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

Serena Nik-Zainal; Helen Davies; Johan Staaf; Manasa Ramakrishna; Dominik Glodzik; Xueqing Zou; Inigo Martincorena; Ludmil B. Alexandrov; Sancha Martin; David C. Wedge; Peter Van Loo; Young Seok Ju; Marcel Smid; Arie B. Brinkman; Sandro Morganella; Miriam R. Aure; Ole Christian Lingjærde; Anita Langerød; Markus Ringnér; Sung Min Ahn; Sandrine Boyault; Jane E. Brock; Annegien Broeks; Adam Butler; Christine Desmedt; Luc Dirix; Serge Dronov; Aquila Fatima; John A. Foekens; Moritz Gerstung; Gerrit K.J. Hooijer; Se Jin Jang; David R. Jones; Hyung Yong Kim; Tari A. King; Savitri Krishnamurthy; Hee Jin Lee; Jeong Yeon Lee; Yilong Li; Stuart McLaren; Andrew Menzies; Ville Mustonen; Sarah O'Meara; Iris Pauporté; Xavier Pivot; Colin A. Purdie; Keiran Raine; Kamna Ramakrishnan; F. Germán Rodríguez-González; Gilles Romieu; Anieta M. Sieuwerts; Peter T. Simpson; Rebecca Shepherd; Lucy Stebbings; Olafur A. Stefansson; Jon Teague; Stefania Tommasi; Isabelle Treilleux; Gert G. Van Den Eynden; Peter Vermeulen; Anne Vincent-Salomon; Lucy Yates; Carlos Caldas; Laura Van t. Veer; Andrew Tutt; Stian Knappskog; Benita Kiat Tee Tan; Jos Jonkers; Åke Borg; Naoto T. Ueno; Christos Sotiriou; Alain Viari; P. Andrew Futreal; Peter J. Campbell; Paul N. Span; Steven Van Laere; Sunil R. Lakhani; Jorunn E. Eyfjord; Alastair M. Thompson; Ewan Birney; Hendrik G. Stunnenberg; Marc J. Van De Vijver; John W.M. Martens; Anne Lise Børresen-Dale; Andrea L. Richardson; Gu Kong; Gilles Thomas; Michael R. Stratton

doi:10.1038/nature17676

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

Serena Nik-Zainal, Helen Davies, Johan Staaf, Manasa Ramakrishna, Dominik Glodzik, Xueqing Zou, Inigo Martincorena, Ludmil B. Alexandrov, Sancha Martin, David C. Wedge, Peter Van Loo, Young Seok Ju, Marcel Smid, Arie B. Brinkman, Sandro Morganella, Miriam R. Aure, Ole Christian Lingjærde, Anita Langerød, Markus Ringnér, Sung Min AhnSandrine Boyault, Jane E. Brock, Annegien Broeks, Adam Butler, Christine Desmedt, Luc Dirix, Serge Dronov, Aquila Fatima, John A. Foekens, Moritz Gerstung, Gerrit K.J. Hooijer, Se Jin Jang, David R. Jones, Hyung Yong Kim, Tari A. King, Savitri Krishnamurthy, Hee Jin Lee, Jeong Yeon Lee, Yilong Li, Stuart McLaren, Andrew Menzies, Ville Mustonen, Sarah O'Meara, Iris Pauporté, Xavier Pivot, Colin A. Purdie, Keiran Raine, Kamna Ramakrishnan, F. Germán Rodríguez-González, Gilles Romieu, Anieta M. Sieuwerts, Peter T. Simpson, Rebecca Shepherd, Lucy Stebbings, Olafur A. Stefansson, Jon Teague, Stefania Tommasi, Isabelle Treilleux, Gert G. Van Den Eynden, Peter Vermeulen, Anne Vincent-Salomon, Lucy Yates, Carlos Caldas, Laura Van t. Veer, Andrew Tutt, Stian Knappskog, Benita Kiat Tee Tan, Jos Jonkers, Åke Borg, Naoto T. Ueno, Christos Sotiriou, Alain Viari, P. Andrew Futreal, Peter J. Campbell, Paul N. Span, Steven Van Laere, Sunil R. Lakhani, Jorunn E. Eyfjord, Alastair M. Thompson, Ewan Birney, Hendrik G. Stunnenberg, Marc J. Van De Vijver, John W.M. Martens, Anne Lise Børresen-Dale, Andrea L. Richardson, Gu Kong, Gilles Thomas, Michael R. Stratton

Research output: Contribution to journal › Article › peer-review

1486 Scopus citations

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.

