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

Journal

Book Volume: 13

Journal Issue: 7

DOI: 10.1371/journal.pone.0197561

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

How to cite

APA:

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). https://dx.doi.org/10.1371/journal.pone.0197561

MLA:

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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