β-Catenin Mutations Are Associated with a Subset of Low-Stage Hepatocellular Carcinoma Negative for Hepatitis B Virus and with Favorable Prognosis

To better understand the role of β-catenin mutation in hepatocellular carcinoma (HCC), we correlated the gene mutation with hepatitis virus B (HBV) and hepatitis virus C (HCV) status and the clinicopathological features in 366 patients with resected primary unifocal HCC. β-Catenin mutations were also analyzed in 55 patients with multifocal HCC (68 tumors). Of the whole series, 57 (13.1%) of 434 tumors examined had β-catenin mutations, 34 occurred at the serine/threonine residues of the GSK-3β region of β-catenin. Outside the GSK-3β phosphorylation site, codons 32 and 34 were two mutational hot spots (17 tumors). The non-HBV-related HCC that was predominantly HCV related had a higher frequency of mutation (P < 0.00001) and more frequent mutations at codon 45 than HBV-related HCC. HBV-related HCC had a younger mean age (P < 0.00001), and higher male-to-female ratio (P < 0.003) and positive familial history of HCC (P < 0.014). Among 366 unifocal HCCs selected for clinicopathological analysis, β-catenin mutations were associated with grade I (P = 0.005) and stage I and II HCC (P < 0.0001), and a better 5-year survival rate (P = 0.00003). These findings suggest mechanisms for β-catenin mutations differ between HBV-related and non-HBV-related HCCs, and that β-catenin mutation is a favorable prognostic factor related to low stage. β-Catenin mutation was associated with nuclear expression of the protein (P < 0.00001), but we failed to detect point or large fragment deletion mutation in 39 HCCs with nuclear β-catenin expression, presumably wild-type protein. HCCs expressing mutant nuclear β-catenin had a better 5-year survival rate (P < 0.007), suggesting that mutant and wild-type nuclear β-catenin proteins are not functionally equivalent and deserve more studies for further clarification.