Home LiteratureArticle Details
PMID: 22976474 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.

Human molecular genetics ·Vol. 21 ·No. 24 ·2012-12-15 ·Pages 5373-84

Siddiq A, Couch FJ, Chen GK, Lindström S, Eccles D, Millikan RC, Michailidou K, Stram DO, Beckmann L, Rhie SK, Ambrosone CB, Aittomäki K, Amiano P, Apicella C, Australian Breast Cancer Tissue Bank Investigators, Baglietto L, Bandera EV, Beckmann MW, Berg CD, Bernstein L, Blomqvist C, Brauch H, Brinton L, Bui QM, Buring JE, Buys SS, Campa D, Carpenter JE, Chasman DI, Chang-Claude J, Chen C, Clavel-Chapelon F, Cox A, Cross SS, Czene K, Deming SL, Diasio RB, Diver WR, Dunning AM, Durcan L, Ekici AB, Fasching PA, Familial Breast Cancer Study, Feigelson HS, Fejerman L, Figueroa JD, Fletcher O, Flesch-Janys D, Gaudet MM, GENICA Consortium, Gerty SM, Rodriguez-Gil JL, Giles GG, van Gils CH, Godwin AK, Graham N, Greco D, Hall P, Hankinson SE, Hartmann A, Hein R, Heinz J, Hoover RN, Hopper JL, Hu JJ, Huntsman S, Ingles SA, Irwanto A, Isaacs C, Jacobs KB, John EM, Justenhoven C, Kaaks R, Kolonel LN, Coetzee GA, Lathrop M, Le Marchand L, Lee AM, Lee IM, Lesnick T, Lichtner P, Liu J, Lund E, Makalic E, Martin NG, McLean CA, Meijers-Heijboer H, Meindl A, Miron P, Monroe KR, Montgomery GW, Müller-Myhsok B, Nickels S, Nyante SJ, Olswold C, Overvad K, Palli D, Park DJ, Palmer JR, Pathak H, Peto J, Pharoah P, Rahman N, Rivadeneira F, Schmidt DF, Schmutzler RK, Slager S, Southey MC, Stevens KN, Sinn HP, Press MF, Ross E, Riboli E, Ridker PM, Schumacher FR, Severi G, Dos Santos Silva I, Stone J, Sund M, Tapper WJ, Thun MJ, Travis RC, Turnbull C, Uitterlinden AG, Waisfisz Q, Wang X, Wang Z, Weaver J, Schulz-Wendtland R, Wilkens LR, Van Den Berg D, Zheng W, Ziegler RG, Ziv E, Nevanlinna H, Easton DF, Hunter DJ, Henderson BE, Chanock SJ, Garcia-Closas M, Kraft P, Haiman CA, Vachon CM

