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

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Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lawrenson, K; Li, Q; Kar, S; Seo, J-H; Tyrer, J; Spindler, TJ; Lee, J; Chen, Y; Karst, A; Drapkin, R; Aben, KKH; Anton-Culver, H; Antonenkova, N; Australian Ovarian Cancer Study Group, ; Baker, H; Bandera, EV; Bean, Y; Beckmann, MW; Berchuck, A; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bruinsma, F; Butzow, R; Campbell, IG; Carty, K; Chang-Claude, J; Chenevix-Trench, G; Chen, A; Chen, Z; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; Dansonka-Mieszkowska, A; Dennis, J; Dicks, E; Doherty, JA; Dörk, T; du Bois, A; Dürst, M; Eccles, D; Easton, DT; Edwards, RP; Eilber, U; Ekici, AB; Fasching, PA; Fridley, BL; Gao, Y-T; Gentry-Maharaj, A; Giles, GG; Glasspool, R; Goode, EL; Goodman, MT; Grownwald, J; Harrington, P; Harter, P; Hasmad, HN; Hein, A; Heitz, F; Hildebrandt, MAT; Hillemanns, P; Hogdall, E; Hogdall, C; Hosono, S; Iversen, ES; Jakubowska, A; James, P; Jensen, A; Ji, B-T; Karlan, BY; Kruger Kjaer, S; Kelemen, LE; Kellar, M; Kelley, JL; Kiemeney, LA; Krakstad, C; Kupryjanczyk, J; Lambrechts, D; Lambrechts, S; Le, ND; Lee, AW; Lele, S; Leminen, A; Lester, J; Levine, DA; Liang, D; Lissowska, J; Lu, K; Lubinski, J; Lundvall, L; Massuger, LFAG; Matsuo, K; McGuire, V; McLaughlin, JR; Nevanlinna, H; McNeish, I; Menon, U; Modugno, F; Moysich, KB; Narod, SA; Nedergaard, L; Ness, RB; Azmi, MAN; Odunsi, K; Olson, SH; Orlow, I; Orsulic, S; Weber, RP; Pearce, CL; Pejovic, T; Pelttari, LM; Permuth-Wey, J; Phelan, CM; Pike, MC; Poole, EM; Ramus, SJ; Risch, HA; Rosen, B; Rossing, MA; Rothstein, JH; Rudolph, A; Runnebaum, IB; Rzepecka, IK; Salvesen, HB; Schildkraut, JM; Schwaab, I; Sellers, TA; Shu, X-O; Shvetsov, YB; Siddiqui, N; Sieh, W; Song, H; Southey, MC; Sucheston, L; Tangen, IL; Teo, S-H; Terry, KL; Thompson, PJ; Timorek, A; Tsai, Y-Y; Tworoger, SS; van Altena, AM; Van Nieuwenhuysen, E; Vergote, I; Vierkant, RA; Wang-Gohrke, S; Walsh, C; Wentzensen, N; Whittemore, AS; Wicklund, KG; Wilkens, LR; Woo, Y-L; Wu, X; Wu, AH; Yang, H; Zheng, W; Ziogas, A; Monteiro, A; Pharoah, PD; Gayther, SA; Freedman, ML

Published Date

  • September 22, 2015

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 8234 -

PubMed ID

  • 26391404

Pubmed Central ID

  • 26391404

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms9234

Language

  • eng

Conference Location

  • England