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


Type

Article

Change log

Authors

Edwards, Stacey L 
Michailidou, Kyriaki 
Nord, Silje 
Cowper-Sal Lari, Richard 

Abstract

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 × 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.

Description

Keywords

Breast Neoplasms, Cell Line, Tumor, Chromatin, Chromosomes, Human, Pair 2, Female, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 3-alpha, Humans, Insulin-Like Growth Factor Binding Protein 5, MCF-7 Cells, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

5

Publisher

Springer Nature
Sponsorship
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
European Commission (223175)
Cancer Research UK (10710)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research UK (16942)
Cancer Research UK (16563)
Cancer Research UK (11022)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (16565)
Cancer Research UK (15602)