title: The topography of mutational processes in breast cancer genomes.
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.
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridgeshire CB10 1SD, UK.
authors.forename: Sandro
authors.initials: S
authors.lastname: Morganella
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.|Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos NM 87545, New Mexico, USA.|Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos NM 87545, New Mexico, USA.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Glodzik
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Zou
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands.
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Radboud University, Faculty of Science, Department of Molecular Biology, 6525GA Nijmegen, The Netherlands.
authors.forename: Arie B
authors.initials: AB
authors.lastname: Brinkman
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea.
authors.forename: Hyung-Yong
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridgeshire CB10 1SD, UK.|Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA.
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Department of Radiation Oncology, and department of Laboratory Medicine, Radboud university medical center, Nijmegen 6525GA, The Netherlands.
authors.forename: Paul N
authors.identifier: http://orcid.org/0000-0002-1930-6638
authors.initials: PN
authors.lastname: Span
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Wilrijk, Belgium and Center for Oncological Research, University of Antwerp, Antwerp B-2610, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
authors.affiliation: Centre for Clinical Research and School of Medicine, University of Queensland, Brisbane, Queensland 4059, Australia.|Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
authors.forename: Sunil R
authors.identifier: http://orcid.org/0000-0003-1879-2555
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Jorunn E
authors.initials: JE
authors.lastname: Eyfjord
authors.affiliation: Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street,Houston, Texas 77030, USA.|Department of Surgical Oncology, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Radboud University, Faculty of Science, Department of Molecular Biology, 6525GA Nijmegen, The Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: van de Vijver
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea.
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
authors.affiliation: Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Sale
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Cristina
authors.identifier: http://orcid.org/0000-0003-4898-5550
authors.initials: C
authors.lastname: Rada
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridgeshire CB10 1SD, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.|East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005260:Female; D015894:Genome, Human; D006801:Humans; D061986:MCF-7 Cells; D016296:Mutagenesis; D009154:Mutation; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D001055:Apolipoproteins B; D002843:Chromatin