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Nat Genet. 2017 Mar;49(3):341-348. doi: 10.1038/ng.3771. Epub 2017 Jan 23.

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.

Author information

1
Wellcome Trust Sanger Institute, Cambridge, UK.
2
The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland, Australia.
3
Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
4
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
5
Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
6
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands.
7
Department of Molecular Biology, Faculties of Science and Medicine, Radboud University, Nijmegen, the Netherlands.
8
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radiumhospital, Oslo, Norway.
9
K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
10
Department of Pathology, Ninewells Hospital &Medical School, Dundee, UK.
11
Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
12
Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
13
European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridgeshire, UK.
14
Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.
15
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
16
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
17
Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea.
18
Equipe Erable, INRIA Grenoble-Rhône-Alpes, Montbonnot-Saint Martin, France.
19
Synergie Lyon Cancer, Centre Léon Bérard, Lyon, France.
20
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
21
Department of Biochemistry, University of Cambridge, Cambridge, UK.
22
East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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.

PMID:
28112740
PMCID:
PMC5988034
DOI:
10.1038/ng.3771
[Indexed for MEDLINE]
Free PMC Article

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