Background: Previously, a less prevalent lamivudine-resistant mutant (rtA181T) was discovered in Taiwanese patients, in which a stop codon in the surface gene concomitantly occurred, leading to impaired secretion of hepatitis B virus (HBV) surface antigen. The rtA181T mutant also conferred drug resistance to adefovir. We discovered a 39-year-old patient with advanced hepatocellular carcionoma, who was seropositive for HBV e antigen but seronegative for HBV surface antigen. Nucleotide sequence analysis revealed the presence of polymerase rtA1 81T/surface truncation mutant in both the serum and hepatoma samples. Surprisingly, this patient has never received lamivudine or adefovir antiviral therapy. Here, we aimed to evaluate the oncogenic potential of HBV rtA181T/surface truncation mutant.
Methods: Site-directed mutagenesis experiments followed by transactivation assays were performed in HepG2 cells to evaluate the transactivation activities of the corresponding pre-S/S truncation mutant for c-Mye, c-Fos and Simian virus 40 promoters. NIH3T3 cells stably expressing the mutant were used to assess the tumourigenicity in nude mice.
Results: Transactivation experiments revealed that the corresponding pre-S/S truncation mutant was capable of transactivating the Simian virus 40 and human c-Mye promoters but not the c-Fos promoter. NIH3T3 cells stably expressing this mutant were tumourigenic in four of the five nude mice tested.
Conclusion: Our data indicate that an HBV polymerase rtA181T/surface truncation mutant could emerge spontaneously without previous antiviral treatment. The presence of this mutant in a patient with advanced hepatocellular carcinoma as well as its oncogenic potential warrants careful re-evaluation of the current strategy of prolonged antiviral therapy.