Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

被引：167

作者：

French, Juliet D. ^{[1
]}

Ghoussaini, Maya ^{[2
]}

Edwards, Stacey L. ^{[1
]}

Meyer, Kerstin B. ^{[3
]}

Michailidou, Kyriaki ^{[4
]}

Ahmed, Shahana ^{[2
]}

Khan, Sofia ^{[5
,6
]}

Maranian, Mel J. ^{[2
]}

O'Reilly, Martin ^{[3
]}

Hillman, Kristine M. ^{[1
]}

Betts, Joshua A. ^{[1
]}

Carro, Thomas ^{[3
]}

Bailey, Peter J. ^{[1
]}

Dicks, Ed ^{[2
]}

Beesley, Jonathan ^{[7
]}

Tyrer, Jonathan ^{[2
]}

Maia, Ana-Teresa ^{[3
]}

Beck, Andrew ^{[8
,9
]}

Knoblauch, Nicholas W. ^{[8
,9
]}

Chen, Constance ^{[10
]}

Kraft, Peter ^{[10
,11
]}

Barnes, Daniel ^{[4
]}

Gonzalez-Neira, Anna ^{[12
]}

Rosario Alonso, M. ^{[12
]}

Herrero, Daniel ^{[12
]}

Tessier, Daniel C. ^{[13
,14
]}

Vincent, Daniel ^{[13
,14
]}

Bacot, Francois ^{[13
,14
]}

Luccarini, Craig ^{[2
]}

Baynes, Caroline ^{[2
]}

Conroy, Don ^{[2
]}

Dennis, Joe ^{[4
]}

Bolla, Manjeet K. ^{[4
]}

Wang, Qin ^{[4
]}

Hopper, John L. ^{[15
]}

Southey, Melissa C. ^{[16
]}

Schmidt, Marjanka K. ^{[17
,18
]}

Broeks, Annegien ^{[18
]}

Verhoef, Senno ^{[19
]}

Cornelissen, Sten ^{[18
]}

Muir, Kenneth ^{[20
]}

Lophatananon, Artitaya ^{[20
]}

Stewart-Brown, Sarah ^{[20
]}

Siriwanarangsan, Pomthep ^{[21
]}

Fasching, Peter A. ^{[22
,23
]}

Loehberg, Christian R. ^{[23
]}

Ekici, Arif B. ^{[24
]}

Beckmann, Matthias W. ^{[23
]}

Peto, Julian ^{[25
]}

Silva, Isabel dos Santos ^{[25
]}

机构：

[1] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia

[2] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England

[3] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge CB2 ORE, England

[4] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England

[5] Univ Helsinki, Dept Obstet & Gynecol, Helsinki 00029, Finland

[6] Univ Helsinki, Cent Hosp, Helsinki 00029, Finland

[7] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4029, Australia

[8] Harvard Univ, Sch Med, Boston, MA 02215 USA

[9] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[10] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA

[11] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA

[12] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain

[13] Ctr Innovat Genome Quebec, Montreal, PQ H3A 0G1, Canada

[14] McGill Univ, Montreal, PQ H3A 0G1, Canada

[15] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia

[16] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia

[17] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, NL-1066 CX Amsterdam, Netherlands

[18] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands

[19] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, NL-1066 CX Amsterdam, Netherlands

[20] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England

[21] Minist Publ Hlth, Bangkok 10400, Thailand

[22] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA

[23] Univ Hosp Erlangen, Dept Obstet & Gynecol, Univ Breast Ctr Franconia, D-91054 Erlangen, Germany

[24] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany

[25] Univ London London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Dept, London WC1E 7HT, England

[26] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[27] Guys & St Thomas NHS Fdn Trust Partnership Kings, NIHR Comprehens Biomed Res Ctr, Div Canc Studies, London SE1 9RT, England

[28] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford 0X3 7BN, England

[29] Univ Oxford, Oxford Biomed Res Ctr, Oxford 0X3 7BN, England

[30] Galway Univ Hosp, Inst Clin Sci, Galway, Ireland

[31] Natl Univ Ireland, Galway, Ireland

[32] Heidelberg Univ, Dept Obstet & Gynecol, D-69115 Heidelberg, Germany

[33] Heidelberg Univ, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany

[34] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany

[35] INSERM, Natl Inst Hlth & Med Res, CESP Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc Team,U1018, F-94807 Villejuif, France

[36] Univ Paris 11, UMRS 1018, F-94807 Villejuif, France

[37] Univ Paris Sorbonne Cite, UMR S775, INSERM, F-75270 Paris 06, France

[38] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark

[39] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark

[40] Copenhagen Univ Hosp, Dept Breast Surg, Herlev Hosp, DK-2730 Herlev, Denmark

[41] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Madrid 28029, Spain

[42] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain

[43] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo 33012, Spain

[44] Ctr Invest Red Enfermedades Raras CIBERER, Madrid 28029, Spain

[45] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA

[46] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany

[47] Saarland Canc Registry, D-66024 Saarbrucken, Germany

[48] Tech Univ Munich, Div Gynaecol & Obstet, D-81675 Munich, Germany

[49] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[50] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, D-50931 Cologne, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2013年 / 92卷 / 04期

关键词：

GENOME-WIDE ASSOCIATION; GROWTH-FACTOR RECEPTOR-2; ESTROGEN-RECEPTOR; DOWN-REGULATION; MULTIPLE LOCI; CELL-CYCLE; GATA-3; GENE; ALPHA; DIFFERENTIATION;

D O I：

10.1016/j.ajhg.2013.01.002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

引用

页码：489 / 503

页数：15

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