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

Here, 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.
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [2] ;  [2] ;  [2] ;  [4] ;  [2] ;  [2] ;  [5] ;  [2] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [9] ;  [3] ;  [11] more »;  [12] ;  [13] ;  [14] ;  [2] ;  [15] ;  [16] ;  [2] ;  [17] ;  [6] ;  [2] ;  [18] ;  [19] ;  [2] ;  [20] ;  [21] ;  [22] ;  [19] ;  [20] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [23] ;  [24] ;  [25] ;  [2] ;  [2] ;  [6] ;  [26] ;  [6] ;  [27] ;  [2] ;  [2] ;  [28] ;  [2] ;  [29] ;  [12] ;  [30] ;  [30] ;  [31] ;  [2] ;  [32] ;  [14] ;  [33] ;  [34] ;  [35] ;  [14] ;  [3] ;  [22] ;  [15] ;  [36] ;  [37] ;  [2] ;  [38] ;  [16] ;  [39] ;  [28] ;  [40] ;  [8] ;  [7] ;  [18] ;  [6] ;  [9] ;  [41] ;  [20] ;  [42] ;  [2] « less
  1. Wellcome Trust Sanger Institute, Cambridge (United Kingdom); Cambridge Univ. Hospitals NHS Foundation Trust, Cambridge (United Kingdom)
  2. Wellcome Trust Sanger Institute, Cambridge (United Kingdom)
  3. Lund Univ., Lund (Sweden)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wellcome Trust Sanger Institute, Cambridge (United Kingdom)
  5. Wellcome Trust Sanger Institute, Cambridge (United Kingdom); Univ. of Leuven, Leuven (Belgium)
  6. Erasmus Univ. Medical Center, Rotterdam (The Netherlands)
  7. Radboud Univ., Nijmegen (The Netherlands)
  8. Wellcome Trust Genome Campus, Cambridge (United Kingdom)
  9. Oslo Univ. Hospital, Oslo (Norway); Univ. of Oslo, Oslo (Norway)
  10. Univ. of Oslo, Oslo (Norway)
  11. Gachon Univ. Gil Medical Center, Incheon (South Korea)
  12. Centre Leon Berard, Lyon Cedex (France)
  13. Brigham and Women's Hospital, Boston, MA (United States)
  14. The Netherlands Cancer Institute, Amsterdam (The Netherlands)
  15. Univ. Libre de Bruxelles, Brussels (Belgium)
  16. Univ. of Antwerp, Antwerp (Belgium)
  17. Dana-Farber Cancer Institute, Boston, MA (United States)
  18. Academic Medical Center, Amsterdam (The Netherlands)
  19. Ulsan Univ., Ulsan (South Korea)
  20. Hanyang Univ., Seoul (South Korea)
  21. Memorial Sloan Kettering Cancer Center, New York, NY (United States)
  22. The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
  23. Institut National du Cancer, Boulogne-Billancourt (France)
  24. Univ. Hospital of Minjoz, Besancon (France)
  25. Ninewells Hospital and Medical School, Dundee (United Kingdom)
  26. ICM Institut Regional du Cancer, Montpellier (France)
  27. The Univ. of Queensland, Queensland (Australia)
  28. Univ. of Iceland, Reykjavik (Iceland)
  29. IRCCS Istiuto Tumori "Giovanni Paolo II", Bari (Italy)
  30. Univ. of Antwerp, Antwerp (Belgium); GZA Hospitals Sint-Augustinus, Antwerp (Belgium)
  31. Paris Sciences Lettres Univ., Paris Cedex (France)
  32. Univ. of Cambridge, Cambridge (United Kingdom)
  33. King's College London, London (United Kingdom); Breast Cancer Now Toby Robins Research Center, London (United Kingdom)
  34. Univ. of Bergen, Bergen (Norway); Haukeland Univ. Hospital, Bergen (Norway)
  35. Singapore General Hospital (Singapore)
  36. INRIA Grenoble-Rhone-Alpes, Montbonnot-Saint Martin (France); Synergie Lyon Cancer, Lyon Cedex (France)
  37. Wellcome Trust Sanger Institute, Cambridge (United Kingdom); UT MD Anderson Cancer Center, Houston, TX (United States)
  38. Radboud Univ. Medical Center, Nijmegen (The Netherlands)
  39. The Univ. of Queensland, Queensland (Australia); The Royal Brisbane and Women's Hospital, Queensland (Australia)
  40. Ninewells Hospital and Medical School, Dundee (United Kingdom); Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
  41. Brigham and Women's Hospital, Boston, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States)
  42. Synergie Lyon Cancer, Lyon Cedex (France)
Publication Date:
OSTI Identifier:
1255873
Report Number(s):
LA-UR--15-24625
Journal ID: ISSN 0028-0836
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 534; Journal Issue: 7605; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES Biological Science