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

Kate Lawrenson, Qiyuan Li, Siddhartha Kar, Ji-Heui Seo, Jonathan Tyrer, Tassja J Spindler, Janet Lee, Yibu Chen, Alison Karst, Ronny Drapkin, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V Bandera, Yukie Bean, Matthias W Beckmann, Andrew Berchuck, Maria Bisogna, Line BjorgeNatalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Georgia Chenevix-Trench, Anne Chen, Zhihua Chen, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Diana Eccles, Douglas T Easton, Robert P Edwards, Ursula Eilber, Estrid Hogdall, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Australian Ovarian Cancer Study Group

49 Citationer (Scopus)

Abstract

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.

OriginalsprogEngelsk
TidsskriftNature Communications
Vol/bind6
Sider (fra-til)8234
ISSN2041-1722
DOI
StatusUdgivet - 2015

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