Abstract
Abstract We have previously used genome-wide association studies and meta-analyses to uncover 17 genetic risk loci for endometrial cancer. However, the regulatory gene targets of these loci have not been systematically evaluated. To identify candidate gene targets at endometrial cancer risk loci, we have assessed chromatin looping interactions between endometrial cancer risk variants and neighboring genes using the global HiChIP chromatin conformation capture technique. To perform HiChIP, estrogen-stimulated Ishikawa endometrial cancer cells were cross-linked and proximity ligation performed. Chromatin associated with RNA polymerase II was isolated and HiChIP libraries prepared before sequencing using the Illumina HiSeq 4000 system. HiChIP paired-end reads were aligned using the HiC-Pro pipeline and filtered for valid reads. The hichipper package was used to identify and characterise global chromatin interactions (FDR < 0.01). At 11 of the 17 endometrial cancer risk loci, we identified chromatin interactions between risk variants and genes (37 coding and 10 non-coding). Interaction distances ranged from 8 kb to 1.7 Mb. Expression of candidate target genes CUX2, CYP19A1, SKAP1, SNX11 and EIF2AK4 was found to associate with endometrial cancer risk in whole blood transcriptome-wide association studies (TWAS). Ingenuity Pathway Analysis revealed that candidate genes were enriched for relevant functional annotations such as tumorigenesis, cell migration, necrosis and viability. Furthermore, enrichment of candidate genes (p=0.001) was observed in the CXCR4 signaling pathway, which is involved with endometrial cancer development, invasion and progression. In summary, we have performed the first global study of chromatin interactions in endometrial cancer cells. This analysis has revealed biologically relevant candidate target genes at endometrial cancer risk loci, five of which are supported by TWAS. Transcriptional regulation of candidate target genes by endometrial cancer risk variants will be verified in future studies. Citation Format: Dylan M. Glubb, Pik Fang Kho, Endometrial Cancer Association Consortium, Deborah Thompson, Amanda Spurdle, Tracy O'Mara. Global study of chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-164.
Published Version
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