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Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2013 Dec 05; Vol. 93 (6), pp. 1046-60. Date of Electronic Publication: 2013 Nov 27. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Alleles
Asian People genetics
Binding Sites
Black People genetics
Case-Control Studies
Cell Line, Tumor
Chromatin Immunoprecipitation
E2F1 Transcription Factor genetics
E2F1 Transcription Factor metabolism
Female
Gene Expression Regulation, Neoplastic
Genetic Association Studies
Haplotypes
Hepatocyte Nuclear Factor 3-alpha genetics
Hepatocyte Nuclear Factor 3-alpha metabolism
Humans
Position-Specific Scoring Matrices
Promoter Regions, Genetic
Protein Binding
RNA Interference
Receptor, Fibroblast Growth Factor, Type 2 metabolism
White People genetics
Breast Neoplasms genetics
Breast Neoplasms metabolism
Chromosome Mapping
Genetic Loci
Receptor, Fibroblast Growth Factor, Type 2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 93
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24290378
- Full Text :
- https://doi.org/10.1016/j.ajhg.2013.10.026