Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
AuthorLawrenson, K; Li, Q; Kar, S; Seo, J-H; Tyrer, J; Spindler, TJ; Lee, J; Chen, Y; Karst, A; Drapkin, R; ...
Source TitleNature Communications
University of Melbourne Author/sGiles, Graham; Southey, Melissa; Ramus, Susan; Campbell, Ian; Bowtell, David; James, Paul; Baglietto, Laura
AffiliationMelbourne School of Population and Global Health
Sir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsLawrenson, K., Li, Q., Kar, S., Seo, J. -H., Tyrer, J., Spindler, T. J., Lee, J., Chen, Y., Karst, A., Drapkin, R., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Berchuck, A., Bisogna, M. ,... Defazio, A. (2015). Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. NATURE COMMUNICATIONS, 6 (1), https://doi.org/10.1038/ncomms9234.
Access StatusOpen Access
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≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<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=6 × 10(-10) for risk variants (P<10(-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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