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Open AccessArticle

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

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Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia
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Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
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Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(1), 170; https://doi.org/10.3390/cancers12010170
Received: 22 November 2019 / Revised: 23 December 2019 / Accepted: 30 December 2019 / Published: 10 January 2020
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. View Full-Text
Keywords: breast cancer risk; GWAS; candidate causal variant; chromatin conformation capture; reporter gene activity; enhancer; promoter breast cancer risk; GWAS; candidate causal variant; chromatin conformation capture; reporter gene activity; enhancer; promoter
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Glubb, D.M.; Shi, W.; Beesley, J.; Fachal, L.; Pritchard, J.-L.; 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. Cancers 2020, 12, 170.

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