Home LiteratureArticle Details
PMID: 24290378 Published · ppublish English Journal Article

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

American journal of human genetics ·Vol. 93 ·No. 6 ·2013-12-05 ·Pages 1046-60

Meyer KB, O'Reilly M, Michailidou K, Carlebur S, Edwards SL, French JD, Prathalingham R, Dennis J, Bolla MK, Wang Q, de Santiago I, Hopper JL, Tsimiklis H, Apicella C, Southey MC, Schmidt MK, Broeks A, Van 't Veer LJ, Hogervorst FB, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Lux MP, Ekici AB, Beckmann MW, Peto J, Dos Santos Silva I, Fletcher O, Johnson N, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Zamora MP, Arias JI, Benitez J, Neuhausen S, Anton-Culver H, Ziogas A, Dur CC, Brenner H, Müller H, Arndt V, Stegmaier C, Meindl A, Schmutzler RK, Engel C, Ditsch N, Brauch H, Brüning T, Ko YD, GENICA Network, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Yatabe Y, Dörk T, Helbig S, Bogdanova NV, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Chenevix-Trench G, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Thienpont B, Christiaens MR, Smeets A, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Bernard L, Couch FJ, Olson JE, Wang X, Purrington K, Giles GG, Severi G, Baglietto L, McLean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Phuah SY, Kristensen V, Grenaker Alnæs G, Børresen-Dale AL, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar RA, Seynaeve CM, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Darabi H, Eriksson K, Hooning MJ, Martens JW, van den Ouweland AM, van Deurzen CH, Hall P, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Reed MW, Blot W, Signorello LB, Cai Q, Pharoah PD, Ghoussaini M, Harrington P, Tyrer J, Kang D, Choi JY, Park SK, Noh DY, Hartman M, Hui M, Lim WY, Buhari SA, Hamann U, Försti A, Rüdiger T, Ulmer HU, Jakubowska A, Lubinski J, Jaworska K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Vachon C, Slager S, Fostira F, Pilarski R, Shen CY, Hsiung CN, Wu PE, Hou MF, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, Ponder BA, Dunning AM, Easton DF

Abstract

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.

