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

Kerstin B Meyer, Martin O'Reilly, Kyriaki Michailidou, Saskia Carlebur, Stacey L Edwards, Juliet D French, Radhika Prathalingham, Joe Dennis, Manjeet K Bolla, Qin Wang, Ines de Santiago, John L Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Laura J Van 't Veer, Frans B Hogervorst, Kenneth MuirArtitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Michael P Lux, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Florence Menegaux, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, M Pilar Zamora, Nick Orr, GENICA Network

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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.

Original languageEnglish
Pages (from-to)1046-60
Number of pages15
JournalThe American Journal of Human Genetics
Volume93
Issue number6
DOIs
Publication statusPublished - 05 Dec 2013

Keywords

  • African Continental Ancestry Group
  • Alleles
  • Asian Continental Ancestry Group
  • Binding Sites
  • Breast Neoplasms
  • Case-Control Studies
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Chromosome Mapping
  • E2F1 Transcription Factor
  • European Continental Ancestry Group
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Association Studies
  • Genetic Loci
  • Haplotypes
  • Hepatocyte Nuclear Factor 3-alpha
  • Humans
  • Position-Specific Scoring Matrices
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • Receptor, Fibroblast Growth Factor, Type 2
  • Journal Article

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    Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., Prathalingham, R., Dennis, J., Bolla, M. K., Wang, Q., de Santiago, I., Hopper, J. L., Tsimiklis, H., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., Van 't Veer, L. J., Hogervorst, F. B., ... GENICA Network (2013). Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1. The American Journal of Human Genetics, 93(6), 1046-60. https://doi.org/10.1016/j.ajhg.2013.10.026