Genome-wide significant risk associations for mucinous ovarian carcinoma

Linda Kelemen, Kate Lawrenson, Jonathan Tyrer, Qiyuan Li, Janet Lee, Ji-Heui Seo, Catherine M Phelan, Jonathan Beesley, Xiaoqing Chen, Tassja J Spindler, Katja K Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa Bandera, Yukie Tarumi Bean, Matthias Beckmann, Maria Bisogna, Line Bjorge, Natalia BogdanovaLouise Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Y Anne Chen, Zhihua Chen, Linda Cook, Daniel Cramer, Julie Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer Doherty, Thilo Dork, Andreas Du Bois, Matthias Durst, Diana M Eccles, Douglas F Easton, Robert Edwards, Ursula Eilber, Arif B Ekici, Svend Aage Engelholm, Peter Fasching, Brooke 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 Iversen, Anna Jakubowska, Allan Jensen, Bu-tian Ji, Beth Karlan, Melissa Kellar, Joseph Kelley, Lambertus Kiemeney, Camilla Krakstad, Susanne Kruger Ruger Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain A McNeish, Usha N Menon, Francesmary Modugno, Joanna Moes-Sosnowska, Kirsten B Moysich, Steven A Narod, Lotte Nedergaard, Roberta B Ness, Heli Nevanlinna, Noor A M Adenan, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Jenny Permuth-Wey, 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, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa Caroline Southey, Lara E Sucheston, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Shelley S Tworoger, Anne M Van Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A Vierkant, Shan Wang-Gohrke, Christine S Walsh, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne Wilkens, Wlodzimierz Sawicki, Yin Ling Woo, Xifeng Wu, Anna H Wu, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Thomas A Sellers, Matthew L Freedman, Georgia Chenevix-Trench, Paul D P Pharoah, Simon A Gayther, Andrew Berchuck

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54 Citations (Scopus)

Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 ? 10-8), rs711830 at 2q31.1 (P = 7.5 ? 10-12) and rs688187 at 19q13.2 (P = 6.8 ? 10-13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 ? 10-4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Original languageEnglish
Pages (from-to)888 - 897
Number of pages10
JournalNature Genetics
Volume47
Issue number8
DOIs
Publication statusPublished - 2015

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