Authors: D. Giosa, D. Lombardo, C. Musolino, V. Chines, G. Raffa, F. Casuscelli di Tocco, D. D’Aliberti, C. Saitta, A. Alibrandi, R. Aiese Cigliano, O. Romeo, G. Navarra, G. Raimondo, T. Pollicino


  • Department of Clinical and Experimental Medicine, University Hospital of Messina, Italy
  • Department of Human Pathology, University Hospital of Messina, Italy
  • Department of Medicine and Surgery, Milano Bicocca University, Italy
  • Department of Economics, University of Messina, Italy
  • Department of ChiBioFarAm, University of Messina, Italy

Publication: Digestive and Liver Disease Journal 

Date: March 2022

Link: A new high-throughput HBV integration sequencing approach shows that mitochondrial DNA is frequently targeted by virus integration in liver cells with active HBV replication


Hepatitis B virus (HBV) may integrate into the genome of an infected cell and contribute to
hepatocarcinogenesis. In this study, we applied a new high-throughput HBV integration sequencing
approach that allows sensitive identification of HBV integration sites and enumeration of integration
clones. We identified 3,339 HBV integration sites in paired tumour and non-tumour tissue samples
from 7 patients with hepatocellular carcinoma (HCC). A total of 2,107 clonally expanded integrations
were detected: 1,817 in tumour and 290 in non-tumour tissues. Moreover, we detected significant
enrichment of clonal integrations in mitochondrial DNA (mtDNA), and HBV integration in mtDNA
preferentially involved OXPHOS genes in tumours and the regulatory D-loop region in non-tumour
tissues. We also found that HBV RNA sequences may be imported into the mitochondria of hepatoma
cells, polynucleotide phosphorylase (PNPASE) is involved in this import, and HBV RNA might be
involved in the process of HBV integration into mtDNA. Our data suggest a novel mechanism by
which HBV insertion might contribute to HCC development.