Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection

Abstract

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide. Hepatitis B virus and hepatitis C virus infections, exposure to aflatoxin, and excessive intake of alcohol have been identified as major risk factors. However, the molecular mechanisms underlying their development are still poorly understood. Recently, beta-catenin, one of the key components of the Wnt signaling pathway, has been found to be mutated in about 20% of HCCs, suggesting a role of the Wnt pathway in their development. In this study, we examined beta-catenin and APC mutations in 22 HCCs associated with HCV infection, using single-strand conformation polymorphism (SSCP) followed by direct DNA sequencing. beta-Catenin mutations were found in nine (41%) cases, but no APC mutations were found. beta-Catenin immunohistochemistry revealed nuclear accumulation of beta-catenin protein in all nine tumors with a beta-catenin mutation and two additional tumors without a mutation. These results suggest that activation of the Wnt signaling pathway by beta-catenin mutation contributes significantly to the hepatocellular carcinogenesis associated with HCV infection.

Figure 1.

Representative DNA sequencing autoradiographs of β-catenin mutations. Left: TCT→CCT mutation at codon 45, leading to Ser→Pro (case 15). Center: ACC→GCC mutation at codon 41, leading to Thr→Ala (case 18, area 1). Right: TCT→TAT mutation at codon 37, leading to Ser→Tyr (case 18, area 2).

Figure 2.

β-Catenin immunohistochemistry. A, left: Nontumorous liver showing weak membrane staining. A, right: Proliferating bile ducts showing strong membrane staining. B, C: Nuclear accumulation of β-catenin protein in neoplastic hepatocytes in hepatocellular carcinoma associated with HCV infection. Magnifications: ×75 (A and B), ×150 (C).