Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, very little is known about the replication of HBV in HCC tissues.
PATIENTS AND METHODS:
We analysed viral and cellular parameters in HCC (T) and non-tumor liver (NT) samples from 99 HBsAg-positive, virologically suppressed patients treated by tumour resection or liver transplantation. We examined total HBV DNA and RNA as well as covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA), which are considered as markers of active HBV replication.
Total HBV DNA and RNA were detected in both T and NT samples in a majority of cases, but only a subset of tumors harboured detectable levels of HBV cccDNA and pgRNA (39% and 67%) compared to NT livers (66% and 90%) (p<0.01). Further evidence for HBV replication in tumor tissues was provided by sequencing of the X gene derived from episomal forms, showing that HBV genotypes differed between T and matched NT samples in 11 cases. The detection of pgRNA and cccDNA in tumours was correlated to the absence of tumorous microvascular invasion and to better patient survival. Analysis of gene expression profiles by Agilent microarrays revealed that pgRNA-positive HCCs were characterized by low levels of cell cycle and DNA repair markers, and expression of the HBV receptor: sodium taurocholate cotransporting polypeptide (NTCP), indicating well-differentiated tumors.
HCC replicating HBV represents a subtype of weakly invasive HCC with a transcriptomic signature. PgRNA originating from non-integrated, complete HBV genomes is a sensitive marker for viral replication and prognosis.
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