Candidate Causal Variants at the 8p12 Breast Cancer Risk Locus Regulate DUSP4
Open Access
- 10 January 2020
- Vol. 12 (1), 170
- https://doi.org/10.3390/cancers12010170
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.Funding Information
- National Health and Medical Research Council (1117073)
This publication has 24 references indexed in Scilit:
- Chromatin interactome mapping at 139 independent breast cancer risk signalsGenome Biology, 2020
- Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genesPublished by Cold Spring Harbor Laboratory ,2019
- The Post-GWAS Era: From Association to FunctionAmerican Journal of Human Genetics, 2018
- Association analysis identifies 65 new breast cancer risk lociNature, 2017
- Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancerNature Genetics, 2015
- Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1American Journal of Human Genetics, 2014
- A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin LoopingCell, 2014
- Large-scale genotyping identifies 41 new loci associated with breast cancer riskNature Genetics, 2013
- Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription RegulationCell, 2012
- Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2Breast Cancer Research, 2011