New Results
Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours
Bernardo Rodriguez-Martin, Eva G. Alvarez, Adrian Baez-Ortega, Jorge Zamora, Fran Supek, Jonas Demeulemeester, Martin Santamarina, Young Seok Ju, Javier Temes, Daniel Garcia-Souto, Harald Detering, Yilong Li, Jorge Rodriguez-Castro, Ana Dueso-Barroso, Alicia L. Bruzos, Stefan C. Dentro, Miguel G. Blanco, Gianmarco Contino, Daniel Ardeljan, Marta Tojo, Nicola D. Roberts, Sonia Zumalave, Paul A. W. Edwards, Joachim Weischenfeldt, Montserrat Puiggros, Zechen Chong, Ken Chen, Eunjung Alice Lee, Jeremiah A. Wala, Keiran Raine, Adam Butler, Sebastian M. Waszak, Fabio C. P. Navarro, Steven E. Schumacher, Jean Monlong, Francesco Maura, Niccolo Bolli, Guillaume Bourque, Mark Gerstein, Peter J. Park, David Wedge, Rameen Beroukhim, David Torrents, Jan O. Korbel, Inigo Martincorena, Rebecca C. Fitzgerald, Peter Van Loo, Haig H. Kazazian, Kathleen H. Burns, Peter J. Campbell, Jose M. C. Tubio, on behalf of the PCAWG Structural Variation Working Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
doi: https://doi.org/10.1101/179705
Bernardo Rodriguez-Martin
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainDepartment of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainThe Biomedical Research Centre (CINBIO), University of Vigo, Vigo 36310, Spain
Eva G. Alvarez
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainDepartment of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainThe Biomedical Research Centre (CINBIO), University of Vigo, Vigo 36310, Spain
Adrian Baez-Ortega
Transmissible Cancer Group, Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK
Jorge Zamora
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainDepartment of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain
Fran Supek
Genome Data Science, Institute for Research in Biomedicine IRBB, The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain
Jonas Demeulemeester
The Francis Crick Institute, London, UKDepartment of Human Genetics, University of Leuven, Leuven, Belgium
Martin Santamarina
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainDepartment of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainThe Biomedical Research Centre (CINBIO), University of Vigo, Vigo 36310, Spain
Young Seok Ju
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Javier Temes
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain
Daniel Garcia-Souto
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain
Harald Detering
Evolutionary Genomics, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain
Yilong Li
Cancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK
Jorge Rodriguez-Castro
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain
Ana Dueso-Barroso
Barcelona Supercomputing Center (BSC-CNS), Barcelona, SpainFaculty of Science and Technology. University of Vic - Central University of Catalonia (UVic-UCC), Vic, Spain
Alicia L. Bruzos
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainDepartment of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainThe Biomedical Research Centre (CINBIO), University of Vigo, Vigo 36310, Spain
Stefan C. Dentro
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA. UKThe Francis Crick Institute, London, UKOxford Big Data Institute, University of Oxford, Oxford, UK
Miguel G. Blanco
Molecular Medicine and Chronic diseases Centre (CIMUS) – IDIS, University of Santiago de Compostela, Santiago de Compostela 15706, SpainDepartamento de Bioquímica e Bioloxía Molecular, CIMUS, Universidade de Santiago de Compostela, 15706 Santiago de Compostela, Spain
Gianmarco Contino
Medical Research Council (MRC) Cancer Unit, University of Cambridge, Cambridge, UK
Daniel Ardeljan
Institute for Genetic Medicine, Johns Hopkins University School of Medicine - Baltimore, MD USA
Marta Tojo
Evolutionary Genomics, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain
Nicola D. Roberts
Cancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK
Sonia Zumalave
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain
Paul A. W. Edwards
Department of Pathology, University of Cambridge, Cambridge, UKCancer Research UK Cambridge Institute, Cambridge, UK
Joachim Weischenfeldt
Biotech Research & Innovation Centre (BRIC); Finsen Laboratory, Rigshospitalet, Copenhagen, DenmarkEuropean Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
Montserrat Puiggros
Barcelona Supercomputing Center (BSC-CNS), Barcelona, Spain
Zechen Chong
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Ken Chen
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Eunjung Alice Lee
Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Jeremiah A. Wala
The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Keiran Raine
Cancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK
Adam Butler
Cancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK
Sebastian M. Waszak
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
Fabio C. P. Navarro
Program in Computational Biology and Bioinformatics, Yale University, Bass 432, 266 Whitney Avenue, New Haven, CTDepartment of Molecular Biophysics and Biochemistry, Yale University, Bass 432, 266 Whitney Avenue, New Haven, CT
Steven E. Schumacher
The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Jean Monlong
