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The Repertoire of Mutational Signatures in Human Cancer

View ORCID ProfileLudmil B Alexandrov, Jaegil Kim, Nicholas J Haradhvala, Mi Ni Huang, View ORCID ProfileAlvin WT Ng, Arnoud Boot, Kyle R Covington, View ORCID ProfileDmitry A Gordenin, Erik Bergstrom, View ORCID ProfileNuria Lopez-Bigas, Leszek J Klimczak, John R McPherson, View ORCID ProfileSandro Morganella, View ORCID ProfileRadhakrishnan Sabarinathan, David A Wheeler, View ORCID ProfileVille Mustonen, Gad Getz, View ORCID ProfileSteven G Rozen, Michael R Stratton, on behalf of the PCAWG Mutational Signatures Working Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
doi: https://doi.org/10.1101/322859
Ludmil B Alexandrov
1Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, La Jolla, San Diego, CA, USA
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Jaegil Kim
2Broad Institute, Cambridge, MA, USA
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Nicholas J Haradhvala
2Broad Institute, Cambridge, MA, USA
3Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
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Mi Ni Huang
4Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore
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Alvin WT Ng
4Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore
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Arnoud Boot
4Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore
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Kyle R Covington
5Human Genome Sequencing Center, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
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Dmitry A Gordenin
6Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA
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Erik Bergstrom
1Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, La Jolla, San Diego, CA, USA
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Nuria Lopez-Bigas
7Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain
8Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain
9Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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Leszek J Klimczak
10Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA
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John R McPherson
4Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore
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Sandro Morganella
11Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Radhakrishnan Sabarinathan
7Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain
8Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain
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David A Wheeler
5Human Genome Sequencing Center, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
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Ville Mustonen
12Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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Gad Getz
2Broad Institute, Cambridge, MA, USA
3Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
13Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
14Harvard Medical School, Boston, MA 02215, USA
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Steven G Rozen
4Centre for Computational Biology and Programme in Cancer & Stem Cell Biology, Duke NUS Medical School, Singapore
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  • For correspondence: steve.rozen@duke-nus.edu.sg mrs@sanger.ac.uk
Michael R Stratton
11Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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  • For correspondence: steve.rozen@duke-nus.edu.sg mrs@sanger.ac.uk
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ABSTRACT

Somatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a comprehensive perspective on the repertoire of mutational processes contributing to the development of human cancer.

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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.
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Posted May 15, 2018.
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The Repertoire of Mutational Signatures in Human Cancer
Ludmil B Alexandrov, Jaegil Kim, Nicholas J Haradhvala, Mi Ni Huang, Alvin WT Ng, Arnoud Boot, Kyle R Covington, Dmitry A Gordenin, Erik Bergstrom, Nuria Lopez-Bigas, Leszek J Klimczak, John R McPherson, Sandro Morganella, Radhakrishnan Sabarinathan, David A Wheeler, Ville Mustonen, Gad Getz, Steven G Rozen, Michael R Stratton, on behalf of the PCAWG Mutational Signatures Working Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 322859; doi: https://doi.org/10.1101/322859
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The Repertoire of Mutational Signatures in Human Cancer
Ludmil B Alexandrov, Jaegil Kim, Nicholas J Haradhvala, Mi Ni Huang, Alvin WT Ng, Arnoud Boot, Kyle R Covington, Dmitry A Gordenin, Erik Bergstrom, Nuria Lopez-Bigas, Leszek J Klimczak, John R McPherson, Sandro Morganella, Radhakrishnan Sabarinathan, David A Wheeler, Ville Mustonen, Gad Getz, Steven G Rozen, Michael R Stratton, on behalf of the PCAWG Mutational Signatures Working Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
bioRxiv 322859; doi: https://doi.org/10.1101/322859

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