Abstract

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

MeSH Terms
Breast Neoplasms/genetics Female Genetic Predisposition to Disease/genetics Genome-Wide Association Study Humans Polymorphism, Single Nucleotide/genetics Receptors, Estrogen/genetics
Chemicals
Receptors, Estrogen
Authors & Affiliations
143 authors, click to expand affiliations / ORCID
Siddiq Afshan
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Couch Fergus J
Chen Gary K
Lindström Sara
Eccles Diana
Millikan Robert C
Michailidou Kyriaki
Stram Daniel O
Beckmann Lars
Rhie Suhn Kyong
Ambrosone Christine B
Aittomäki Kristiina
Amiano Pilar
Apicella Carmel
Australian Breast Cancer Tissue Bank Investigators
Baglietto Laura
Bandera Elisa V
Beckmann Matthias W
Berg Christine D
Bernstein Leslie
Blomqvist Carl
Brauch Hiltrud
Brinton Louise
Bui Quang M
Buring Julie E
Buys Saundra S
Campa Daniele
Carpenter Jane E
Chasman Daniel I
Chang-Claude Jenny
Chen Constance
Clavel-Chapelon Françoise
Cox Angela
Cross Simon S
Czene Kamila
Deming Sandra L
Diasio Robert B
Diver W Ryan
Dunning Alison M
Durcan Lorraine
Ekici Arif B
Fasching Peter A
Familial Breast Cancer Study
Feigelson Heather Spencer
Fejerman Laura
Figueroa Jonine D
Fletcher Olivia
Flesch-Janys Dieter
Gaudet Mia M
GENICA Consortium
Gerty Susan M
Rodriguez-Gil Jorge L
Giles Graham G
van Gils Carla H
Godwin Andrew K
Graham Nikki
Greco Dario
Hall Per
Hankinson Susan E
Hartmann Arndt
Hein Rebecca
Heinz Judith
Hoover Robert N
Hopper John L
Hu Jennifer J
Huntsman Scott
Ingles Sue A
Irwanto Astrid
Isaacs Claudine
Jacobs Kevin B
John Esther M
Justenhoven Christina
Kaaks Rudolf
Kolonel Laurence N
Coetzee Gerhard A
Lathrop Mark
Le Marchand Loic
Lee Adam M
Lee I-Min
Lesnick Timothy
Lichtner Peter
Liu Jianjun
Lund Eiliv
Makalic Enes
Martin Nicholas G
McLean Catriona A
Meijers-Heijboer Hanne
Meindl Alfons
Miron Penelope
Monroe Kristine R
Montgomery Grant W
Müller-Myhsok Bertram
Nickels Stefan
Nyante Sarah J
Olswold Curtis
Overvad Kim
Palli Domenico
Park Daniel J
Palmer Julie R
Pathak Harsh
Peto Julian
Pharoah Paul
Rahman Nazneen
Rivadeneira Fernando
Schmidt Daniel F
Schmutzler Rita K
Slager Susan
Southey Melissa C
Stevens Kristen N
Sinn Hans-Peter
Press Michael F
Ross Eric
Riboli Elio
Ridker Paul M
Schumacher Fredrick R
Severi Gianluca
Dos Santos Silva Isabel
Stone Jennifer
Sund Malin
Tapper William J
Thun Michael J
Travis Ruth C
Turnbull Clare
Uitterlinden Andre G
Waisfisz Quinten
Wang Xianshu
Wang Zhaoming
Weaver Joellen
Schulz-Wendtland Rüdiger
Wilkens Lynne R
Van Den Berg David
Zheng Wei
Ziegler Regina G
Ziv Elad
Nevanlinna Heli
Easton Douglas F
Hunter David J
Henderson Brian E
Chanock Stephen J
Garcia-Closas Montserrat
Kraft Peter
Haiman Christopher A
Vachon Celine M
References (28)
28 references, click to expand
  1. Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers.
    Ann Oncol. 2011 Jan;22 Suppl 1:i11-7 PMID: 21285145
  2. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.
    Hum Mol Genet. 2011 Aug 15;20(16):3289-303 PMID: 21596841
  3. Genome-wide association study identifies three new melanoma susceptibility loci.
    Nat Genet. 2011 Oct 09;43(11):1108-13 PMID: 21983787
  4. A multilevel data integration resource for breast cancer study.
    BMC Syst Biol. 2010 Jun 03;4:76 PMID: 20525248
  5. NordicDB: a Nordic pool and portal for genome-wide control data.
    Eur J Hum Genet. 2010 Dec;18(12):1322-6 PMID: 20664631
  6. Genetics of pigmentation in skin cancer--a review.
    Mutat Res. 2010 Oct;705(2):141-153 PMID: 20601102
  7. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.
    Nat Genet. 2007 Jul;39(7):870-4 PMID: 17529973
  8. ProbABEL package for genome-wide association analysis of imputed data.
    BMC Bioinformatics. 2010 Mar 16;11:134 PMID: 20233392
  9. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.
    Nat Genet. 2011 Oct 30;43(12):1210-4 PMID: 22037553
  10. Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.
    PLoS Genet. 2010 Nov 11;6(11):e1001204 PMID: 21085629
  11. Common regulatory variation impacts gene expression in a cell type-dependent manner.
    Science. 2009 Sep 4;325(5945):1246-50 PMID: 19644074
  12. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies.
    Bioinformatics. 2010 Oct 1;26(19):2474-6 PMID: 20702402
  13. Population substructure and control selection in genome-wide association studies.
    PLoS One. 2008 Jul 02;3(7):e2551 PMID: 18596976
  14. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.
    Nat Genet. 2010 Oct;42(10):885-92 PMID: 20852631
