HBV induced carcinogenesis.

Hepatocellular carcinoma (HCC) is one of the rare human neoplasms associated with viral infections. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important etiological factors of HCC, accounting for more than 70% of cases worldwide. The risk of HCC development is greatly increased in chronic viral carriers exposed to other recognized risk factors, including exposure to aflatoxin B1, alcoholic cirrhosis and diabetes. The importance of HBV genotypes and precore or core promoter mutants remains incompletely understood. The role of HBV in tumour formation appears to be complex and may involve both direct and indirect mechanisms. Integration of HBV DNA into the host genome occurs at early steps of clonal tumour expansion, and it has been shown to induce direct insertional mutagenesis of diverse cancer-related genes in a number of cases. Chronic liver inflammation and hepatic regeneration induced by cellular immune responses may favour the accumulation of genetic alterations in infected hepatocytes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein LHBs may contribute in deregulating the cellular transcription program and proliferation control, and sensitize liver cells to carcinogenic factors. Recent genetic studies have provided insight into the mechanisms underlying viral-associated hepatocarcinogenesis. It has been shown that the rate of chromosomal alterations is significantly increased in HBV-related tumours compared with tumours associated with other risk factors. HBV might therefore play a role in enhancing genomic instability. Inactivation of p53 by mutations and regional allelic deletions is found more frequently in tumours associated with HBV infection. By contrast, HBV related tumours harbour a low rate of beta-catenin mutations. Together, these data strongly support the notion that chronic HBV infection might trigger specific oncogenic pathways, thus playing a role beyond stimulation of host immune responses and chronic necro-inflammatory liver disease.