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Nature Communications

Publication date: 2015-09-22
Pages: 8234 -
Publisher: Nature Portfolio

Author:

Lawrenson, Kate
Li, Qiyuan ; Kar, Siddhartha ; Seo, Ji-Heui ; Tyrer, Jonathan ; Spindler, Tassja J ; Lee, Janet ; Chen, Yibu ; Karst, Alison ; Drapkin, Ronny ; Aben, Katja KH ; Anton-Culver, Hoda ; Antonenkova, Natalia ; 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 AT ; 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 FAG ; 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

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, GENOME-WIDE ASSOCIATION, LONG-RANGE INTERACTION, ANALYSES REVEAL, HOX GENES, RISK, IDENTIFICATION, EXPRESSION, BREAST, VARIANTS, LOCUS, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Neoplasm Proteins, Neoplasms, Glandular and Epithelial, Nuchal Cord, Ovarian Neoplasms, Protein Binding, Quantitative Trait Loci, Australian Ovarian Cancer Study Group

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.