β-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.

Loss of Membranous Expression of β-Catenin Is Associated with Tumor Progression in Cutaneous Melanoma and Rarely Caused by Exon 3 Mutations

“…In our study, CTNNB1 mutations (S37Y, S37P, D32E, and D32G) were found in two primary CM and in one metastatic melanoma, and these point mutations were similar to those previously reported by Huang et al (24). The mutations in codon 37 involve the sequence for GSK-3␤ phosphorylation, implicated in the down-regulation of ␤-catenin through phosphorylation of serine residues.…”

Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-hetero- zygosity on chromosome 16q21-q23 and 9p21-p23

“…β-catenin, as a part of E-cadherin/catenin complex, is involved in two major functions: cell adhesion and transmission of the proliferating signal of the Wingless/Wnt pathway. β-catenin mutation in exon 3 activate the gene itself in HCCs [15], [16], [33]. However, the mutation of this gene is rare in those HCC with allelic loss of 16q21-q23 as evidenced from data in this paper.…”

“…Results of previous studies showed a variation of p53 mutations from various areas in terms of frequency, spectrum and timing: mutation of codon 249 is associated with AFB1 exposure in rural regions of China (Qidong) and Africa (Mozambique and Senegal) and may represent an early event during hepatocarcinogenesis, whereas different mutation spectrum of p53 was observed in Japan and big cities of China(Shanghai and Beijing) [11][12][13]. In addition, activation or DNA amplification of c-myc and cyclin D, mutations of β-Catenin and IGFIIR/M6P have been observed in HCC [14][15][16]. Another approach to find the genes associated with HCCs is to screen for regions with frequent genetic alteration by using whole-genome scanning technologies including microsatellite analysis (MSA) and comparative genomic hybridization (CGH).…”

Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas

“…b-Catenin mutations were found in 13-43% of the cases, depending on the series (de La Coste et al, 1998;Huang et al, 1999;Legoix et al, 1999;Nhieu et al, 1999;Terris et al, 1999;Hsu et al, 2000;LaurentPuig et al, 2001). Biallelic inactivations of AXIN1 through mutations associated with loss of heterozygosity or homozygous deletion are observed in 5-8% of the HCCs (Satoh et al, 2000;Laurent-Puig et al, 2001).…”