Genome-wide significant risk associations for mucinous ovarian carcinoma

Linda E. Kelemen, Kate Lawrenson, Jonathan Tyrer, Qiyuan Li, Janet M. Lee, Ji Heui Seo, Catherine M. Phelan, Jonathan Beesley, Xiaoqing Chen, Tassja J. Spindler, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V. Bandera, Yukie Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia BogdanovaLouise A. Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G. Campbell, Karen Carty, Jenny Chang-Claude, Y. Ann 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, Arif B. Ekici, Svend Aage Engelholm, Peter A. Fasching, Brooke L. Fridley, Yu Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind 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, Allan Jensen, Bu Tian Ji, Beth Y. Karlan, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Susanne K. Kjaer, 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, Iain McNeish, Usha Menon, Francesmary Modugno, Joanna Moes-Sosnowska, Kirsten B. Moysich, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Heli Nevanlinna, Noor Azmi Mat Adenan, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste Leigh Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer 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 B. Salvesen, Joellen M. Schildkraut, Ira Schwaab, Xiao Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara 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, Wang Gohrke Shan, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Wlodzimierz Sawicki, Yin Ling Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Thomas A. Sellers, Matthew L. Freedman, Georgia Chenevix-Trench, Paul D.P. Pharoah, Simon A. Gayther, Andrew Berchuck

Research output: Contribution to journalArticle

54 Scopus citations

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 (US)
Pages (from-to)888-897
Number of pages10
JournalNature genetics
Volume47
Issue number8
DOIs
StatePublished - Aug 30 2015

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Kelemen, L. E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J. M., Seo, J. H., Phelan, C. M., Beesley, J., Chen, X., Spindler, T. J., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., ... Berchuck, A. (2015). Genome-wide significant risk associations for mucinous ovarian carcinoma. Nature genetics, 47(8), 888-897. https://doi.org/10.1038/ng.3336