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

Abstract

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:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1255873
Report Number(s):
LA-UR-15-24625
Journal ID: ISSN 0028-0836
Grant/Contract Number:  
AC52-06NA25396
Resource 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
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B., Martin, Sancha, Wedge, David C., Van Loo, Peter, Ju, Young Seok, Smid, Marcel, Brinkman, Arie B., Morganella, Sandro, Aure, Miriam R., Lingjærde, Ole Christian, Langerod, Anita, Ringner, Markus, Ahn, Sung -Min, Boyault, Sandrine, Brock, Jane E., Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc, Dronov, Serge, Fatima, Aquila, Foekens, John A., Gerstung, Moritz, Hooijer, Gerrit K. J., Jang, Se Jin, Jones, David R., Kim, Hyung -Yong, King, Tari A., Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong -Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O’Meara, Sarah, Pauporte, Iris, Pivot, Xavier, Purdie, Colin A., Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-Gonzalez, F. German, Romieu, Gilles, Sieuwerts, Anieta M., Simpson, Peter T., Shepherd, Rebecca, Stebbings, Lucy, Stefansson, Olafur A., Teague, Jon, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert G., Vermeulen, Peter, Vincent-Salomon, Anne, Yates, Lucy, Caldas, Carlos, Veer, Laura van’t, Tutt, Andrew, Knappskog, Stian, Tan, Benita Kiat Tee, Jonkers, Jos, Borg, Ake, Ueno, Naoto T., Sotiriou, Christos, Viari, Alain, Futreal, P. Andrew, Campbell, Peter J., Span, Paul N., Van Laere, Steven, Lakhani, Sunil R., Eyfjord, Jorunn E., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Borresen-Dale, Anne -Lise, Richardson, Andrea L., Kong, Gu, Thomas, Gilles, and Stratton, Michael R. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. United States: N. p., 2016. Web. doi:10.1038/nature17676.
Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B., Martin, Sancha, Wedge, David C., Van Loo, Peter, Ju, Young Seok, Smid, Marcel, Brinkman, Arie B., Morganella, Sandro, Aure, Miriam R., Lingjærde, Ole Christian, Langerod, Anita, Ringner, Markus, Ahn, Sung -Min, Boyault, Sandrine, Brock, Jane E., Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc, Dronov, Serge, Fatima, Aquila, Foekens, John A., Gerstung, Moritz, Hooijer, Gerrit K. J., Jang, Se Jin, Jones, David R., Kim, Hyung -Yong, King, Tari A., Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong -Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O’Meara, Sarah, Pauporte, Iris, Pivot, Xavier, Purdie, Colin A., Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-Gonzalez, F. German, Romieu, Gilles, Sieuwerts, Anieta M., Simpson, Peter T., Shepherd, Rebecca, Stebbings, Lucy, Stefansson, Olafur A., Teague, Jon, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert G., Vermeulen, Peter, Vincent-Salomon, Anne, Yates, Lucy, Caldas, Carlos, Veer, Laura van’t, Tutt, Andrew, Knappskog, Stian, Tan, Benita Kiat Tee, Jonkers, Jos, Borg, Ake, Ueno, Naoto T., Sotiriou, Christos, Viari, Alain, Futreal, P. Andrew, Campbell, Peter J., Span, Paul N., Van Laere, Steven, Lakhani, Sunil R., Eyfjord, Jorunn E., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Borresen-Dale, Anne -Lise, Richardson, Andrea L., Kong, Gu, Thomas, Gilles, & Stratton, Michael R. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. United States. doi:10.1038/nature17676.
Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B., Martin, Sancha, Wedge, David C., Van Loo, Peter, Ju, Young Seok, Smid, Marcel, Brinkman, Arie B., Morganella, Sandro, Aure, Miriam R., Lingjærde, Ole Christian, Langerod, Anita, Ringner, Markus, Ahn, Sung -Min, Boyault, Sandrine, Brock, Jane E., Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc, Dronov, Serge, Fatima, Aquila, Foekens, John A., Gerstung, Moritz, Hooijer, Gerrit K. J., Jang, Se Jin, Jones, David R., Kim, Hyung -Yong, King, Tari A., Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong -Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O’Meara, Sarah, Pauporte, Iris, Pivot, Xavier, Purdie, Colin A., Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-Gonzalez, F. German, Romieu, Gilles, Sieuwerts, Anieta M., Simpson, Peter T., Shepherd, Rebecca, Stebbings, Lucy, Stefansson, Olafur A., Teague, Jon, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert G., Vermeulen, Peter, Vincent-Salomon, Anne, Yates, Lucy, Caldas, Carlos, Veer, Laura van’t, Tutt, Andrew, Knappskog, Stian, Tan, Benita Kiat Tee, Jonkers, Jos, Borg, Ake, Ueno, Naoto T., Sotiriou, Christos, Viari, Alain, Futreal, P. Andrew, Campbell, Peter J., Span, Paul N., Van Laere, Steven, Lakhani, Sunil R., Eyfjord, Jorunn E., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Borresen-Dale, Anne -Lise, Richardson, Andrea L., Kong, Gu, Thomas, Gilles, and Stratton, Michael R. Mon . "Landscape of somatic mutations in 560 breast cancer whole-genome sequences". United States. doi:10.1038/nature17676. https://www.osti.gov/servlets/purl/1255873.
@article{osti_1255873,
title = {Landscape of somatic mutations in 560 breast cancer whole-genome sequences},
author = {Nik-Zainal, Serena and Davies, Helen and Staaf, Johan and Ramakrishna, Manasa and Glodzik, Dominik and Zou, Xueqing and Martincorena, Inigo and Alexandrov, Ludmil B. and Martin, Sancha and Wedge, David C. and Van Loo, Peter and Ju, Young Seok and Smid, Marcel and Brinkman, Arie B. and Morganella, Sandro and Aure, Miriam R. and Lingjærde, Ole Christian and Langerod, Anita and Ringner, Markus and Ahn, Sung -Min and Boyault, Sandrine and Brock, Jane E. and Broeks, Annegien and Butler, Adam and Desmedt, Christine and Dirix, Luc and Dronov, Serge and Fatima, Aquila and Foekens, John A. and Gerstung, Moritz and Hooijer, Gerrit K. J. and Jang, Se Jin and Jones, David R. and Kim, Hyung -Yong and King, Tari A. and Krishnamurthy, Savitri and Lee, Hee Jin and Lee, Jeong -Yeon and Li, Yilong and McLaren, Stuart and Menzies, Andrew and Mustonen, Ville and O’Meara, Sarah and Pauporte, Iris and Pivot, Xavier and Purdie, Colin A. and Raine, Keiran and Ramakrishnan, Kamna and Rodríguez-Gonzalez, F. German and Romieu, Gilles and Sieuwerts, Anieta M. and Simpson, Peter T. and Shepherd, Rebecca and Stebbings, Lucy and Stefansson, Olafur A. and Teague, Jon and Tommasi, Stefania and Treilleux, Isabelle and Van den Eynden, Gert G. and Vermeulen, Peter and Vincent-Salomon, Anne and Yates, Lucy and Caldas, Carlos and Veer, Laura van’t and Tutt, Andrew and Knappskog, Stian and Tan, Benita Kiat Tee and Jonkers, Jos and Borg, Ake and Ueno, Naoto T. and Sotiriou, Christos and Viari, Alain and Futreal, P. Andrew and Campbell, Peter J. and Span, Paul N. and Van Laere, Steven and Lakhani, Sunil R. and Eyfjord, Jorunn E. and Thompson, Alastair M. and Birney, Ewan and Stunnenberg, Hendrik G. and van de Vijver, Marc J. and Martens, John W. M. and Borresen-Dale, Anne -Lise and Richardson, Andrea L. and Kong, Gu and Thomas, Gilles and Stratton, Michael R.},
abstractNote = {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.},
doi = {10.1038/nature17676},
journal = {Nature (London)},
number = 7605,
volume = 534,
place = {United States},
year = {2016},
month = {5}
}

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