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Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Shi, Wei 
Beesley, Jonathan 
Pritchard, Jayne-Louise  ORCID logo  https://orcid.org/0000-0001-7822-2592

Abstract

Genome-wide association studies have revealed a locus at 8p12 that is associated with breast cancer risk. Fine-mapping of this locus identified 16 candidate causal variants (CCVs). However, as these variants are intergenic, their function is unclear. To map chromatin looping from this risk locus to a previously identified candidate target gene, DUSP4, we performed chromatin conformation capture analyses in normal and tumoural breast cell lines. We identified putative regulatory elements, containing CCVs, which looped to the DUSP4 promoter region. Using reporter gene assays, we found that the risk allele of CCV rs7461885 reduced the activity of a DUSP4 enhancer element, consistent with the function of DUSP4 as a tumour suppressor gene. Furthermore, the risk allele of CCV rs12155535, located in another DUSP4 enhancer element, was negatively correlated with looping of this element to the DUSP4 promoter region, suggesting that this allele would be associated with reduced expression. These findings provide the first evidence that CCV risk alleles downregulate DUSP4 expression, suggesting that this gene is a regulatory target of the 8p12 breast cancer risk locus.

Description

Keywords

GWAS, breast cancer risk, candidate causal variant, chromatin conformation capture, enhancer, promoter, reporter gene activity

Journal Title

Cancers (Basel)

Conference Name

Journal ISSN

2072-6694
2072-6694

Volume Title

12

Publisher

MDPI AG
Sponsorship
Cancer Research UK (20861)
Cancer Research UK (16565)