Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 22 November 2019 / Approved: 24 November 2019 / Online: 24 November 2019 (05:12:07 CET)

How to cite: Glubb, D.M.; Shi, W.; Beesley, J.; Fachal, L.; Pritchard, J.; McCue, K.; Barnes, D.R.; Antoniou, A.C.; Dunning, A.M.; Easton, D.F.; Chenevix-Trench, G. Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4. Preprints 2019, 2019110271 (doi: 10.20944/preprints201911.0271.v1). Glubb, D.M.; Shi, W.; Beesley, J.; Fachal, L.; Pritchard, J.; McCue, K.; Barnes, D.R.; Antoniou, A.C.; Dunning, A.M.; Easton, D.F.; Chenevix-Trench, G. Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4. Preprints 2019, 2019110271 (doi: 10.20944/preprints201911.0271.v1).

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 tumoral breast cell lines. We identified putative regulatory elements, containing CCVs, that loop 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 tumor 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.

Subject Areas

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

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