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.

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.

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.

β‐catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type β‐catenin overexpression appeared to have pathologic and prognostic significance. Cancer 2001;92:136–45. © 2001 American Cancer Society.