Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis -eQTL associations at 47 regions associated with HGSOC risk ( P r 10 (cid:2) 5 ). For three cis -eQTL associations ( P o 1.4 (cid:3) 10 (cid:2) 3 , FDR o 0.05) at 1p36 ( CDC42 ), 1p34 ( CDCA8 ) and 2q31 ( HOXD9 ), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes ( P ¼ 6 (cid:3) 10 (cid:2) 10 for risk variants ( P o 10 (cid:2) 4 ) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

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