Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
Authors: Lawrenson Kate , Li Qiyuan , Kar Siddhartha , Seo Ji-Heui , Tyrer Jonathan , Spindler Tassja J. , Lee Janet , Chen Yibu , Karst Alison , Drapkin Ronny , Aben Katja K. H. , Anton-Culver Hoda , Antonenkova Natalia ,   Australian Ovarian Cancer Study Group, Bowtell David , Webb Penelope M. , deFazio Anna , Baker Helen , Bandera Elisa V. , Bean Yukie , Beckmann Matthias W. , Berchuck Andrew , Bisogna Maria , Bjorge Line , Bogdanova Natalia , Brinton Louise A. , Brooks-Wilson Angela , Bruinsma Fiona , Butzow Ralf , Campbell Ian G. , Carty Karen , Chang-Claude Jenny , Chenevix-Trench Georgia , Chen Anne , Chen Zhihua , Cook Linda S. , Cramer Daniel W. , Cunningham Julie M. , Cybulski Cezary , Dansonka-Mieszkowska Agnieszka , Dennis Joe , Dicks Ed , Doherty Jennifer A. , Dörk Thilo , du Bois Andreas , Dürst Matthias , Eccles Diana , Easton Douglas T. , Edwards Robert P. , Eilber Ursula , Ekici Arif B. , Fasching Peter A. , Fridley Brooke L. , Gao Yu-Tang , Gentry-Maharaj Aleksandra , Giles Graham G. , Glasspool Rosalind , Goode Ellen L. , Goodman Marc T. , Grownwald Jacek , Harrington Patricia , Harter Philipp , Hasmad Hanis Nazihah , Hein Alexander , Heitz Florian , Hildebrandt Michelle A. T. , Hillemanns Peter , Hogdall Estrid , Hogdall Claus , Hosono Satoyo , Iversen Edwin S. , Jakubowska Anna , James Paul , Jensen Allan , Ji Bu-Tian , Karlan Beth Y. , Kruger Kjaer Susanne , Kelemen Linda E. , Kellar Melissa , Kelley Joseph L. , Kiemeney Lambertus A. , Krakstad Camilla , Kupryjanczyk Jolanta , Lambrechts Diether , Lambrechts Sandrina , Le Nhu D. , Lee Alice W. , Lele Shashi , Leminen Arto , Lester Jenny , Levine Douglas A. , Liang Dong , Lissowska Jolanta , Lu Karen , Lubinski Jan , Lundvall Lene , Massuger Leon F. A. G. , Matsuo Keitaro , McGuire Valerie , McLaughlin John R. , Nevanlinna Heli , McNeish Ian , Menon Usha , Modugno Francesmary , Moysich Kirsten B. , Narod Steven A. , Nedergaard Lotte , Ness Roberta B. , Azmi Mat Adenan Noor , Odunsi Kunle , Olson Sara H. , Orlow Irene , Orsulic Sandra , Weber Rachel Palmieri , Pearce Celeste L. , Pejovic Tanja , Pelttari Liisa M. , Permuth-Wey Jennifer , Phelan Catherine M. , Pike Malcolm C. , Poole Elizabeth M. , Ramus Susan J. , Risch Harvey A. , Rosen Barry , Rossing Mary Anne , Rothstein Joseph H. , Rudolph Anja , Runnebaum Ingo B. , Rzepecka Iwona K. , Salvesen Helga B. , Schildkraut Joellen M. , Schwaab Ira , Sellers Thomas A. , Shu Xiao-Ou , Shvetsov Yurii B. , Siddiqui Nadeem , Sieh Weiva , Song Honglin , Southey Melissa C. , Sucheston Lara , Tangen Ingvild L. , Teo Soo-Hwang , Terry Kathryn L. , Thompson Pamela J. , Timorek Agnieszka , Tsai Ya-Yu , Tworoger Shelley S. , van Altena Anne M. , Van Nieuwenhuysen Els , Vergote Ignace , Vierkant Robert A. , Wang-Gohrke Shan , Walsh Christine , Wentzensen Nicolas , Whittemore Alice S. , Wicklund Kristine G. , Wilkens Lynne R. , Woo Yin-Ling , Wu Xifeng , Wu Anna H. , Yang Hannah , Zheng Wei , Ziogas Argyrios , Monteiro Alvaro , Pharoah Paul D. , Gayther Simon A. , Freedman Matthew L. 
Published: September 2015

AbstractGenome-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.