Epithelial‐Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Ernest K. Amankwah, Hui‐Yi Lin, Jonathan P. Tyrer, Kate Lawrenson, Joe Dennis, Ganna Chornokur, Katja K. H. Aben, Hoda Anton‐Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V. Bandera, Yukie T. Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A. Brinton, Angela Brooks‐Wilson, Clareann H. Bunker, Ralf Butzow, Ian G. Campbell, Karen Carty, Zhihua Chen, Y. Ann Chen, Jenny Chang‐Claude, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka‐Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A. Doherty, Thilo Dörk, Matthias Dürst, Douglas F. Easton, Diana M. Eccles, Robert P. Edwards, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Yu‐Tang Gao, Aleksandra Gentry‐Maharaj, Graham G. Giles, Rosalind Glasspool, Marc T. Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Hanis N. Hasmad, Alexander Hein, Florian Heitz, Michelle A. T. Hildebrandt, Peter Hillemanns, Claus K. Hogdall, Estrid Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Allan Jensen, Bu‐Tian Ji, Beth Y. Karlan, Heather Jim, Melissa Kellar, 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, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F. A. G. Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Ian McNeish, Usha Menon, Roger L. Milne, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L. Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer Permuth‐Wey, Malcolm C. Pike, Elizabeth M. Poole, Harvey A. Risch, Barry Rosen, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Eva Schernhammer, Ira Schwaab, Xiao‐Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Beata Spiewankiewicz, Lara Sucheston‐Campbell, Soo‐Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Lotte Thomsen, Ingvild L. Tangen, Shelley S. Tworoger, Anne M. van Altena, Robert A. Vierkant, Ignace Vergote, Christine S. Walsh, Shan Wang‐Gohrke, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Anna H. Wu, Xifeng Wu, Yin‐Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Linda E. Kelemen, Andrew Berchuck, Georgia Chenevix‐Trench on behalf of the AOCS management group, Joellen M. Schildkraut, Susan J. Ramus, Ellen L. Goode, Alvaro N. A. Monteiro, Simon A. Gayther, Steven A. Narod, Paul D. P. Pharoah, Thomas A. Sellers, Catherine M. Phelan

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.