New Results
Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
View ORCID ProfileSebastian M Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A Roberts, German M Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B Alexandrov, Oliver Drechsel, L Jonathan Dursi, Ayellet V Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A Aaltonen, Eva G Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Olivier Harismendy, Dmitry A Gordenin, Jose MC Tubio, Francisco M De La Vega, Douglas F Easton, Xavier Estivill, Jan O Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
doi: https://doi.org/10.1101/208330
Sebastian M Waszak
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Grace Tiao
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
Bin Zhu
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Tobias Rausch
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Francesc Muyas
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
Bernardo Rodríguez-Martín
Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Raquel Rabionet
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
Sergei Yakneen
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Georgia Escaramis
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
Yilong Li
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Natalie Saini
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA.
Steven A Roberts
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
German M Demidov
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
Esa Pitkänen
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Olivier Delaneau
Swiss Institute of Bioinformatics, University of Geneva, 1 Michel Servet, Geneva CH1211, Switzerland.Department of Genetic Medicine and Development, University of Geneva, 1 Michel Servet, Geneva CH1211, Switzerland.Institute of Genetics and Genomics in Geneva, University of Geneva, 1 Michel Servet, Geneva CH1211, Switzerland.
Jose Maria Heredia-Genestar
Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Doctor Aiguader 88, Barcelona, 08003, Spain.
Joachim Weischenfeldt
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.Biotech Research &Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, Rigshospitalet, Denmark.
Suyash S Shringarpure
Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
Jieming Chen
Institute for Computational Health Sciences and Department of Pediatrics, University of California, San Francisco, California 94143, USA.
Hidewaki Nakagawa
RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Ludmil B Alexandrov
Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
Oliver Drechsel
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
L Jonathan Dursi
Ontario Institute for Cancer Research, 661 University Ave, Suite 510, Toronto, ON M5G 0A3, Canada.
Ayellet V Segre
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
Erik Garrison
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Serap Erkek
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Nina Habermann
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Lara Urban
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Ekta Khurana
Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
Andy Cafferkey
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Shuto Hayashi
Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Seiya Imoto
Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Lauri A Aaltonen
Department of Medical and Clinical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Finland.
Eva G Alvarez
Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Adrian Baez-Ortega
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK.
Matthew Bailey
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06520, USA.
Mattia Bosio
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
Alicia L Bruzos
Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Ivo Buchhalter
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Carlos D. Bustamante
Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Claudia Calabrese
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Anthony DiBiase
Cray Inc. 901 Fifth Avenue, Seattle, WA 98164, USA.
Mark Gerstein
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.Department of Computer Science, Yale University, New Haven, CT, 06520, USA.Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, 06520, USA.
Aliaksei Z Holik
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
Xing Hua
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Kuan-lin Huang
The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Ivica Letunic
Biobyte solutions GmbH, Bothestrasse 142, 69126 Heidelberg, Germany.
Leszek J Klimczak
Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.
Roelof Koster
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Sushant Kumar
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
Mike McLellan
The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Jay Mashl
The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Lisa Mirabello
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Steven Newhouse
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Aparna Prasad
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
Gunnar Rätsch
Department of Computer Science, Swiss Federal Institute of Technology in Zurich, 8092, Switzerland.
Matthias Schlesner
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Roland Schwarz
Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Pramod Sharma
Cray Inc. 901 Fifth Avenue, Seattle, WA 98164, USA.
Tal Shmaya
Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
Nikos Sidiropoulos
Biotech Research &Innovation Centre (BRIC), Copenhagen University and Finsen Laboratory, Rigshospitalet, Denmark.
Lei Song
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Hana Susak
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.
Tomas Tanskanen
Department of Medical and Clinical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Finland.
Marta Tojo
Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
David C Wedge
Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Oxford, UK.
Mark Wright
Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Ying Wu
Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.
Kai Ye
McDonnell Genome Institute, Washington University, St. Louis, Missouri 63108, USA.Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri 63108, USA.
Venkata D Yellapantula
McDonnell Genome Institute, Washington University, St. Louis, Missouri 63108, USA.Division of Oncology, Department of Medicine, Washington University, St. Louis, Missouri 63108, USA.
Jorge Zamora
Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Atul J Butte
Institute for Computational Health Sciences and Department of Pediatrics, University of California, San Francisco, California 94143, USA.
Gad Getz
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.Harvard Medical School, Boston, Massachusetts 02115, USA.
Jared Simpson
Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
Li Ding
The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Tomas Marques-Bonet
Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Doctor Aiguader 88, Barcelona, 08003, Spain.
Arcadi Navarro
Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, Doctor Aiguader 88, Barcelona, 08003, Spain.
Alvis Brazma
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Peter Campbell
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
Stephen J Chanock
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, Maryland 20892, USA.
Nilanjan Chatterjee
Department of Biostatistics, Bloomberg School of Public Health and Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Oliver Stegle
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
Reiner Siebert
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Stephan Ossowski
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.Universitat Pompeu Fabra, Barcelona, Spain.Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Olivier Harismendy
Moores Cancer Center, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Dmitry A Gordenin
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA.
Jose MC Tubio
Mobile Genomes & Disease, The Biomedical Research Centre - CINBIO, University of Vigo, 36310 Vigo, Spain.Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo 36310, Spain.
Francisco M De La Vega
Annai Systems, 1700 Aviara Parkway 130063, Carlsbad, CA 92013, USA.Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
Douglas F Easton
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Xavier Estivill
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
Jan O Korbel
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridge, UK.
Abstract
Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Posted November 01, 2017.
Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
Sebastian M Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A Roberts, German M Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B Alexandrov, Oliver Drechsel, L Jonathan Dursi, Ayellet V Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A Aaltonen, Eva G Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Olivier Harismendy, Dmitry A Gordenin, Jose MC Tubio, Francisco M De La Vega, Douglas F Easton, Xavier Estivill, Jan O Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 208330; doi: https://doi.org/10.1101/208330
Germline determinants of the somatic mutation landscape in 2,642 cancer genomes
Sebastian M Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A Roberts, German M Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B Alexandrov, Oliver Drechsel, L Jonathan Dursi, Ayellet V Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A Aaltonen, Eva G Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Olivier Harismendy, Dmitry A Gordenin, Jose MC Tubio, Francisco M De La Vega, Douglas F Easton, Xavier Estivill, Jan O Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 208330; doi: https://doi.org/10.1101/208330
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