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

被引：1667

作者：

Nik-Zainal, Serena ^{[1
,2
]}

Davies, Helen ^{[1
]}

Staaf, Johan ^{[3
]}

Ramakrishna, Manasa ^{[1
]}

Glodzik, Dominik ^{[1
]}

Zou, Xueqing ^{[1
]}

Martincorena, Inigo ^{[1
]}

Alexandrov, Ludmil B. ^{[1
,4
,5
]}

Martin, Sancha ^{[1
]}

Wedge, David C. ^{[1
]}

Van Loo, Peter ^{[1
,6
]}

Ju, Young Seok ^{[1
]}

Smid, Marcel ^{[7
,8
]}

Brinkman, Arie B. ^{[9
]}

Morganella, Sandro ^{[10
]}

Aure, Miriam R. ^{[11
,12
]}

Lingjaerde, Ole Christian ^{[12
,13
]}

Langerod, Anita ^{[11
,12
]}

Ringner, Markus ^{[3
]}

Ahn, Sung-Min ^{[14
]}

Boyault, Sandrine ^{[15
]}

Brock, Jane E. ^{[16
]}

Broeks, Annegien ^{[17
]}

Butler, Adam ^{[1
]}

Desmedt, Christine ^{[18
]}

Dirix, Luc ^{[19
]}

Dronov, Serge ^{[1
]}

Fatima, Aquila ^{[20
]}

Foekens, John A. ^{[7
,8
]}

Gerstung, Moritz ^{[1
]}

Hooijer, Gerrit K. J. ^{[21
]}

Jang, Se Jin ^{[22
]}

Jones, David R. ^{[1
]}

Kim, Hyung-Yong ^{[23
]}

King, Tari A. ^{[24
]}

Krishnamurthy, Savitri ^{[25
]}

Lee, Hee Jin ^{[22
]}

Lee, Jeong-Yeon ^{[26
]}

Li, Yilong ^{[1
]}

McLaren, Stuart ^{[1
]}

Menzies, Andrew ^{[1
]}

Mustonen, Ville ^{[1
]}

O'Meara, Sarah ^{[1
]}

Pauporte, Iris ^{[27
]}

Pivot, Xavier ^{[28
]}

Purdie, Colin A. ^{[29
]}

Raine, Keiran ^{[1
]}

Ramakrishnan, Kamna ^{[1
]}

Rodriguez-Gonzalez, F. German ^{[7
,8
]}

Romieu, Gilles ^{[30
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[2] Cambridge Univ Hosp NHS Fdn Trust, East Anglian Med Genet Serv, Cambridge CB2 9NB, England

[3] Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden

[4] Los Alamos Natl Lab, Theoret Biol & Biophys T6, POB 1663, Los Alamos, NM 87545 USA

[5] Los Alamos Natl Lab, Ctr Nonlinear Studies, POB 1663, Los Alamos, NM 87545 USA

[6] Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium

[7] Erasmus Univ, Med Ctr, Erasmus MC Canc Inst, Dept Med Oncol, NL-3015 CN Rotterdam, Netherlands

[8] Erasmus Univ, Med Ctr, Canc Genom Netherlands, NL-3015 CN Rotterdam, Netherlands

[9] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 GA Nijmegen, Netherlands

[10] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[11] Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, N-0310 Oslo, Norway

[12] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0310 Oslo, Norway

[13] Univ Oslo, Dept Comp Sci, Oslo, Norway

[14] Gachon Univ, Gil Med Ctr, Gachon Inst Genome Med & Sci, Inchon, South Korea

[15] Ctr Leon Berard, Translat Res Lab, 28 Rue Laennec, F-69373 Lyon 08, France

[16] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[17] Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands

[18] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab, Bd Waterloo 121, B-1000 Brussels, Belgium

[19] Univ Antwerp, Fac Med & Hlth Sci, Oncol Res Ctr, Translat Canc Res Unit, B-2020 Antwerp, Belgium

[20] Dana Farber Canc Inst, Boston, MA 02215 USA

[21] Univ Amsterdam, Acad Med Ctr, Dept Pathol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[22] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Ulsan 680749, South Korea

[23] Hanyang Univ, Coll Med, Dept Pathol, Seoul 133791, South Korea

[24] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA

[25] Univ Texas MD Anderson Canc Ctr, Morgan Welch Inflammatory Breast Canc Res Program, 1515 Holcombe Boulevard, Houston, TX 77030 USA

[26] Hanyang Univ, IBBR, Seoul 133791, South Korea

[27] Natl Canc Inst, Div Res, Dept Clin Res, 52 Ave Morizet, F-92513 Boulogne, France

[28] Univ Hosp Minjoz, INSERM UMR 1098, Bd Fleming, F-25000 Besancon, France

[29] Ninewells Hosp & Med Sch, Dept Pathol, Dundee DD1 9SY, Scotland

[30] ICM Inst Reg Canc, Oncol Senol, Montpellier, France

[31] Univ Queensland, UQ Ctr Clin Res, Brisbane, Qld 4029, Australia

[32] Univ Queensland, Sch Med, Brisbane, Qld 4029, Australia

[33] Univ Iceland, Fac Med, Canc Res Lab, IS-101 Reykjavik, Iceland

[34] IRCCS Ist Tumori Giovanni Paolo II, Bari, Italy

[35] Ctr Leon Berard, Dept Pathol, 28 Rue Laennec, F-69373 Lyon 08, France

[36] GZA Hosp Sint Augustinus, Dept Pathol, Antwerp, Belgium

[37] Paris Sci Lettres Univ, Inst Curie, Dept Pathol, 26 Rue Ulm, F-75248 Paris 05, France

[38] INSERM U934, 26 Rue Ulm, F-75248 Paris 05, France

[39] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England

[40] Kings Coll London, Breast Canc Now Res Unit, London SE1 9RT, England

[41] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London SW3 6JB, England

[42] Univ Bergen, Dept Clin Sci, N-5020 Bergen, Norway

[43] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway

[44] Natl Canc Ctr Singapore, 11 Hosp Dr, Singapore 169610, Singapore

[45] Singapore Gen Hosp, Outram Rd, Singapore 169608, Singapore

[46] INRIA Grenoble Rhone Alpes, Equipe Erable, 655 Ave Europe, F-38330 Montbonnot St Martin, France

[47] Ctr Leon Berard, Synergie Lyon Canc, 28 Rue Laennec, F-69373 Lyon 08, France

[48] UT MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77230 USA

[49] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, Dept Lab Med, NL-6525 GA Nijmegen, Netherlands

[50] Royal Brisbane & Womens Hosp, Pathol Queensland, Brisbane, Qld 4029, Australia

来源：

NATURE | 2016年 / 534卷 / 7605期

基金：

英国惠康基金; 新加坡国家研究基金会; 欧盟第七框架计划; 欧洲研究理事会; 美国能源部;

关键词：

TERT PROMOTER MUTATIONS; INVERTED REPEATS; GENE FUSIONS; COPY NUMBER; DNA-REPAIR; SIGNATURES; TUMORS; CARCINOMAS; DISCOVERY; HETEROZYGOSITY;

D O I：

10.1038/nature17676

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：47 / +

页数：20

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