Original language	English (US)
Pages (from-to)	47-54
Number of pages	8
Journal	Nature
Volume	534
Issue number	7605
DOIs	https://doi.org/10.1038/nature17676
State	Published - May 2 2016

ASJC Scopus subject areas

General

Access to Document

10.1038/nature17676

Cite this

Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L. B., Martin, S., Wedge, D. C., Van Loo, P., Ju, Y. S., Smid, M., Brinkman, A. B., Morganella, S., Aure, M. R., Lingjærde, O. C., Langerød, A., Ringnér, M., ... Stratton, M. R. (2016). Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature, 534(7605), 47-54. https://doi.org/10.1038/nature17676

Nik-Zainal, S, Davies, H, Staaf, J, Ramakrishna, M, Glodzik, D, Zou, X, Martincorena, I, Alexandrov, LB, Martin, S, Wedge, DC, Van Loo, P, Ju, YS, Smid, M, Brinkman, AB, Morganella, S, Aure, MR, Lingjærde, OC, Langerød, A, Ringnér, M, Ahn, SM, Boyault, S, Brock, JE, Broeks, A, Butler, A, Desmedt, C, Dirix, L, Dronov, S, Fatima, A, Foekens, JA, Gerstung, M, Hooijer, GKJ, Jang, SJ, Jones, DR, Kim, HY, King, TA, Krishnamurthy, S, Lee, HJ, Lee, JY, Li, Y, McLaren, S, Menzies, A, Mustonen, V, O'Meara, S, Pauporté, I, Pivot, X, Purdie, CA, Raine, K, Ramakrishnan, K, Rodríguez-González, FG, Romieu, G, Sieuwerts, AM, Simpson, PT, Shepherd, R, Stebbings, L, Stefansson, OA, Teague, J, Tommasi, S, Treilleux, I, Van Den Eynden, GG, Vermeulen, P, Vincent-Salomon, A, Yates, L, Caldas, C, Veer, LVT, Tutt, A, Knappskog, S, Tan, BKT, Jonkers, J, Borg, Å, Ueno, NT, Sotiriou, C, Viari, A, Futreal, PA, Campbell, PJ, Span, PN, Van Laere, S, Lakhani, SR, Eyfjord, JE, Thompson, AM, Birney, E, Stunnenberg, HG, Van De Vijver, MJ, Martens, JWM, Børresen-Dale, AL, Richardson, AL, Kong, G, Thomas, G & Stratton, MR 2016, 'Landscape of somatic mutations in 560 breast cancer whole-genome sequences', Nature, vol. 534, no. 7605, pp. 47-54. https://doi.org/10.1038/nature17676

@article{8607fb4da89449cb96f7b670e550bee9,

title = "Landscape of somatic mutations in 560 breast cancer whole-genome sequences",

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.",

author = "Serena Nik-Zainal and Helen Davies and Johan Staaf and Manasa Ramakrishna and Dominik Glodzik and Xueqing Zou and Inigo Martincorena and Alexandrov, {Ludmil B.} and Sancha Martin and Wedge, {David C.} and {Van Loo}, Peter and Ju, {Young Seok} and Marcel Smid and Brinkman, {Arie B.} and Sandro Morganella and Aure, {Miriam R.} and Lingj{\ae}rde, {Ole Christian} and Anita Langer{\o}d and Markus Ringn{\'e}r and Ahn, {Sung Min} and Sandrine Boyault and Brock, {Jane E.} and Annegien Broeks and Adam Butler and Christine Desmedt and Luc Dirix and Serge Dronov and Aquila Fatima and Foekens, {John A.} and Moritz Gerstung and Hooijer, {Gerrit K.J.} and Jang, {Se Jin} and Jones, {David R.} and Kim, {Hyung Yong} and King, {Tari A.} and Savitri Krishnamurthy and Lee, {Hee Jin} and Lee, {Jeong Yeon} and Yilong Li and Stuart McLaren and Andrew Menzies and Ville Mustonen and Sarah O'Meara and Iris Pauport{\'e} and Xavier Pivot and Purdie, {Colin A.} and Keiran Raine and Kamna Ramakrishnan and Rodr{\'i}guez-Gonz{\'a}lez, {F. Germ{\'a}n} and Gilles Romieu and Sieuwerts, {Anieta M.} and Simpson, {Peter T.} and Rebecca Shepherd and Lucy Stebbings and Stefansson, {Olafur A.} and Jon Teague and Stefania Tommasi and Isabelle Treilleux and {Van Den Eynden}, {Gert G.} and Peter Vermeulen and Anne Vincent-Salomon and Lucy Yates and Carlos Caldas and Veer, {Laura Van t.} and Andrew Tutt and Stian Knappskog and Tan, {Benita Kiat Tee} and Jos Jonkers and {\AA}ke Borg and Ueno, {Naoto T.} and Christos Sotiriou and Alain Viari 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 Ewan Birney and Stunnenberg, {Hendrik G.} and {Van De Vijver}, {Marc J.} and Martens, {John W.M.} and B{\o}rresen-Dale, {Anne Lise} and Richardson, {Andrea L.} and Gu Kong and Gilles Thomas and Stratton, {Michael R.}",

year = "2016",

month = may,

day = "2",

doi = "10.1038/nature17676",

language = "English (US)",

volume = "534",

pages = "47--54",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7605",

}

TY - JOUR

T1 - Landscape of somatic mutations in 560 breast cancer whole-genome sequences

AU - Nik-Zainal, Serena

AU - Davies, Helen

AU - Staaf, Johan

AU - Ramakrishna, Manasa

AU - Glodzik, Dominik

AU - Zou, Xueqing

AU - Martincorena, Inigo

AU - Alexandrov, Ludmil B.

AU - Martin, Sancha

AU - Wedge, David C.

AU - Van Loo, Peter

AU - Ju, Young Seok

AU - Smid, Marcel

AU - Brinkman, Arie B.

AU - Morganella, Sandro

AU - Aure, Miriam R.

AU - Lingjærde, Ole Christian

AU - Langerød, Anita

AU - Ringnér, Markus

AU - Ahn, Sung Min

AU - Boyault, Sandrine

AU - Brock, Jane E.

AU - Broeks, Annegien

AU - Butler, Adam

AU - Desmedt, Christine

AU - Dirix, Luc

AU - Dronov, Serge

AU - Fatima, Aquila

AU - Foekens, John A.

AU - Gerstung, Moritz

AU - Hooijer, Gerrit K.J.

AU - Jang, Se Jin

AU - Jones, David R.

AU - Kim, Hyung Yong

AU - King, Tari A.

AU - Krishnamurthy, Savitri

AU - Lee, Hee Jin

AU - Lee, Jeong Yeon

AU - Li, Yilong

AU - McLaren, Stuart

AU - Menzies, Andrew

AU - Mustonen, Ville

AU - O'Meara, Sarah

AU - Pauporté, Iris

AU - Pivot, Xavier

AU - Purdie, Colin A.

AU - Raine, Keiran

AU - Ramakrishnan, Kamna

AU - Rodríguez-González, F. Germán

AU - Romieu, Gilles

AU - Sieuwerts, Anieta M.

AU - Simpson, Peter T.

AU - Shepherd, Rebecca

AU - Stebbings, Lucy

AU - Stefansson, Olafur A.

AU - Teague, Jon

AU - Tommasi, Stefania

AU - Treilleux, Isabelle

AU - Van Den Eynden, Gert G.

AU - Vermeulen, Peter

AU - Vincent-Salomon, Anne

AU - Yates, Lucy

AU - Caldas, Carlos

AU - Veer, Laura Van t.

AU - Tutt, Andrew

AU - Knappskog, Stian

AU - Tan, Benita Kiat Tee

AU - Jonkers, Jos

AU - Borg, Åke

AU - Ueno, Naoto T.

AU - Sotiriou, Christos

AU - Viari, Alain

AU - Futreal, P. Andrew

AU - Campbell, Peter J.

AU - Span, Paul N.

AU - Van Laere, Steven

AU - Lakhani, Sunil R.

AU - Eyfjord, Jorunn E.

AU - Thompson, Alastair M.

AU - Birney, Ewan

AU - Stunnenberg, Hendrik G.

AU - Van De Vijver, Marc J.

AU - Martens, John W.M.

AU - Børresen-Dale, Anne Lise

AU - Richardson, Andrea L.

AU - Kong, Gu

AU - Thomas, Gilles

AU - Stratton, Michael R.

PY - 2016/5/2

Y1 - 2016/5/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84973594792&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973594792&partnerID=8YFLogxK

U2 - 10.1038/nature17676

DO - 10.1038/nature17676

M3 - Article

C2 - 27135926

AN - SCOPUS:84973594792

SN - 0028-0836

VL - 534

SP - 47

EP - 54

JO - Nature

JF - Nature

IS - 7605

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this