Hepatitis B envelope protein mutants in human hepatocellular carcinoma tissues

Hepatitis B virus (HBV) envelope mutants in the region encoding the highly immunogenic major hydrophilic region (MHR) of surface antigen (HBsAg) have been associated with vaccine failure and chronic infection, To determine if these mutants are associated with the development of human hepatocellular carcinoma (HCC), we measured the frequency and nature of such mutants in 23 HBV-associated HCC and various control tissues by performing Southern blot analysis, the polymerase chain reaction (PCR) and direct sequencing, The H BV genome was present mainly in an integrated form and, in most of the samp les, the envelope gene was intact. Amino acid substitutions, involving the MHR region in the HCC tissues, were analysed in 11 (61.1%) of 18 patients w ith HCC. The mutation Gly145Arg, which has been reported to be associated w ith immunoevasion, was found in seven of the 18 HCC tissues. A significantl y higher frequency of mutations was found in RCC tissues (11 of 18) than in the corresponding non-tumorous tissue of the same patients (one of eight), and in samples from patients with acute (one of 19) or chronic (three of 3 1) HBV infection (P < 0.001, Fisher's exact test). The accumulation of thes e envelope mutants in the HCC tissue suggests that such envelope protein mu tations may play a role in the process of oncogenesis and that specific vac cines may need to be developed to prevent the occurrence of mutant HBV-asso ciated HCC, Alternatively, the progressive accumulation of mutants in patie nts with acute hepatitis, chronic hepatitis and HCC may reflect the increas ed length of duration of HBV infection in these groups of liver lesions.