Unique Features of Hepatitis B Virus-Related Hepatocellular Carcinoma in Pathogenesis and Clinical Significance

Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus-host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV-HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC.