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

  • Author(s): Lawrenson, K
  • Li, Q
  • Kar, S
  • Seo, JH
  • Tyrer, J
  • Spindler, TJ
  • Lee, J
  • Chen, Y
  • Karst, A
  • Drapkin, R
  • Aben, KKH
  • Anton-Culver, H
  • Antonenkova, N
  • 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, YT
  • 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, BT
  • Karlan, BY
  • Kjaer, SK
  • Kelemen, LE
  • Kellar, M
  • Kelley, JL
  • Kiemeney, LA
  • Krakstad, C
  • Kupryjanczyk, J
  • Lambrechts, D
  • et al.
Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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 × 10-10for 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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