Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections

Abstract

Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches.

Keywords: genetic alteration; hepatitis B virus (HBV); hepatitis C virus (HCV); hepatocellular carcinoma (HCC); somatic mutation.

Figure 1. Early and late events of HBV and HCV-related liver carcinogenesis

The HBV HBx protein facilitates integration of HBV into host DNA, resulting in major genetic alteration of the host genome. HBV- and HCV-encoded proteins contribute to the alteration of several signaling pathways. Both viruses promote the growth of infected cells and activate several signaling pathways including RAS, PI3K, EGFR, and IGFR1.