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

Madalene 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 Bjorge, Natalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Clareann H. Bunker, Ralf Butzow, Ian G. CampbellKaren 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 M. 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 K. Hogdall, Estrid Høgdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, Allan Jensen, Bu Tian Ji, Audrey Y. Jung, Beth Y. Karlan, Melissa Kellar, Lambertus A. Kiemeney, Boon Kiong Lim, Susanne K. Kjaer, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Shashi Lele, Jenny Lester, Douglas A. Levine, Zheng Li, 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, Roger L. Milne, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Heli Nevanlinna, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, James Paul, Tanja Pejovic, Liisa M. Pelttari, Jenny B. Permuth, Malcolm C. Pike, Elizabeth M. Poole, Barry 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 Spiewankiewicz, 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 S. 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 L. Pearce, Andrew Berchuck, Joellen M. Schildkraut, Susan J. Ramus, Alvaro 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

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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 bio-features 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.

Original languageEnglish (US)
Article numbere0197561
JournalPloS one
Volume13
Issue number7
DOIs
StatePublished - Jul 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Earp, M., Tyrer, J. P., Winham, S. J., Lin, H. Y., Chornokur, G., Dennis, J., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bruinsma, F., Bunker, C. H., Butzow, R., ... Phelan, C. M. (2018). Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PloS one, 13(7), [e0197561]. https://doi.org/10.1371/journal.pone.0197561