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

Journal article


Publication Details

Author(s): 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
Journal: PLoS ONE
Publication year: 2018
Volume: 13
Journal issue: 7
ISSN: 1932-6203


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.


FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe
Hein, Alexander PD Dr.
Frauenklinik


External institutions with authors

Aichi Cancer Center Research Institute
Beatson West of Scotland Cancer Centre (BWSCC)
Brigham and Women's Hospital (BWH)
British Columbia Cancer Agency
California State University (CSUF)
Cancer Council Victoria
Cedars-Sinai Medical Center
Danish Cancer Society Research Center
Deutsches Krebsforschungszentrum (DKFZ)
Duke University
Fred Hutchinson Cancer Research Center
Friedrich-Schiller-Universität Jena
Harvard University
Haukeland University Hospital / Haukeland universitetssykehus
HELIOS Kliniken
Helsingin yliopisto / University of Helsinki
H. Lee Moffitt Cancer Center & Research Institute
Icahn School of Medicine at Mount Sinai
Institute for Oncology Ljubljana (OIL)
Institut für Humangenetik Wiesbaden
Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven
Louisiana State University
Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie
Mayo Clinic
Medical University of South Carolina (MUSC)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Memorial Sloan Kettering Cancer Center
National Cancer Institute (NCI)
N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology
Oregon Health and Science University (OSHU)
Peter MacCallum Cancer Centre
Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU)
Princess Anne Hospital
Public Health Ontario
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Radboud University Nijmegen
Roswell Park Cancer Institute
Rutgers Cancer Institute of New Jersey
Shanghai Cancer Institute / 上海市肿瘤研究所
Stanford University
Texas Southern University (TSU)
The Netherlands Cancer Institute
The University of Melbourne
University College London (UCL)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of California Irvine
University of Cambridge
University of Copenhagen
University of Hawaii (U.H.)
University of Malaya (UM) / Universiti Malaya
University of Michigan
University of New Mexico
University of New South Wales (UNSW)
University of Pittsburgh
University of Southern California (USC)
University of Texas MD Anderson Cancer Center
University of Toronto
University of Virginia (UVA)
Vanderbilt University


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).

BibTeX: 

Last updated on 2019-21-07 at 07:50