Department of Human Genetics, McGill University, Montreal, H3A 1B1, Canada
Francesco Maura
Department of Oncology and Onco-Hematology, University of Milan, Milan, ItlayDepartment of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyCancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK
Niccolo Bolli
Department of Oncology and Onco-Hematology, University of Milan, Milan, ItlayDepartment of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Guillaume Bourque
Department of Human Genetics, McGill University, Montreal, H3A 1B1, Canada
Mark Gerstein
Program in Computational Biology and Bioinformatics, Yale University, Bass 432, 266 Whitney Avenue, New Haven, CTDepartment of Molecular Biophysics and Biochemistry, Yale University, Bass 432, 266 Whitney Avenue, New Haven, CT
Peter J. Park
Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
David Wedge
Oxford Big Data Institute, University of Oxford, Oxford, UKCancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UKOxford NIHR Biomedical Research Centre, Oxford, UK
Rameen Beroukhim
The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
David Torrents
Barcelona Supercomputing Center (BSC-CNS), Barcelona, SpainInstitucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Jan O. Korbel
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
Inigo Martincorena
Cancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UK
Rebecca C. Fitzgerald
Medical Research Council (MRC) Cancer Unit, University of Cambridge, Cambridge, UK
Peter Van Loo
The Francis Crick Institute, London, UKDepartment of Human Genetics, University of Leuven, Leuven, Belgium
Haig H. Kazazian
Institute for Genetic Medicine, Johns Hopkins University School of Medicine - Baltimore, MD USA
Kathleen H. Burns
Department of Pathology, Johns Hopkins University School of Medicine - Baltimore, MD USAInstitute for Genetic Medicine, Johns Hopkins University School of Medicine - Baltimore, MD USA
Peter J. Campbell
Cancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UKDepartment of Haematology, University of Cambridge, Cambridge CB2 2XY, UK
Jose M. C. Tubio
Mobile Genomes and Disease, Molecular Medicine and Chronic diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainDepartment of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, SpainCancer Ageing and Somatic Mutation Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB101SA, UKThe Biomedical Research Centre (CINBIO), University of Vigo, Vigo 36310, Spain
Abstract
About half of all cancers have somatic integrations of retrotransposons. To characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 37 histological cancer subtypes. We identified 19,166 somatically acquired retrotransposition events, affecting 35% of samples, and spanning a range of event types. L1 insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, sometimes removing tumour suppressor genes, as well as inducing complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications in the development of human tumours.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Posted September 07, 2018.
Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours
Bernardo Rodriguez-Martin, Eva G. Alvarez, Adrian Baez-Ortega, Jorge Zamora, Fran Supek, Jonas Demeulemeester, Martin Santamarina, Young Seok Ju, Javier Temes, Daniel Garcia-Souto, Harald Detering, Yilong Li, Jorge Rodriguez-Castro, Ana Dueso-Barroso, Alicia L. Bruzos, Stefan C. Dentro, Miguel G. Blanco, Gianmarco Contino, Daniel Ardeljan, Marta Tojo, Nicola D. Roberts, Sonia Zumalave, Paul A. W. Edwards, Joachim Weischenfeldt, Montserrat Puiggros, Zechen Chong, Ken Chen, Eunjung Alice Lee, Jeremiah A. Wala, Keiran Raine, Adam Butler, Sebastian M. Waszak, Fabio C. P. Navarro, Steven E. Schumacher, Jean Monlong, Francesco Maura, Niccolo Bolli, Guillaume Bourque, Mark Gerstein, Peter J. Park, David Wedge, Rameen Beroukhim, David Torrents, Jan O. Korbel, Inigo Martincorena, Rebecca C. Fitzgerald, Peter Van Loo, Haig H. Kazazian, Kathleen H. Burns, Peter J. Campbell, Jose M. C. Tubio, on behalf of the PCAWG Structural Variation Working Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 179705; doi: https://doi.org/10.1101/179705
Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours
Bernardo Rodriguez-Martin, Eva G. Alvarez, Adrian Baez-Ortega, Jorge Zamora, Fran Supek, Jonas Demeulemeester, Martin Santamarina, Young Seok Ju, Javier Temes, Daniel Garcia-Souto, Harald Detering, Yilong Li, Jorge Rodriguez-Castro, Ana Dueso-Barroso, Alicia L. Bruzos, Stefan C. Dentro, Miguel G. Blanco, Gianmarco Contino, Daniel Ardeljan, Marta Tojo, Nicola D. Roberts, Sonia Zumalave, Paul A. W. Edwards, Joachim Weischenfeldt, Montserrat Puiggros, Zechen Chong, Ken Chen, Eunjung Alice Lee, Jeremiah A. Wala, Keiran Raine, Adam Butler, Sebastian M. Waszak, Fabio C. P. Navarro, Steven E. Schumacher, Jean Monlong, Francesco Maura, Niccolo Bolli, Guillaume Bourque, Mark Gerstein, Peter J. Park, David Wedge, Rameen Beroukhim, David Torrents, Jan O. Korbel, Inigo Martincorena, Rebecca C. Fitzgerald, Peter Van Loo, Haig H. Kazazian, Kathleen H. Burns, Peter J. Campbell, Jose M. C. Tubio, on behalf of the PCAWG Structural Variation Working Group, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 179705; doi: https://doi.org/10.1101/179705
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