Gene S of hepatitis B virus (EBV) is the gene that codes for the surface antigen (HBsAg). The HBsAg gene is one long open reading frame but contains three in frame “start” (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large S, middle S, and small S (pre-S1+pre-S2+S, pre-S2+S, and S, respectively) are produced. During the course of chronic hepatitis B infection, the viral genome would frequently develop mutations. These mutations represent the attempt of the virus to escape from host immune-surveillance.
Hepatocarcinogenesis of HBV-related HCC is believed to be a “hit-and-run” event as most of the surgically removed cancerous HCC tissues contain rare, if any, freely replicative viruses. Therefore, if certain viral mutations were assumed to be responsible for initiation of the oncogenic process, one could not identify them because the mutant viruses should have been lost in the subsequent steps of hepatocarcinogenesis.