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Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

2018; Public Library of Science; Volume: 13; Issue: 7 Linguagem: Inglês

10.1371/journal.pone.0197561

1932-6203

Madalene A. Earp, Jonathan P. Tyrer, Stacey J. Winham, Hui‐Yi Lin, Ganna Chornokur, Joe Dennis, Katja K.H. Aben, Hoda Anton‐Culver, Natalia Antonenkova, Elisa V. Bandera, Yukie T. Bean, Matthias W. Beckmann, Line Bjørge, Natalia Bogdanova, Louise A. Brinton, Angela Brooks‐Wilson, Fiona Bruinsma, Clareann H. Bunker, Ralf Bützow, Ian Campbell, Karen Carty, Jenny Chang‐Claude, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka‐Mieszkowska, Evelyn Despierre, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F. Easton, Diana Eccles, Robert P. Edwards, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Aleksandra Gentry‐Maharaj, Graham G. Giles, Rosalind Glasspool, Marc T. Goodman, Jacek Gronwald, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Claus Høgdall, Estrid Høgdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Audrey Jung, Beth Y. Karlan, Melissa Kellar, Lambertus A. Kiemeney, Boon Kiong Lim, Susanne K. Kjær, Camilla Krakstad, Jolanta Kupryjańczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Shashi Lele, Jenny Lester, Douglas A. Levine, Zheng Li, Dong Liang, Jolanta Lissowska, Karen H. Lu, Jan Lubiński, Lene Lundvall, Leon F.A.G. Massuger, Keitaro Matsuo, Valerie McGuire, Esther M. John, Iain A. McNeish, Usha Menon, Roger L. Milne, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Heli Nevanlinna, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Oršulić, James Paul, Tanja Pejović, Liisa M. Pelttari, Jenny B. Permuth, Malcolm C. Pike, Elizabeth M. Poole, Barry P. Rosen, Mary Anne Rossing, Joseph H. Rothstein, Ingo B. Runnebaum, Iwona K. Rzepecka, Eva Schernhammer, Ira Schwaab, Xiao‐Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Beata Śpiewankiewicz, Lara Sucheston‐Campbell, Ingvild L. Tangen, Soo‐Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Lotte Thomsen, Shelley S. Tworoger, Anne M. van Altena, Ignace Vergote, Liv Cecilie Vestrheim Thomsen, Robert A. Vierkant, Christine Walsh, Shan Wang‐Gohrke, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Yin Ling Woo, Anna H. Wu, Xifeng Wu, Yong-Bing Xiang, Hannah Yang, Wei Zheng, Argyrios Ziogas, Alice W. Lee, Celeste Leigh Pearce, Andrew Berchuck, Joellen M. Schildkraut, Susan J. Ramus, Álvaro N.A. Monteiro, Steven A. Narod, Thomas A. Sellers, Simon A. Gayther, Linda E. Kelemen, Georgia Chenevix‐Trench, Harvey A. Risch, Paul D.P. Pharoah, Ellen L. Goode, Catherine M. Phelan,

Ovarian cancer diagnosis and treatment

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10−6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.