Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture

Eva G. Álvarez, Jonas Demeulemeester, Paula Otero, Clemency Jolly, Daniel García-Souto, Ana Pequeño-Valtierra, Jorge Zamora, Marta Tojo, Javier Temes, Adrian Baez-Ortega, Bernardo Rodriguez-Martin, Ana Oitaben, Alicia L. Bruzos, Mónica Martínez-Fernández, Kerstin Haase, Sonia Zumalave, Rosanna Abal, Jorge Rodríguez-Castro, Aitor Rodriguez-Casanova, Angel Diaz-Lagares, Yilong Li, Keiran M. Raine, Adam P. Butler, Iago Otero, Atsushi Ono, Hiroshi Aikata, Kazuaki Chayama, Masaki Ueno, Shinya Hayami, Hiroki Yamaue, Kazuhiro Maejima, Miguel G. Blanco, Xavier Forns, Carmen Rivas, Juan Ruiz-Bañobre, Sofía Pérez-del-Pulgar, Raúl Torres-Ruiz, Sandra Rodriguez-Perales, Urtzi Garaigorta, Peter J. Campbell, Hidewaki Nakagawa, Peter Loo and Jose M. C. Tubio ()
Additional contact information
Eva G. Álvarez: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Jonas Demeulemeester: The Francis Crick Institute
Paula Otero: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Clemency Jolly: The Francis Crick Institute
Daniel García-Souto: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Ana Pequeño-Valtierra: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Jorge Zamora: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Marta Tojo: The Biomedical Research Centre (CINBIO), Universidade de Vigo
Javier Temes: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Adrian Baez-Ortega: University of Cambridge
Bernardo Rodriguez-Martin: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Ana Oitaben: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Alicia L. Bruzos: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Mónica Martínez-Fernández: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Kerstin Haase: The Francis Crick Institute
Sonia Zumalave: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Rosanna Abal: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Jorge Rodríguez-Castro: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Aitor Rodriguez-Casanova: University Clinical Hospital of Santiago de Compostela (CHUS/SERGAS)
Angel Diaz-Lagares: University Clinical Hospital of Santiago de Compostela (CHUS/SERGAS)
Yilong Li: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton
Keiran M. Raine: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton
Adam P. Butler: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton
Iago Otero: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Atsushi Ono: Graduate School of Biomedical and Health Sciences, Hiroshima University
Hiroshi Aikata: Graduate School of Biomedical and Health Sciences, Hiroshima University
Kazuaki Chayama: Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University
Masaki Ueno: Wakayama Medical University
Shinya Hayami: Wakayama Medical University
Hiroki Yamaue: Wakayama Medical University
Kazuhiro Maejima: RIKEN Center for Integrative Medical Sciences
Miguel G. Blanco: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Xavier Forns: Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd
Carmen Rivas: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Juan Ruiz-Bañobre: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela
Sofía Pérez-del-Pulgar: Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd
Raúl Torres-Ruiz: Molecular Cytogenetics and Genome Engineering Group, Centro Nacional de Investigaciones Oncológicas (CNIO)
Sandra Rodriguez-Perales: Molecular Cytogenetics and Genome Engineering Group, Centro Nacional de Investigaciones Oncológicas (CNIO)
Urtzi Garaigorta: Centro Nacional de Biotecnología – Consejo Superior de Investigaciones Científicas (CNB – CSIC)
Peter J. Campbell: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton
Hidewaki Nakagawa: RIKEN Center for Integrative Medical Sciences
Peter Loo: The Francis Crick Institute
Jose M. C. Tubio: Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration.

Date: 2021
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DOI: 10.1038/s41467-021-26805-8

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