title: A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.
abstract: Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Glodzik
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Sandro
authors.initials: S
authors.lastname: Morganella
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.affiliation: The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.
authors.forename: Peter T
authors.identifier: http://orcid.org/0000-0002-4816-8289
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Zou
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Diez-Perez
authors.affiliation: Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, USA.|Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.affiliation: Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.
authors.forename: Arie B
authors.initials: AB
authors.lastname: Brinkman
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Inga Hansine
authors.initials: IH
authors.lastname: Rye
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Hege
authors.initials: H
authors.lastname: Russnes
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Keiran
authors.identifier: http://orcid.org/0000-0002-5634-1539
authors.initials: K
authors.lastname: Raine
authors.affiliation: Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Purdie
authors.affiliation: The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.|Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Sunil R
authors.identifier: http://orcid.org/0000-0003-1879-2555
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.|Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridgeshire, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Department of Pathology, Academic Medical Center, 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, the Netherlands.
authors.forename: John W M
authors.identifier: http://orcid.org/0000-0002-3428-3366
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.|K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea.
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
authors.affiliation: Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.|Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Viari
authors.affiliation: Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Gerard
authors.initials: G
authors.lastname: Evan
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D016678:Genome / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics