The topography of mutational processes in breast cancer genomes

Sandro Morganella, Ludmil B. Alexandrov, Dominik Glodzik, Xueqing Zou, Helen Davies, Johan Staaf, Anieta M. Sieuwerts, Arie B. Brinkman, Sancha Martin, Manasa Ramakrishna, Adam Butler, Hyung-Yong Kim, Åke Borg, Christos Sotiriou, P. Andrew Futreal, Peter J. Campbell, Paul N. Span, Steven Van Laere, Sunil R. Lakhani, Jorunn E. Eyfjord, Alastair M. Thompson, Hendrik G. Stunnenberg, Marc J. van de Vijver, John W. M. Martens, Anne-Lise Børresen-Dale, Andrea L. Richardson, Gu Kong, Gilles Thomas, Julian Sale, Cristina Rada, Michael R. Stratton, Ewan Birney and Serena Nik-Zainal ()
Additional contact information
Sandro Morganella: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
Ludmil B. Alexandrov: Wellcome Trust Sanger Institute
Dominik Glodzik: Wellcome Trust Sanger Institute
Xueqing Zou: Wellcome Trust Sanger Institute
Helen Davies: Wellcome Trust Sanger Institute
Johan Staaf: Lund University
Anieta M. Sieuwerts: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Arie B. Brinkman: Radboud University, Faculty of Science
Sancha Martin: Wellcome Trust Sanger Institute
Manasa Ramakrishna: Wellcome Trust Sanger Institute
Adam Butler: Wellcome Trust Sanger Institute
Hyung-Yong Kim: College of Medicine, Hanyang University
Åke Borg: Lund University
Christos Sotiriou: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles
P. Andrew Futreal: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
Peter J. Campbell: Wellcome Trust Sanger Institute
Paul N. Span: Radboud university medical center
Steven Van Laere: Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Wilrijk, Belgium and Center for Oncological Research, University of Antwerp
Sunil R. Lakhani: Centre for Clinical Research and School of Medicine, University of Queensland
Jorunn E. Eyfjord: Cancer Research Laboratory, Faculty of Medicine, University of Iceland
Alastair M. Thompson: University of Texas MD Anderson Cancer Center
Hendrik G. Stunnenberg: Radboud University, Faculty of Science
Marc J. van de Vijver: Academic Medical Center
John W. M. Martens: Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center
Anne-Lise Børresen-Dale: Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
Andrea L. Richardson: Brigham and Women's Hospital
Gu Kong: College of Medicine, Hanyang University
Gilles Thomas: Synergie Lyon Cancer, Centre Léon Bérard
Julian Sale: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Cristina Rada: MRC Laboratory of Molecular Biology, Francis Crick Avenue
Michael R. Stratton: Wellcome Trust Sanger Institute
Ewan Birney: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus
Serena Nik-Zainal: Wellcome Trust Sanger Institute

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

Date: 2016
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DOI: 10.1038/ncomms11383

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