Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

被引:270
作者
Milne, Roger L. [1 ,2 ]
Kuchenbaecker, Karoline B. [3 ,4 ]
Michailidou, Kyriaki [3 ,5 ]
Beesley, Jonathan [6 ]
Kar, Siddhartha [7 ]
Lindstrom, Sara [8 ,9 ]
Hui, Shirley [10 ]
Lemacon, Audrey [11 ]
Soucy, Penny [11 ]
Dennis, Joe [3 ]
Jiang, Xia [9 ]
Rostamianfar, Asha [10 ]
Finucane, Hilary [9 ,12 ]
Bolla, Manjeet K. [3 ]
McGuffog, Lesley [3 ]
Wang, Qin [3 ]
Aalfs, Cora M. [13 ]
Adams, Marcia [14 ]
Adlard, Julian [15 ]
Agata, Simona [16 ]
Ahmed, Shahana [7 ]
Ahsan, Habibul [17 ]
Aittomaki, Kristiina [18 ]
Al-Ejeh, Fares [19 ]
Allen, Jamie [3 ]
Ambrosone, Christine B. [20 ]
Amos, Christopher I. [21 ]
Andrulis, Irene L. [22 ,23 ]
Anton-Culver, Hoda [24 ]
Antonenkova, Natalia N. [25 ]
Arndt, Volker [26 ]
Arnold, Norbert [27 ]
Aronson, Kristan J. [28 ,29 ]
Auber, Bernd [30 ]
Auer, Paul L. [31 ,32 ]
Ausems, Margreet G. E. M. [33 ]
Azzollini, Jacopo [34 ]
Bacot, Francois [35 ,36 ]
Balmana, Judith [37 ]
Barile, Monica [38 ]
Barjhoux, Laure [39 ]
Barkardottir, Rosa B. [40 ,41 ]
Barrdahl, Myrto [42 ]
Barnes, Daniel [3 ]
Barrowdale, Daniel [3 ]
Baynes, Caroline [7 ]
Beckmann, Matthias W. [43 ]
Benitez, Javier [44 ,45 ,46 ]
Bermisheva, Marina [47 ]
Bernstein, Leslie [48 ]
机构
[1] Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia
[2] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia
[3] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England
[4] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Hinxton, England
[5] Cyprus Inst Neurol & Genet, Dept Elect Microscopy Mol Pathol, Nicosia, Cyprus
[6] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia
[7] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England
[8] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA
[9] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA
[10] Univ Toronto, Donnelly Ctr, Toronto, ON, Canada
[11] Laval Univ, Ctr Hosp Univ Quebec, Res Ctr, Genom Ctr, Quebec City, PQ, Canada
[12] MIT, Dept Math, Cambridge, MA 02139 USA
[13] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands
[14] Johns Hopkins Univ, Sch Med, Inst Med Genet, CIDR, Baltimore, MD USA
[15] Chapel Allerton Hosp, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England
[16] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy
[17] Univ Chicago, Ctr Canc Epidemiol & Prevent, Chicago, IL 60637 USA
[18] Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland
[19] QIMR Berghofer Med Res Inst, personalised Med Team, Brisbane, Qld, Australia
[20] Roswell Pk Canc Inst, Buffalo, NY 14263 USA
[21] Dartmouth Coll, Ctr Genom Med, Dept Biomed Data Sci, Geisel Sch Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA
[22] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada
[23] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
[24] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA
[25] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS
[26] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany
[27] Univ Hosp Schleswig Holstein, Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Dept Gynecol & Obstet, Campus Kiel, Kiel, Germany
[28] Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada
[29] Queens Univ, Canc Res Inst, Kingston, ON, Canada
[30] Hannover Med Sch, Inst Human Genet, Hannover, Germany
[31] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA
[32] Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA
[33] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands
[34] Fdn IRCCS, Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy
[35] McGill Univ, Montreal, PQ, Canada
[36] Genom Quebec Innovat Ctr, Montreal, PQ, Canada
[37] Univ Hosp, Dept Med Oncol, Barcelona, Spain
[38] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy
[39] Ctr Leon Berard, Batiment Cheney D, Lyon, France
[40] Landspitali, Dept Pathol, Lab Cell Biol, Reykjavik, Iceland
[41] Univ Iceland, BMC Biomed Ctr, Fac Med, Reykjavik, Iceland
[42] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany
[43] Univ Hosp, Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Dept Gynaecol & Obstet, Erlangen, Germany
[44] Spanish Natl Canc Res Ctr CNIO, Ctr Nacl Genotipado CEGEN, Human Genotyping Unit, Human Canc Genet Programme, Madrid, Spain
[45] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain
[46] Spanish Network Rare Dis CIBERER, Madrid, Spain
[47] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia
[48] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA
[49] Univ Clermont Auvergne, INSERM, Ctr Jean Perrin, U1240,Imagerie Mol & Strategies Theranost, Clermont Ferrand, France
[50] Clin Canc Genet, Duarte, CA USA
基金
加拿大健康研究院; 英国医学研究理事会; 美国国家卫生研究院;
关键词
GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; FUNCTIONAL VARIANTS; MUTATION CARRIERS; OVARIAN CANCERS; COMMON VARIANTS; MODIFIERS; ENHANCER; REVEALS;
D O I
10.1038/ng.3785
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 x 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
引用
收藏
页码:1767 / 1778
页数:12
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