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Nature. 2016 Jun 2;534(7605):47-54. doi: 10.1038/nature17676. Epub 2016 May 2.

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
2
East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK.
3
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund SE-223 81, Sweden.
4
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, New Mexico, USA.
5
Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
6
Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium.
7
Department of Medical Oncology, Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam 3015CN, The Netherlands.
8
Radboud University, Department of Molecular Biology, Faculty of Science, 6525GA Nijmegen, The Netherlands.
9
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
10
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo 0310, Norway.
11
K. G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo 0310, Norway.
12
Department of Computer Science, University of Oslo, Oslo, Norway.
13
Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea.
14
Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France.
15
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
16
The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
17
Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium.
18
Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
19
Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
20
Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
21
Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, Ulsan, South Korea.
22
Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, South Korea.
23
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
24
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard., Houston, Texas 77030, USA.
25
Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea.
26
Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France.
27
University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besançon 25000, France.
28
Pathology Department, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
29
Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France.
30
The University of Queensland, UQ Centre for Clinical Research and School of Medicine, Brisbane, Queensland 4029, Australia.
31
Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
32
IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.
33
Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France.
34
Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium.
35
Institut Curie, Paris Sciences Lettres University, Department of Pathology and INSERM U934, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
36
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
37
Breast Cancer Now Research Unit, King's College London, London SE1 9RT, UK.
38
Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
39
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
40
Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway.
41
National Cancer Centre Singapore, 11 Hospital Drive, 169610, Singapore.
42
Singapore General Hospital, Outram Road, 169608, Singapore.
43
Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Avenue de l'Europe, 38330 Montbonnot-Saint Martin, France.
44
Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France.
45
Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas 77230, USA.
46
Department of Radiation Oncology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
47
Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
48
Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.

Abstract

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

PMID:
27135926
PMCID:
PMC4910866
DOI:
10.1038/nature17676
[Indexed for MEDLINE]
Free PMC Article

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