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

被引：278

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

来源：

NATURE GENETICS | 2017年 / 49卷 / 12期

基金：

美国国家卫生研究院; 加拿大健康研究院; 英国医学研究理事会;

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

页码：1767 / 1778

页数：12

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