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

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journal contribution
posted on 26.11.2021, 14:02 authored by 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 Van Loo, Jose MC Tubio
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.

Funding

Crick (Grant ID: 10202, Grant title: Van Loo FC001202)

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