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 M. Karst, Ronny Drapkin, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V. Bandera, Yukie Tarumi 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, Y Anne Chen, Zhihua Chen, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer Anne Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana M Eccles, Douglas T. Easton, Robert P. Edwards, Ursula Eilber, Arif B Ekici, Peter A. Fasching, Brooke L. Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind M Glasspool, Ellen L Goode, Marc T Goodman, Jacek Grownwald, Patricia Harrington, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Paul James, Allan Jensen, Bu-tian Ji, Beth Y. Karlan, Susanne Kruger Ruger Kjaer, Linda E. Kelemen, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Heli Nevanlinna, Ian McNeish, Usha N Menon, Francesmary Modugno, Kirsten B Moysich, Steven A Narod, Lotte Nedergaard, Roberta B Ness, Mat Adenan Noor Azmi, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Jennifer Permuth-Wey, Catherine M Phelan, Malcolm C Pike, Elizabeth M Poole, Susan J Ramus, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga Birgitte Salvesen, Joellen M Schildkraut, Ira Schwaab, Thomas A Sellers, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara E Sucheston, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Agnieszka Timorek, Ya-Yu Tsai, Shelley S Tworoger, Anne Mvan Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A Vierkant, Shan Wang-Gohrke, Christine S Walsh, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R. Wilkens, Yin Ling Woo, Xifeng Wu, Anna H Wu, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Alvaro Monteiro, Paul D P Pharoah, Simon A Gayther, Matthew L Freedman, David Bowtell, Penelope M Webb, Anna DeFazio, Australian Ovarian Cancer Study Group (AOCS)

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31 Citations (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.

Original languageEnglish
Article number8234
Number of pages14
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 22 Sep 2015
Externally publishedYes

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