MeSH Terms
Alleles Asians/genetics Binding Sites Blacks/genetics Breast Neoplasms/genetics,metabolism Case-Control Studies Cell Line, Tumor Chromatin Immunoprecipitation Chromosome Mapping E2F1 Transcription Factor/genetics,metabolism Female Gene Expression Regulation, Neoplastic Genetic Association Studies Genetic Loci Haplotypes Hepatocyte Nuclear Factor 3-alpha/genetics,metabolism Humans Position-Specific Scoring Matrices Promoter Regions, Genetic Protein Binding RNA Interference Receptor, Fibroblast Growth Factor, Type 2/genetics,metabolism Whites/genetics
Chemicals
E2F1 Transcription Factor FOXA1 protein, human Hepatocyte Nuclear Factor 3-alpha Receptor, Fibroblast Growth Factor, Type 2
Authors & Affiliations
203 authors, click to expand affiliations / ORCID
Meyer Kerstin B
CRUK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Electronic address: kerstin.meyer@cruk.cam.ac.uk.
O'Reilly Martin
Michailidou Kyriaki
Carlebur Saskia
Edwards Stacey L
French Juliet D
Prathalingham Radhika
Dennis Joe
Bolla Manjeet K
Wang Qin
de Santiago Ines
Hopper John L
Tsimiklis Helen
Apicella Carmel
Southey Melissa C
Schmidt Marjanka K
Broeks Annegien
Van 't Veer Laura J
Hogervorst Frans B
Muir Kenneth
Lophatananon Artitaya
Stewart-Brown Sarah
Siriwanarangsan Pornthep
Fasching Peter A
Lux Michael P
Ekici Arif B
Beckmann Matthias W
Peto Julian
Dos Santos Silva Isabel
Fletcher Olivia
Johnson Nichola
Sawyer Elinor J
Tomlinson Ian
Kerin Michael J
Miller Nicola
Marme Federick
Schneeweiss Andreas
Sohn Christof
Burwinkel Barbara
Guénel Pascal
Truong Thérèse
Laurent-Puig Pierre
Menegaux Florence
Bojesen Stig E
Nordestgaard Børge G
Nielsen Sune F
Flyger Henrik
Milne Roger L
Zamora M Pilar
Arias Jose I
Benitez Javier
Neuhausen Susan
Anton-Culver Hoda
Ziogas Argyrios
Dur Christina C
Brenner Hermann
Müller Heiko
Arndt Volker
Stegmaier Christa
Meindl Alfons
Schmutzler Rita K
Engel Christoph
Ditsch Nina
Brauch Hiltrud
Brüning Thomas
Ko Yon-Dschun
GENICA Network
Nevanlinna Heli
Muranen Taru A
Aittomäki Kristiina
Blomqvist Carl
Matsuo Keitaro
Ito Hidemi
Iwata Hiroji
Yatabe Yasushi
Dörk Thilo
Helbig Sonja
Bogdanova Natalia V
Lindblom Annika
Margolin Sara
Mannermaa Arto
Kataja Vesa
Kosma Veli-Matti
Hartikainen Jaana M
Chenevix-Trench Georgia
kConFab Investigators
Australian Ovarian Cancer Study Group
Wu Anna H
Tseng Chiu-Chen
Van Den Berg David
Stram Daniel O
Lambrechts Diether
Thienpont Bernard
Christiaens Marie-Rose
Smeets Ann
Chang-Claude Jenny
Rudolph Anja
Seibold Petra
Flesch-Janys Dieter
Radice Paolo
Peterlongo Paolo
Bonanni Bernardo
Bernard Loris
Couch Fergus J
Olson Janet E
Wang Xianshu
Purrington Kristen
Giles Graham G
Severi Gianluca
Baglietto Laura
McLean Catriona
Haiman Christopher A
Henderson Brian E
Schumacher Fredrick
Le Marchand Loic
Simard Jacques
Goldberg Mark S
Labrèche France
Dumont Martine
Teo Soo-Hwang
Yip Cheng-Har
Phuah Sze-Yee
Kristensen Vessela
Grenaker Alnæs Grethe
Børresen-Dale Anne-Lise
Zheng Wei
Deming-Halverson Sandra
Shrubsole Martha
Long Jirong
Winqvist Robert
Pylkäs Katri
Jukkola-Vuorinen Arja
Kauppila Saila
Andrulis Irene L
Knight Julia A
Glendon Gord
Tchatchou Sandrine
Devilee Peter
Tollenaar Robert A E M
Seynaeve Caroline M
García-Closas Montserrat
Figueroa Jonine
Chanock Stephen J
Lissowska Jolanta
Czene Kamila
Darabi Hartef
Eriksson Kimael
Hooning Maartje J
Martens John W M
van den Ouweland Ans M W
van Deurzen Carolien H M
Hall Per
Li Jingmei
Liu Jianjun
Humphreys Keith
Shu Xiao-Ou
Lu Wei
Gao Yu-Tang
Cai Hui
Cox Angela
Reed Malcolm W R
Blot William
Signorello Lisa B
Cai Qiuyin
Pharoah Paul D P
Ghoussaini Maya
Harrington Patricia
Tyrer Jonathan
Kang Daehee
Choi Ji-Yeob
Park Sue K
Noh Dong-Young
Hartman Mikael
Hui Miao
Lim Wei-Yen
Buhari Shaik A
Hamann Ute
Försti Asta
Rüdiger Thomas
Ulmer Hans-Ulrich
Jakubowska Anna
Lubinski Jan
Jaworska Katarzyna
Durda Katarzyna
Sangrajrang Suleeporn
Gaborieau Valerie
Brennan Paul
McKay James
Vachon Celine
Slager Susan
Fostira Florentia
Pilarski Robert
Shen Chen-Yang
Hsiung Chia-Ni
Wu Pei-Ei
Hou Ming-Feng
Swerdlow Anthony
Ashworth Alan
Orr Nick
Schoemaker Minouk J
Ponder Bruce A J
Dunning Alison M
Easton Douglas F
References (34)
34 references, click to expand
  1. FOXA1 in breast cancer.
    Expert Rev Mol Med. 2009 Mar 05;11:e8 PMID: 19261198
  2. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.
    PLoS Biol. 2008 May 6;6(5):e108 PMID: 18462018
  3. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer.
    Nature. 2012 Jan 04;481(7381):389-93 PMID: 22217937
  4. Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men.
