exposure could not be identified. The immunohistochemical findings indicate a role for accumulation of beta -catenin and possibly in creased Wnt signaling in aflatoxin B1-associated HCC. The low frequency of CTNNB1 mutations, however, suggests that mutation of another Wnt signaling component, such as the Wnt scaffolding protein axin or the adenomatous poly posis coli protein, both of which modulate beta -catenin stability, also ma y be involved in aflatoxin-associated HCC. Published (C) zool Wiley-Liss. I nc.(dagger)