Precore/core mutations of hepatitis B virus in hepatocellular carcinomas developed on noncirrhotic livers.

Abstract

Hepatitis B virus genomes have been detected in hepatocellular carcinoma developed without the pretumoral step of cirrhosis; this finding is consistent with a direct effect of the virus in liver cell transformation. The aim of this study was to investigate the molecular bases for the hepatitis B virus persistence. Three hepatitis B surface antigen-positive and 2 hepatitis B surface antigen-negative patients with hepatocellular carcinoma and without cirrhosis were studied for precore/core mutations in tumorous and nontumorous tissues. The precore/core region was amplified and analyzed both by cloning and sequencing and by direct sequencing. Nonsynonymous mutations were identified selectively in tumorous tissues. Clusters of mutations were identified in the viral encapsidation (epsilon) signal, in immunodominant epitopes of the core protein, and in the polymerase. Common associated point mutations were found in 3 patients infected with hepatitis B virus genotype A in the epsilon signal and in the polymerase gene. Precore/core mutations located in domains involved in hepatitis B virus replication and immune response to the virus were identified. The selective presence of some of these mutations in tumorous tissues is consistent with their role in the persistence of the virus in neoplastic cells and, possibly, in liver oncogenesis.