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J Exp Clin Cancer Res. 2019 Jun 14;38(1):261. doi: 10.1186/s13046-019-1273-1.

Viral integration drives multifocal HCC during the occult HBV infection.

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The Hepatic Surgery Centre at Tongji Hospital, Tongji Medical College, HUST; Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, China.
Department of Computer Science, City University of Hong Kong, Hong Kong, People's Republic of China.
School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW2007, Australia.
Department of Biology, Laboratory of Genomics and Molecular Biomedicine, University of Copenhagen, Universitesparken 13, 2100, Copenhagen, Denmark.
The Newcastle upon Tyne Hospitals NHS Foundation Trust at Freeman Hospital, Newcastle, UK.
Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, USA.
Laboratory of Molecular Ecology and Evolution, Institute of Estuarine and Coastal Research, East China Normal University, Shanghai, China.
School of Bioscience and Bioengineering at South China University of Technology, Guangzhou, China.
School of Biological Science and Medical Engineering at Southeast University, Nanjing, China.
The Department of Pathology at Tongji Hospital, Tongji Medical College, HUST, Wuhan, 430030, China.
The Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, 430030, China.



Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation.


We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome.


HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin.


Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis.


Hepatitis B; Hepatocellular carcinoma; Single-cell sequencing; Viral integration; Virome capture sequencing; Whole genome sequencing

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