Abstract PO004: Enhancer-promoter chromatin looping is enriched for endometrial cancer GWAS risk variation and reveals biologically relevant candidate susceptibility genes

Abstract

Large-scale genome-wide association studies (GWAS) conducted by the Endometrial Cancer Association Consortium have identified candidate endometrial cancer risk variants at 16 loci. The vast majority of these candidate endometrial cancer risk variants are located in non-coding genomic regions. Studies of other GWAS have shown enrichment of trait-associated variants in enhancer elements suggesting that they may regulate gene expression through chromatin looping. In the current study, we analysed chromatin looping to identify the genes that may mediate the effects of these variants. We used a modified HiChIP technique to capture chromatin loops associated with H3K27Ac (characteristic of active enhancers and promoters) in a normal immortalized and three tumoral endometrial cell lines. Duplicate HiChIP libraries were analysed using paired-end sequencing and bioinformatic pipelines (HiC-Pro, hichipper and IDR2D) to identify replicating cis chromatin loops. The replicating loops were intersected with gene promoter regions to identify promoter-associated chromatin loops and we found significant enrichment of endometrial cancer risk variation in these loops. We identified 74 candidate target genes at 13 endometrial cancer risk loci by intersecting promoter-associated loops with candidate risk variants and prioritising genes with matching RNA-seq expression. The candidate target genes were more conserved than other genes on average, nearly three times more likely to be differentially regulated in endometrial tumours and their encoded proteins interacted more amongst themselves than would be expected by chance. Moreover, functional prioritisation of the wider protein-protein interaction network revealed a set of interacting proteins that was 9-fold enriched for somatic endometrial cancer drivers. In summary, our findings indicate that endometrial cancer risk variation at least partly mediates its effects through enhancer-promoter chromatin looping and corresponding data reveal a set of biologically relevant candidate target genes. Citation Format: Dylan M. Glubb, Pamela Pollock, Amanda Spurdle, Tracy A. O'Mara. Enhancer-promoter chromatin looping is enriched for endometrial cancer GWAS risk variation and reveals biologically relevant candidate susceptibility genes [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO004.