Somatic Mutations, Viral Integration and Epigenetic Modification in the Evolution of Hepatitis B Virus-Induced Hepatocellular Carcinoma

Liver cancer in men is the second leading cause of cancer death and hepatocellular carcinoma (HCC) accounts for 70%-85% of the total liver cancer worldwide. Chronic infection with hepatitis B virus (HBV) is the major cause of HCC. Chronic, intermittently active inflammation provides "fertile field" for "mutation, selection, and adaptation" of HBV and the infected hepatocytes, a long-term evolutionary process during HBV-induced carcinogenesis. HBV mutations, which are positively selected by insufficient immunity, can promote and predict the occurrence of HCC. Recently, advanced sequencing technologies including whole genome sequencing, exome sequencing, and RNA sequencing provide opportunities to better under-stand the insight of how somatic mutations, structure variations, HBV integrations, and epigenetic modifications contribute to HCC development. Genomic variations of HCC caused by various etiological factors may be different, but the common driver mutations are important to elucidate the HCC evolutionary process. Genome-wide analyses of HBV integrations are helpful in clarifying the targeted genes of HBV in carcinogenesis and disease progression. RNA sequencing can identify key molecules whose expressions are epigenetically modified during HCC evolution. In this review, we summarized the current findings of next generation sequencings for HBV-HCC and proposed a theory framework of Cancer Evolution and Development based on the current knowledge of HBV-induced HCC to characterize and interpret evolutionary mechanisms of HCC and possible other cancers. Understanding the key viral and genomic variations involved in HCC evolution is essential for generating effective diagnostic, prognostic, and predictive biomarkers as well as therapeutic targets for the interventions of HBV-HCC.