Re-analysis of hepatitis B virus integration sites reveals potential new loci associated with oncogenesis in hepatocellular carcinoma

doi:10.5501/wjv.v12.i3.209

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World Journal of Virology

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2220-3249

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Virol. Jun 25, 2023; 12(3): 209-220
Published online Jun 25, 2023. doi: 10.5501/wjv.v12.i3.209

Re-analysis of hepatitis B virus integration sites reveals potential new loci associated with oncogenesis in hepatocellular carcinoma

Ryuta Kojima, Shingo Nakamoto, Tadayoshi Kogure, Yaojia Ma, Keita Ogawa, Terunao Iwanaga, Na Qiang, Junjie Ao, Ryo Nakagawa, Ryosuke Muroyama, Masato Nakamura, Tetsuhiro Chiba, Jun Kato, Naoya Kato

Ryuta Kojima, Shingo Nakamoto, Tadayoshi Kogure, Yaojia Ma, Keita Ogawa, Terunao Iwanaga, Na Qiang, Junjie Ao, Ryo Nakagawa, Ryosuke Muroyama, Masato Nakamura, Tetsuhiro Chiba, Jun Kato, Naoya Kato, Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

Author contributions: Kojima R and Nakamoto S contributed to the conception, design, and writing of the manuscript; Kojima R contributed to data management and analysis; Kogure T, Ma Y, Ogawa K, Iwanaga T, Qiang N, Ao J, Nakagawa R, Muroyama R, Nakamura M, Chiba T, Kato J, and Kato N contributed to manuscript review and editing; Kato N contributed to the project administration.

Institutional review board statement: This study is not applicable as it is a re-analysis of publicly available data.

Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.

Data sharing statement: All the data supporting this study are stored in the SRA database with accession number SRA335342.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Corresponding author: Shingo Nakamoto, MD, PhD, Assistant Professor, Department of Gastroenterology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan. nakamotoer@faculty.chiba-u.jp

Received: December 28, 2022
Peer-review started: December 28, 2022
First decision: January 17, 2023
Revised: February 12, 2023
Accepted: April 12, 2023
Article in press: April 12, 2023
Published online: June 25, 2023
Processing time: 174 Days and 17 Hours

ARTICLE HIGHLIGHTS

Research background

Many hepatitis B virus (HBV)-infected patients suffer from hepatocellular carcinoma (HCC), but a little focus is given to detect HBV integration pattern in the treatment of HCC. Detection of HBV integration can be improved by introducing a reliable detection method.

Research motivation

HBV frequently integrates at the 11q13.3 region, where the CCND1 gene is located, and this region is frequently amplified in several types of cancer, including HCC.

Research objectives

We aimed to analyze the features of HBV integration in HCC using a new reference database and integration detection method.

Research methods

Published data, consisting of 426 liver tumor samples and 426 paired adjacent non-tumor samples, were re-analyzed to identify the integration sites. Updated human reference genomes, Genome Reference Consortium Human Build 38 (GRCh38), and Telomere-to-Telomere Consortium CHM13 (T2T-CHM13 (v2.0)) were used. In addition, GRIDSS VIRUSBreakend, which utilizes a virus-centric variant calling and assembly approach, was used to detect HBV integration sites.

Research results

A total of 5361 integration sites were detected using T2T-CHM13. In the tumor samples, integration hotspots in the cancer driver genes, such as TERT and KMT2B, were consistent with those in the original study. GRIDSS VIRUSBreakend detected integrations in more samples than original analysis. Enrichment of integration was observed at chromosome 11q13.3, including the CCND1 promoter, in tumor samples. Recurrent integration sites were observed in mitochondrial genes.

Research conclusions

GRIDSS VIRUSBreakend using T2T-CHM13 is accurate and sensitive in detecting HBV integration and provides new insights into the regions of HBV integration and their potential roles in HCC development.

Research perspectives

Further research is needed to examine how HBV integration interacts with driver gene expression and copy number alteration.