Correlation of TP53 mutations with HCV positivity in hepatocarcinogenesis: Identification of a novel TP53 microindel in hepatocellular carcinoma with HCV infection

Abstract

Although it is known that chronic hepatitis C virus (HCV) infection may contribute to tumor initiation and development, the molecular processes causing hepatocellular carcinoma (HCC) remain unclear. Microindels are unique, infrequent mutations that result in inserted and deleted sequences at the same nucleotide position, and are important contributors to cancer. To date, microindels in the p53 tumor suppressor gene (TP53) have not been fully examined in tumors. In the present study, 116 cases of HCC were screened for mutations in the TP53 gene (exon 5-8) by single-stranded conformational polymorphism analysis followed by direct sequencing. A special type of complex TP53 mutation, 616ins14del1 (14-1 microindel), was identified in a case of HCC with HCV infection. This rare TP53 microindel led to the generation of a truncated protein of 211 amino acids that lacked the DNA-binding domain and tetramerization domain. Immunohistochemistry showed loss of p53 protein expression and downregulation of p21WAF/CIP, Mdm2 and Bax in the tumor cells, indicating an impaired p53 signaling pathway. Nineteen of the 116 (16.4%) HCCs carried a total of 19 TP53 mutations. Notably, 5 of the 13 HCV-positive (38.5%) cases contained a TP53 mutation, and there was a significant association between TP53 mutations and HCV positivity (P=0.0379). No correlation of TP53 mutations with hepatitis B virus (HBV) positivity was observed. In summary, we identified a novel TP53 microindel in HCC, and provided evidence of HCC characterized by HCV infections typically associated with mutational inactivation of the TP53 gene.