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

Earp M, Tyrer JP, Winham SJ, Lin HY, Chornokur G, Dennis J, Aben KKH, Anton-Culver H, Antonenkova N, Bandera EV, Bean YT, Beckmann M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Bunker CH, Butzow R, Campbell IG, Carty K, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Despierre E, Doherty JA, Doerk T, Du Bois A, Duerst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching P, Fridley BL, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall CK, Hogdall E, Hosono S, Iversen ES, Jakubowska A, Jensen A, Ji BT, Jung AY, Karlan BY, Kellar M, Kiemeney LA, Lim BK, Kjaer SK, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lele S, Lester J, Levine DA, Li Z, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LFAG, Matsuo K, Mcguire V, Mclaughlin JR, Mcneish I, Menon U, Milne RL, Modugno F, Moysich KB, Ness RB, Nevanlinna H, Odunsi K, Olson SH, Orlow I, Orsulic S, Paul J, Pejovic T, Pelttari LM, Permuth JB, Pike MC, Poole EM, Rosen B, Rossing MA, Rothstein JH, Runnebaum IB, Rzepecka IK, Schernhammer E, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Spiewankiewicz B, Sucheston-Campbell L, Tangen IL, Teo SH, Terry KL, Thompson PJ, Thomsen L, Tworoger SS, Van Altena AM, Vergote I, Thomsen LCV, Vierkant RA, Walsh CS, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo YL, Wu AH, Wu X, Xiang YB, Yang H, Zheng W, Ziogas A, Lee AW, Pearce CL, Berchuck A, Schildkraut JM, Ramus SJ, Monteiro ANA, Narod SA, Sellers TA, Gayther SA, Kelemen LE, Chenevix-Trench G, Risch HA, Pharoah PDP, Goode EL, Phelan CM (2018)

Publication Type: Journal article

Publication year: 2018


Book Volume: 13

Journal Issue: 7

DOI: 10.1371/journal.pone.0197561


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.

Authors with CRIS profile

Involved external institutions

Mayo Clinic US United States (USA) (US) University of Cambridge GB United Kingdom (GB) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) The Netherlands Cancer Institute NL Netherlands (NL) University of California Irvine US United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology BY Belarus (BY) Rutgers Cancer Institute of New Jersey US United States (USA) (US) Oregon Health and Science University (OSHU) US United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus NO Norway (NO) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) National Cancer Institute (NCI) US United States (USA) (US) British Columbia Cancer Agency CA Canada (CA) Cancer Council Victoria AU Australia (AU) University of Pittsburgh US United States (USA) (US) Helsingin yliopisto / University of Helsinki FI Finland (FI) Peter MacCallum Cancer Centre AU Australia (AU) Beatson West of Scotland Cancer Centre (BWSCC) GB United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) University of New Mexico (UNM) / Universidad de Nuevo México US United States (USA) (US) Brigham and Women's Hospital (BWH) US United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie PL Poland (PL) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) Fred Hutchinson Cancer Research Center US United States (USA) (US) HELIOS Kliniken DE Germany (DE) Friedrich-Schiller-Universität Jena DE Germany (DE) Princess Anne Hospital GB United Kingdom (GB) University College London (UCL) GB United Kingdom (GB) Cedars-Sinai Medical Center US United States (USA) (US) University of Texas MD Anderson Cancer Center US United States (USA) (US) University of Copenhagen DK Denmark (DK) Danish Cancer Society Research Center DK Denmark (DK) Aichi Cancer Center Research Institute JP Japan (JP) Duke University US United States (USA) (US) Radboud University Nijmegen NL Netherlands (NL) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Roswell Park Cancer Institute US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) Texas Southern University (TSU) US United States (USA) (US) Stanford University US United States (USA) (US) Public Health Ontario CA Canada (CA) Harvard University US United States (USA) (US) Institut für Humangenetik Wiesbaden DE Germany (DE) Vanderbilt University US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US) Louisiana State University US United States (USA) (US) The University of Melbourne AU Australia (AU) Institute for Oncology Ljubljana (OIL) SI Slovenia (SI) University of Hawaii (U.H.) US United States (USA) (US) University of Malaya (UM) / Universiti Malaya MY Malaysia (MY) University of Southern California (USC) US United States (USA) (US) Shanghai Cancer Institute / 上海市肿瘤研究所 CN China (CN) California State University (CSUF) US United States (USA) (US) University of Michigan US United States (USA) (US) University of Virginia (UVA) US United States (USA) (US) University of New South Wales (UNSW) AU Australia (AU) University of Toronto CA Canada (CA) Medical University of South Carolina (MUSC) US United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) Yale University US United States (USA) (US)

How to cite


Earp, M., Tyrer, J.P., Winham, S.J., Lin, H.-Y., Chornokur, G., Dennis, J.,... Phelan, C.M. (2018). Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS ONE, 13(7).


Earp, Madalene, et al. "Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility." PLoS ONE 13.7 (2018).

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