Please use this identifier to cite or link to this item: http://hdl.handle.net/10125/40203

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

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Title:Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
Authors:Le Marchand, Loic
Date Issued:Sep 2014
Publisher:Nature
Relation:http://www.nature.com/ncomms/2014/140923/ncomms5999/full/ncomms5999.html
Abstract:

Note: A full list of authors and affiliations appears at the end of the article.


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.


Pages/Duration:12
URI:http://hdl.handle.net/10125/40203
DOI:10.1038/ncomms5999
Appears in Collections: University of Hawaii Cancer Center Faculty & Researcher Works


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