TY - JOUR
T1 - Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture
AU - Álvarez, Eva G.
AU - Demeulemeester, Jonas
AU - Otero, Paula
AU - Jolly, Clemency
AU - García-Souto, Daniel
AU - Pequeño-Valtierra, Ana
AU - Zamora, Jorge
AU - Tojo, Marta
AU - Temes, Javier
AU - Baez-Ortega, Adrian
AU - Rodriguez-Martin, Bernardo
AU - Oitaben, Ana
AU - Bruzos, Alicia L.
AU - Martínez-Fernández, Mónica
AU - Haase, Kerstin
AU - Zumalave, Sonia
AU - Abal, Rosanna
AU - Rodríguez-Castro, Jorge
AU - Rodriguez-Casanova, Aitor
AU - Diaz-Lagares, Angel
AU - Li, Yilong
AU - Raine, Keiran M.
AU - Butler, Adam P.
AU - Otero, Iago
AU - Ono, Atsushi
AU - Aikata, Hiroshi
AU - Chayama, Kazuaki
AU - Ueno, Masaki
AU - Hayami, Shinya
AU - Yamaue, Hiroki
AU - Maejima, Kazuhiro
AU - Blanco, Miguel G.
AU - Forns, Xavier
AU - Rivas, Carmen
AU - Ruiz-Bañobre, Juan
AU - Pérez-del-Pulgar, Sofía
AU - Torres-Ruiz, Raúl
AU - Rodriguez-Perales, Sandra
AU - Garaigorta, Urtzi
AU - Campbell, Peter J.
AU - Nakagawa, Hidewaki
AU - Van Loo, Peter
AU - Tubio, Jose M.C.
N1 - Funding Information:
We thank the Supercomputing Centre of Galicia (CESGA) for providing complementary computational resources. J.M.C.T is supported by European Research Council Grant ERC-2016-STG – ERC Starting Grant 716290, and Ministerio de Ciencia, Innovación y Universidades, Grants PGC2018-102245-B-100 and RYC-2014-14999. E.G.A. and P.O. are supported by Ministerio de Educacion Cultura y Deporte, fellowships FPU17/05396 and FPU18/03421, respectively. D.G-S. is supported by postdoctoral contract ED481B-2018/091 from Xunta de Galicia. B.R-M., A.O. and S.Z. are supported by Xunta de Galicia fellowships ED481A-2016/151, ED481A-2020/214 and ED481A-2018/199, respectively. A.L.B. is supported by Spanish Ministry of Economics and Competitiveness (MINECO) PhD fellowship BES-2016-078166. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). For the purpose of Open Access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). M.M-F. is funded by the Spanish Association for Cancer Research (AECC, grant207mart). S.R-P. is supported by grants from the Spanish National Research and Development Plan, Instituto de Salud Carlos III, and FEDER (PI17/02303, PI20/01837 and DTS19/00111); AEI/MICIU EXPLORA Project BIO2017-91272-EXP and AECC_Lab_2020 Project (Asociación Española Contra el Cáncer). X.F. and S.P-P. are supported by grants from the Instituto de Salud Carlos III through the Spanish National Plan for Scientific and Technical Research and Innovation (PI18/00079 and PI19/00036, respectively), co-funded by the European Regional Development Fund (ERDF), and from Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (grant 2017_SGR_1753) and CERCA Programme/ Generalitat de Catalunya. J.R-B. is supported by a Rio Hortega Fellowship from the Institute of Health Carlos III (CM19/00087) and a 2020 TTD Research Grant from the Spanish Cooperative Group for the Teatment of Digestive Tumours (TTD). J.D. is a postdoctoral fellow of the Research Foundation – Flanders (FWO). U.G. is supported by Ministerio de Ciencia e Innovación grants PID2020-118970RB-100, SAF2016-75169-R and RYC-2014-15805. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. A.D-L. is supported by a Juan Rodés contract from ISCIII (JR17/00016). A.R-C. is supported by GAIN and Xunta de Galicia (IN853B 2018/03).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-26805-8
DO - 10.1038/s41467-021-26805-8
M3 - Article
C2 - 34824211
AN - SCOPUS:85119887756
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6910
ER -