    PLoS Genet. 2011 Sep;7(9):e1002290 PMID: 21949660
  5. 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
  6. Allele-specific regulation of FGFR2 expression is cell type-dependent and may increase breast cancer risk through a paracrine stimulus involving FGF10.
    Breast Cancer Res. 2011 Jul 18;13(4):R72 PMID: 21767389
  7. Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression.
    Nat Genet. 2012 Nov;44(11):1191-8 PMID: 23001124
  8. Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1.
    EMBO J. 2011 Jun 24;30(15):3019-27 PMID: 21701558
  9. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
    Nature. 2012 Apr 18;486(7403):346-52 PMID: 22522925
  10. Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes.
    Breast Cancer Res Treat. 2012 Jun;133(3):843-51 PMID: 21748294
  11. Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state.
    Mol Syst Biol. 2011 Aug 30;7:526 PMID: 21878914
  12. Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
    Nat Genet. 2013 Apr;45(4):353-61, 361e1-2 PMID: 23535729
  13. Integrative eQTL-based analyses reveal the biology of breast cancer risk loci.
    Cell. 2013 Jan 31;152(3):633-41 PMID: 23374354
  14. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
    Nat Genet. 2013 Apr;45(4):371-84, 384e1-2 PMID: 23535731
  15. Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis.
    Dev Biol. 2008 Sep 1;321(1):77-87 PMID: 18585375
  16. Genome-wide analysis of estrogen receptor binding sites.
    Nat Genet. 2006 Nov;38(11):1289-97 PMID: 17013392
  17. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.
    PLoS Genet. 2008 Apr 25;4(4):e1000054 PMID: 18437204
  18. FOXA1 is a key determinant of estrogen receptor function and endocrine response.
    Nat Genet. 2011 Jan;43(1):27-33 PMID: 21151129
  19. Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans.
    Hum Mol Genet. 2011 Nov 15;20(22):4491-503 PMID: 21852243
  20. FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women.
    Carcinogenesis. 2010 Aug;31(8):1417-23 PMID: 20554749
  21. rs2981582 is associated with FGFR2 expression in normal breast.
    Cancer Genet Cytogenet. 2010 Mar;197(2):193-4 PMID: 20193855
  22. Genome-wide association study identifies novel breast cancer susceptibility loci.
    Nature. 2007 Jun 28;447(7148):1087-93 PMID: 17529967
  23. Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer.
    Mol Endocrinol. 2009 Sep;23(9):1397-405 PMID: 19497954
  24. Activating somatic FGFR2 mutations in breast cancer.
    PLoS One. 2013;8(3):e60264 PMID: 23527311
  25. ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions.
    Methods. 2009 Jul;48(3):240-8 PMID: 19275939
  26. Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome.
    Breast Cancer Res. 2007;9(3):R33 PMID: 17535433
  27. FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin.
    Genome Res. 2007 Jun;17(6):877-85 PMID: 17179217
  28. Systematic localization of common disease-associated variation in regulatory DNA.
    Science. 2012 Sep 7;337(6099):1190-5 PMID: 22955828
  29. RUNX2 in mammary gland development and breast cancer.
    J Cell Physiol. 2013 Jun;228(6):1137-42 PMID: 23169547
  30. The classification of mRNA expression levels by the phosphorylation state of RNAPII CTD based on a combined genome-wide approach.
    BMC Genomics. 2011 Oct 20;12:516 PMID: 22011111
  31. Genetic variants in fibroblast growth factor receptor 2 (FGFR2) contribute to susceptibility of breast cancer in Chinese women.
    Carcinogenesis. 2008 Dec;29(12):2341-6 PMID: 18845558
  32. Pioneer transcription factors: establishing competence for gene expression.
    Genes Dev. 2011 Nov 1;25(21):2227-41 PMID: 22056668
  33. FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation.
    Hum Mol Genet. 2009 May 1;18(9):1692-703 PMID: 19223389
  34. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.
    Am J Hum Genet. 2013 Apr 4;92(4):489-503 PMID: 23540573
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
Published
2013-12-05
Epub
2013-00-27
Pages
1046-60
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC3852923
Subset
IM
Grants
Breast Cancer Now · BREAST CANCER NOW RESEARCH CENTRE · United Kingdom
NCI NIH HHS · R01 CA077398 · United States
Cancer Research UK · 10119 · United Kingdom
Cancer Research UK · 10118 · United Kingdom
Cancer Research UK · 10124 · United Kingdom
NCI NIH HHS · R01 CA092447 · United States
Cancer Research UK · 11022 · United Kingdom
Wellcome Trust · 090532 · United Kingdom
NCI NIH HHS · P30 CA015083 · United States
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