Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

被引：92

作者：

Ghoussaini, Maya ^{[1
]}

Edwards, Stacey L. ^{[2
,3
]}

Michailidou, Kyriaki ^{[4
]}

Nord, Silje ^{[5
]}

Lari, Richard Cowper-Sal ^{[6
]}

Desai, Kinjal ^{[6
,7
]}

Kar, Siddhartha ^{[4
]}

Hillman, Kristine M. ^{[2
,3
]}

Kaufmann, Susanne ^{[2
,3
]}

Glubb, Dylan M. ^{[2
]}

Beesley, Jonathan ^{[2
]}

Dennis, Joe ^{[4
]}

Bolla, Manjeet K. ^{[4
]}

Wang, Qin ^{[4
]}

Dicks, Ed ^{[1
]}

Guo, Qi ^{[1
]}

Schmidt, Marjanka K. ^{[8
]}

Shah, Mitul ^{[1
]}

Luben, Robert ^{[4
]}

Brown, Judith ^{[4
]}

Czene, Kamila ^{[9
]}

Darabi, Hatef ^{[9
]}

Eriksson, Mikael ^{[9
]}

Klevebring, Daniel ^{[9
]}

Bojesen, Stig E. ^{[10
,11
,12
]}

Nordestgaard, Borge G. ^{[10
,11
,12
]}

Nielsen, Sune F. ^{[10
,11
]}

Flyger, Henrik ^{[13
]}

Lambrechts, Diether ^{[14
,15
]}

Thienpont, Bernard ^{[15
,16
]}

Neven, Patrick ^{[17
,18
]}

Wildiers, Hans ^{[17
,18
]}

Broeks, Annegien ^{[8
]}

Van't Veer, Laura J. ^{[8
]}

Rutgers, Emiel J. Th ^{[8
]}

Couch, Fergus J. ^{[19
]}

Olson, Janet E. ^{[20
]}

Hallberg, Emily ^{[20
]}

Vachon, Celine ^{[20
]}

Chang-Claude, Jenny ^{[21
]}

Rudolph, Anja ^{[21
]}

Seibold, Petra ^{[21
]}

Flesch-Janys, Dieter ^{[22
,23
]}

Peto, Julian ^{[24
]}

dos-Santos-Silva, Isabel ^{[24
]}

Gibson, Lorna ^{[24
]}

Nevanlinna, Heli ^{[25
]}

Muranen, Taru A. ^{[25
]}

Aittomaki, Kristiina ^{[26
]}

Blomqvist, Carl ^{[27
]}

机构：

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

[2] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia

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

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

[5] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway

[6] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5T 2M9, Canada

[7] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA

[8] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands

[9] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden

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

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

[12] Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark

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

[14] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Leuven, Belgium

[15] VIB, VRC, B-3000 Leuven, Belgium

[16] Univ Leuven, Vesalius Res Ctr, B-3000 Leuven, Belgium

[17] Univ Leuven, Dept Oncol, B-3000 Leuven, Belgium

[18] Univ Hosp Leuven, Multidisciplinary Breast Ctr, Dept Gen Med Oncol, B-3000 Leuven, Belgium

[19] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[20] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA

[21] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany

[22] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, D-20246 Hamburg, Germany

[23] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany

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

[25] Helsinki Univ Cent Hosp, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland

[26] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Clin Genet, FI-00029 Helsinki, Finland

[27] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, FI-00029 Helsinki, Finland

[28] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore

[29] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea

[30] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul 151742, South Korea

[31] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea

[32] Seoul Natl Univ, Coll Med, Dept Surg, Seoul 110799, South Korea

[33] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 8128582, Japan

[34] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan

[35] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi 4848681, Japan

[36] Aichi Canc Ctr Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi 4848681, Japan

[37] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Environm Epidemiol Canc, F-94807 Villejuif, France

[38] Univ Paris Sud, UMRS 1018, F-94807 Villejuif, France

[39] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany

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

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

[42] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[43] Crt Invest Red Enfermedades Raras CIBERER, Valencia 46010, Spain

[44] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid 28029, Spain

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

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

[47] Hosp Monte Naranco, Serv Anat Pathol, Oviedo 33012, Spain

[48] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med,Div Epidemiol, Nashville, TN 37203 USA

[49] Shanghai Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China

[50] Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 加拿大健康研究院; 新加坡国家研究基金会; 美国国家卫生研究院; 芬兰科学院;

关键词：

FACTOR-BINDING PROTEIN-5; CYCLIN D1 EXPRESSION; FUNCTIONAL VARIANTS; GROWTH; ASSOCIATION; FOXA1; PHASE;

D O I：

10.1038/ncomms5999

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：

07 ; 0710 ; 09 ;

摘要：

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval = 0.84 - 0.87; P = 1.7 x 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

引用

页数：12

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