Article Text

Original research
Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma
  1. Camille Péneau1,2,
  2. Sandrine Imbeaud1,2,
  3. Tiziana La Bella1,2,
  4. Theo Z Hirsch1,2,
  5. Stefano Caruso1,2,
  6. Julien Calderaro3,
  7. Valerie Paradis4,5,
  8. Jean-Frederic Blanc6,7,8,
  9. Eric Letouzé1,2,
  10. Jean-Charles Nault1,2,9,
  11. Giuliana Amaddeo10,
  12. Jessica Zucman-Rossi1,2,11
  1. 1Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France
  2. 2Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, Paris, France
  3. 3Service d’Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, Créteil, France
  4. 4Service de Pathologie, Hôpital Beaujon, APHP, Clichy, France
  5. 5Université Paris Diderot, CNRS, Centre de Recherche 27 sur l'Inflammation (CRI), Paris, France
  6. 6Service Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France
  7. 7Service de Pathologie, CHU Bordeaux GH Pellegrin, Bordeaux, France
  8. 8Université Bordeaux, Inserm, Research in Translational Oncology, BaRITOn, Bordeaux, France
  9. 9Service d’Hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Bobigny, France
  10. 10Service d’Hépato-Gastro-Entérologie, Hôpital Henri Mondor, APHP, Université Paris Est Créteil, Inserm U955, Institut Mondor de recherche biomedicale, Creteil, Île-de-France, France
  11. 11Hôpital Européen Georges Pompidou, AP-HP, Paris, France
  1. Correspondence to Professor Jessica Zucman-Rossi, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, INSERM, Paris 75006, France; jessica.zucman-rossi{at}


Objective Infection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features.

Design A novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping.

Results Replicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes (TERT, TP53, MYC) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis.

Conclusion Deep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.

  • hepatocellular carcinoma
  • hepatitis B
  • cancer genetics

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

Statistics from

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Twitter @Zucmanrossi

  • Contributors JZ-R conceived and directed the research. CP and JZ-R designed the study and wrote the manuscript. CP and TLB performed the experiments. CP, SI, TZH, SC, EL and JZ-R analysed and interpreted the data. JC, VP, J-FB, J-CN and GA provided essential biological resources and collected clinical data. All authors approved the final manuscript and contributed to critical revisions to its intellectual context.

  • Funding This work was supported by ANRS (French national agency for research on AIDS and viral hepatitis). The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, FRM prix Rosen, Ligue Contre le Cancer Comité de Paris (prix René et André Duquesne) and Fondation Mérieux. CP was supported by a fellowship from ANRS (French national agency for research on AIDS and viral hepatitis). TLB was supported by an “Attractivite IDEX" fellowship from IUH, TZH by a fellowship from Cancéropole Ile de France and Fondation d'Entreprise Bristol-Myers Squibb pour la Recherche en Immuno-Oncologie, and SC by CARPEM and the Labex OncoImmunology.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the institutional review board (IRB) committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. The sequencing data of the LICA-FR cohort reported in this paper have been deposited to the European Genome-phenome Archive (EGA) database (RNA-seq fastq files accessions (EGAS00001001284), (EGAS00001002879), (EGAS00001003310), (EGAS00001003837) and (EGAS00001004629); WES bam files accessions (EGAS00001000217), (EGAS00001001002), (EGAS00001003063), (EGAS00001003130), (EGAS00001003837) and (EGAS00001004629); WGS bam files accessions (EGAS00001000706), (EGAS00001002408), (EGAS00001002888), (EGAS00001003063), (EGAS00001003837) and (EGAS00001004629), through the International Cancer Genome Consortium (ICGC) data access committee. Data are available for reuse and can be consulted at the following address: with access permission from ICGC Data Access Compliance Office.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.