  15. Patterns of cis regulatory variation in diverse human populations.
    PLoS Genet. 2012;8(4):e1002639 PMID: 22532805
  16. Rationale, design, and methodology of the Women's Genome Health Study: a genome-wide association study of more than 25,000 initially healthy american women.
    Clin Chem. 2008 Feb;54(2):249-55 PMID: 18070814
  17. Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice.
    Hum Mol Genet. 2009 Apr 15;18(8):1395-404 PMID: 19168544
  18. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.
    PLoS Genet. 2011 Feb 03;7(2):e1002003 PMID: 21304890
  19. FunciSNP: an R/bioconductor tool integrating functional non-coding data sets with genetic association studies to identify candidate regulatory SNPs.
    Nucleic Acids Res. 2012 Oct;40(18):e139 PMID: 22684628
  20. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups.
    JAMA. 2007 Dec 26;298(24):2869-76 PMID: 18159056
  21. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma.
    Nat Genet. 2008 Jul;40(7):886-91 PMID: 18488027
  22. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1.
    Nat Genet. 2009 Mar;41(3):324-8 PMID: 19219042
  23. Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading.
    Cancer. 1984 Nov 15;54(10):2237-42 PMID: 6488142
  24. Mapping and analysis of chromatin state dynamics in nine human cell types.
    Nature. 2011 May 5;473(7345):43-9 PMID: 21441907
  25. Sun exposure, vitamin D receptor gene polymorphisms, and breast cancer risk in a multiethnic population.
    Am J Epidemiol. 2007 Dec 15;166(12):1409-19 PMID: 17934201
  26. Common breast cancer susceptibility loci are associated with triple-negative breast cancer.
    Cancer Res. 2011 Oct 1;71(19):6240-9 PMID: 21844186
  27. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.
    J Natl Cancer Inst. 2011 Feb 2;103(3):250-63 PMID: 21191117
  28. Mapping the genetic architecture of gene expression in human liver.
    PLoS Biol. 2008 May 6;6(5):e107 PMID: 18462017
Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/dds381
Published
2012-12-15
Epub
2012-00-13
Pages
5373-84
Language
English
Region
England
NLM ID
9208958
PMCID
PMC3510753
Subset
IM
Grants
NCI NIH HHS · K01 CA160607 · United States
NIEHS NIH HHS · P30 ES010126 · United States
NCI NIH HHS · U01-CA69417 · United States
NCI NIH HHS · CA49449 · United States
NCI NIH HHS · CA67262 · United States
NCI NIH HHS · CA047988 · United States
NCI NIH HHS · U01-CA98758 · United States
NCI NIH HHS · CA-06-503 · United States
NCI NIH HHS · CA50385 · United States
NCI NIH HHS · 5UO1CA098233 · United States
NCI NIH HHS · CA116201 · United States
NCI NIH HHS · R01-CA73629 · United States
NCI NIH HHS · R25 CA092049 · United States
Wellcome Trust · United Kingdom
NHLBI NIH HHS · HL04385 · United States
NCI NIH HHS · CA 65725 · United States
NCI NIH HHS · U01-CA98233 · United States
NCI NIH HHS · U01-CA98710 · United States
NCI NIH HHS · U01-CA98216 · United States
NCI NIH HHS · R01-CA63464 · United States
NCI NIH HHS · RFA-CA-06-503 · United States
NCI NIH HHS · P30 CA016056-32 · United States
Cancer Research UK · 11022 · United Kingdom
NCI NIH HHS · CA122340 · United States
NCI NIH HHS · CA87969 · United States
NCI NIH HHS · R01-CA100598 · United States
NCI NIH HHS · P30 CA016086 · United States
Medical Research Council · G0700491 · United Kingdom
NCI NIH HHS · P50 CA058223 · United States
NCI NIH HHS · P50-CA58223 · United States
NCI NIH HHS · P50 CA116201 · United States
NCI NIH HHS · CA120120 · United States
NCI NIH HHS · R01 CA077398 · United States
Intramural NIH HHS · United States
NCI NIH HHS · 5U01CA113916 · United States
NCI NIH HHS · U01 CA69638 · United States
NHLBI NIH HHS · HL080467 · United States
NCI NIH HHS · CA132839 · United States
NCI NIH HHS · R01-CA77305 · United States
NCI NIH HHS · R01-CA100374 · United States
NCI NIH HHS · R01 CA122340 · United States
NCI NIH HHS · U01CA69631 · United States
Cancer Research UK · 10118 · United Kingdom
NCI NIH HHS · P30 CA071789 · United States
NCI NIH HHS · P50 CA089393 · United States
NCI NIH HHS · R01 CA120120 · United States
NCI NIH HHS · K24 CA169004 · United States
NCI NIH HHS · CA109147 · United States
NCI NIH HHS · R37-CA54281 · United States
NICHD NIH HHS · N01-HD-3-3175 · United States
NIEHS NIH HHS · P30-ES10126 · United States
Cancer Research UK · 10124 · United Kingdom
Breast Cancer Now · 2004NOV49 · United Kingdom
External Links
PubMed source DOI: 10.1093/hmg/dds381 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2