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

Serena Nik-Zainal (1) , Helen R. Davies (1) , Johan Staaf (2) , Manasa Ramakrishna (1) , Dominik Glodzik (1) , Xueqing Zou (1) , Inigo Martincorena (1) , Ludmil B. Alexandrov (1) , Sancha Martin (1) , David C. Wedge (1) , Peter van Loo (1) , Young Seok Ju (1) , Marcel Smid (3) , Arie B. Brinkman (4) , Sandro Morganella (1) , Miriam R. Aure (5) , Ole Christian Lingjærde (6) , Anita Langerød (5) , Markus Ringnér (2) , Sung-Min Ahn (7) , Sandrine Boyault (8) , Jane E. Brock (9) , Anne Broeks (10) , Adam Butler (1) , Christine Desmedt (11) , Luc Dirix (12) , Serge Dronov (1) , Aquila Fatima (13) , John A. Foekens (3) , Moritz Gerstung (1) , Gerrit K. J. Hooijer (14) , Se Jin Jang (15) , David R. Jones (16, 1) , Hyung-Yong Kim (17) , Tari A. King (18) , Savitri Krishnamurthy (19) , Hee Jin Lee (15) , Jeong-Yeon Lee (20) , Yilong Li (1) , Stuart Mclaren (1) , Andrew Menzies (1) , Ville Mustonen (1) , Sarah O’meara (1) , Iris Pauporté (21) , Xavier Pivot (22) , Colin A. Purdie (23) , Keiran Raine (1) , Kamna Ramakrishnan (1) , F. Germán Rodríguez-González (3, 24, 25) , Gilles Romieu (26) , Anieta M. Sieuwerts (27, 28) , Peter Simpson (29) , Rebecca Shepherd (1) , Lucy Stebbings (1) , Olafur A. Stefansson (30) , Jon Teague (1) , Stefania Tommasi (31) , Isabelle Treilleux (32) , Gert G. van den Eynden (33) , Peter Vermeulen (34) , Anne Vincent-Salomon (35, 36) , Lucy Yates (1) , Carlos Caldas (37) , Laura Van’t Veer (38, 39) , Andrew Tutt (40) , Stian Knappskog (41) , Benita Kiat Tee Tan (42) , Jos Jonkers (43) , Åke Borg (2) , Naoto T. Ueno (44, 45) , Christos Sotiriou (46) , Alain Viari (47, 48) , P. Andrew Futreal (1) , Peter J. Campbell (1) , Paul N. Span (49, 50) , Steven van Laere (51, 52) , Sunil R. Lakhani (29) , Jorunn E. Eyfjord (30) , Alastair M. Thompson (53) , Ewan Birney (1) , Hendrik G. Stunnenberg (54) , Marc J. van de Vijver (14) , John W. M. Martens (3) , Anne-Lise Børresen-Dale (5) , Andrea L. Richardson (55) , Gu Kong (56) , Gilles Thomas (57) , Michael R. Stratton (1)

1 The Wellcome Trust Sanger Institute [Cambridge]
2 Skane University Hospital [Lund]
3 Erasmus MC - Erasmus University Medical Center [Rotterdam]
4 Radboud University [Nijmegen]
5 Oslo University Hospital Radiumhospitalet
6 UiO - University of Oslo
7 Gachon University Hospital
8 U1162 - Génomique Fonctionnelle des Tumeurs Solides
9 Brigham and Women's Hospital [Boston]
10 NKI - Netherlands Cancer Institute
11 Breast Cancer Translational Research Laboratory
12 Algemeen Ziekenhuis St Augustinus Oncology
13 Dana-Farber Cancer Institute [Boston]
14 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
15 University of Ulsan
16 JSC - NASA Johnson Space Center
17 University of Stuttgart
18 Esso UK Ltd, Department of Exploration,
19 CSE - Department of Computer Science & Engineering [Riverside]
20 Department of Geriatric Medicine [Singapore] (Alexandra Hospital)
21 INCa - Institut national du cancer
22 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
23 Department of Pathology [Dundee]
24 Canary Institute for Cancer Research (ICIC)
25 Department of Biochemistry and Physiology, Faculty of Health Sciences
26 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
27 Department of Medical Oncology [Rotterdam]
28 Cancer Genomics Centre
29 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
30 University of Iceland [Reykjavik]
31 Beckman Research Institute [Duarte, CA]
32 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
33 UA - University of Antwerp
34 ECB - European Central Bank
35 U830 - Unité de génétique et biologie des cancers
36 Department of Tumor Biology
37 CAM - University of Cambridge [UK]
38 Division of Diagnostic Oncology
39 Agendia BV
40 Breakthrough Breast Cancer Centre
41 UiB - University of Bergen
42 NCCS - National Cancer Centre Singapore
43 Division of Molecular Biology
44 National Institutes of Natural Sciences
45 The Graduate University for Advanced Studies
46 Institut Jules Bordet [Bruxelles]
47 Baobab
48 ERABLE - Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale
49 Department of Radiation Oncology 874
50 Department of Laboratory Medicine
51 Department Medical Oncology
52 Department of Pathology
53 GESTAR - Goddard Earth Sciences and Technology and Research
54 Department of Molecular Biology [Nijmegen]
55 OEB - Department of Organismic and Evolutionary Biology [Cambridge]
56 Department of Computing [London]
57 Fondation Synergie Lyon Cancer [Lyon]

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.

Domaines: Sciences du Vivant [q-bio]

Serena Nik-Zainal, Helen R. Davies, Johan Staaf, Manasa Ramakrishna, Dominik Glodzik, et al.. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature, 2016, 534 (7605), pp.47 - 54. ⟨10.1038/nature17676⟩. ⟨hal-01388447⟩