Abstract
Background: Lamivudine is widely used in patients with chronic hepatitis B virus (HBV) infection. In cirrhotic patients, long-term lamivudine therapy significantly reduced the risk of hepatocellular carcinoma (HCC). However, in a small but substantial portion of patients, HCC still developed despite lamivudine therapy. Prolonged usage of lamivudine led to mutations in the polymerase gene, where concurrent nonsense mutations in the HBV S gene occasionally occurred. The significance of such mutations in hepatocarcinogenesis remains elusive. Here, we aimed to understand the oncogenicity of HBV pre-S/S nonsense mutations identified in patients with HCC that developed after lamivudine therapy. Methods: Of 141 consecutive hepatitis B surface antigen-positive HCC patients, 8 developed HCC after receiving lamivudine therapy. The HBV pre-S/S sequences in their serum and tissue samples were analysed. A sex- and age-matched group of HCC patients who never received lamivudine therapy were included as controls. Site-directed mutagenesis experiments were performed to generate identified pre-S/S nonsense mutations in expression vectors for tumourigenicity analysis. Results: Seven of eight patients in the lamivudine-treated group harboured nonsense mutations in the S gene compared with none in the control group (P<0.001). Site-directed mutagenesis and transient transfection experiments revealed that these mutants could transactivate oncogene promoters. NIH3T3 cells stably expressing sL21*, sW156* and sW172* pre-S/S mutants had increased tumourigenicity in nude mice. Conclusions: HCCs developed in lamivudine-treated patients who frequently carried nonsense mutations in the S gene. Such pre-S/S mutants are potentially oncogenic and might counteract the effect of lamivudine in preventing hepatocarcinogenesis.
Original language | English |
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Pages (from-to) | 249-261 |
Number of pages | 13 |
Journal | Antiviral Therapy |
Volume | 14 |
Issue number | 2 |
State | Published - 2009 |
Externally published | Yes |