Schematic summary of the clinical association of HBV pre-S gene deletions with liver disease progression and HCC development and recurrence. In patients with chronic HBV infection, the prevalence of overall pre-S gene deletions (including pre-S1, pre-S2, and pre-S1 + pre-S2 gene deletions) in the blood gradually increases with liver disease progression from the high to intermediate to low replicative phases of chronic hepatitis B, to liver cirrhosis, and reaches the highest level at the stage of HCC development. The presence of pre-S gene deletions (pre-S1, pre-S2, and/or pre-S1 + pre-S2 gene deletions) or pre-S2 gene deletions between nts 38 and 55 (nt 38 to 55) predicts higher incidence of liver cirrhosis and HCC development. Moreover, in patients with HBV-related HCC, the presence of deletions spanning the pre-S2 gene segment, pre-S2 gene deletion at nts 1 to 54 (nt 1 to 54), pre-S2 gene deletions at ≥5%, or pre-S2 plus pre-S1+pre-S2 gene deletions at >25% in the blood or type II GGHs comprising ≥10% of hepatocytes in the liver tissues predicts the higher risk of HCC recurrence after curative surgical resection. Abbreviations: HCC, hepatocellular carcinoma; GGHs, ground glass hepatocytes.