β-catenin mutation and overexpression in hepatocellular carcinoma: Clinicopathologic and prognostic significance

Abstract

BACKGROUND. β-Catenin has been recognized as a critical member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis. METHODS. To determine the clinical significance of β-catenin in hepatocellular carcinoma (HCC), we performed mutational analysis at exon 3 of the gene, investigated the subcellular protein expression, and analyzed their clinicopathologic and prognostic significance in 60 patients with resected primary HCC. RESULTS. By direct DNA sequencing, somatic mutations of the β-catenin gene were detected in 7 (12%) HCCs. All the mutations were found at the region (exon 3) responsible for phosphorylation and ubiquitination, therefore likely to result in stabilization of free cytoplasmic β-catenin. Nuclear accumulation of the β-catenin protein, similar to the response to the Wnt signal, was found in 10 (17%) HCCs and was closely associated with gene mutation (P < 0.001). In the remaining cases, nonnuclear type overexpression, that is, overexpression in the cytoplasm and/or cytoplasmic membrane, was observed in 31 (62%) HCCs, thus suggesting that the mechanisms leading to β-catenin overexpression may be heterogeneous. HCCs with a nonnuclear type of β-catenin overexpression were more frequently larger than 5 cm in diameter (P = 0.022) and had poorer cellular differentiation (P = 0.037), and the patients had significantly shorter disease-free survival lengths (P = 0.041). Review of the data from previous studies in HCC showed that β-catenin mutations were more frequent in HCV-associated HCC than in HBV-associated ones. CONCLUSIONS, β-catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type β-catenin overexpression appeared to have pathologic and prognostic significance. © 2001 American Cancer Society.