Earp M 1 , Tyrer JP 2 , Winham SJ 1 , Lin HY 3 , Chornokur G 4 , Dennis J 2 Show all authors , Aben KKH 5 , Anton-Culver H 6 , Antonenkova N 7 , Bandera EV 8 , Bean YT 9 , Beckmann MW 10 , Bjorge L 11 , Bogdanova N 12 , Brinton LA 13 , Brooks-Wilson A 14 , Bruinsma F 15 , Bunker CH 16 , Butzow R 17 , Campbell IG 18 , Carty K 19 , Chang-Claude J 20 , Cook LS 21 , Cramer DW 22 , Cunningham JM 23 , Cybulski C 24 , Dansonka-Mieszkowska A 25 , Despierre E 26 , Doherty JA 27 , Dörk T 12 , du Bois A 28 , Dürst M 29 , Easton DF 30 , Eccles DM 31 , Edwards RP 32 , Ekici AB 33 , Fasching PA 10 , Fridley BL 34 , Gentry-Maharaj A 35 , Giles GG 15 , Glasspool R 19 , Goodman MT 36 , Gronwald J 24 , Harter P 28 , Hein A 10 , Heitz F 28 , Hildebrandt MAT 37 , Hillemanns P 12 , Hogdall CK 38 , Høgdall E 39 , Hosono S 40 , Iversen ES 41 , Jakubowska A 24 , Jensen A 39 , Ji BT 13 , Jung AY 20 , Karlan BY 42 , Kellar M 9 , Kiemeney LA 43 , Kiong Lim B 44 , Kjaer SK 39 , Krakstad C 11 , Kupryjanczyk J 25 , Lambrechts D 45 , Lambrechts S 46 , Le ND 47 , Lele S 48 , Lester J 42 , Levine DA 49 , Li Z 1 , Liang D 50 , Lissowska J 51 , Lu K 52 , Lubinski J 24 , Lundvall L 38 , Massuger LFAG 53 , Matsuo K 40 , McGuire V 54 , McLaughlin JR 55 , McNeish I 55 , Menon U 35 , Milne RL 15 , Modugno F 16 , Moysich KB 48 , Ness RB 56 , Nevanlinna H 57 , Odunsi K 58 , Olson SH 59 , Orlow I 59 , Orsulic S 42 , Paul J 19 , Pejovic T 9 , Pelttari LM 57 , Permuth JB 4 , Pike MC 59 , Poole EM 60 , Rosen B 61 , Rossing MA 27 , Rothstein JH 62 , Runnebaum IB 29 , Rzepecka IK 25 , Schernhammer E 60 , Schwaab I 63 , Shu XO 64 , Shvetsov YB 65 , Siddiqui N 65 , Sieh W 62 , Song H 66 , Southey MC 67 , Spiewankiewicz B 68 , Sucheston-Campbell L 48 , Tangen IL 11 , Teo SH 69 , Terry KL 70 , Thompson PJ 36 , Thomsen L 71 , Tworoger SS 4 , van Altena AM 72 , Vergote I 46 , Vestrheim Thomsen LC 11 , Vierkant RA 1 , Walsh CS 42 , Wang-Gohrke S 73 , Wentzensen N 13 , Whittemore AS 74 , Wicklund KG 27 , Wilkens LR 65 , Woo YL 44 , Wu AH 75 , Wu X 37 , Xiang YB 76 , Yang H 13 , Zheng W 77 , Ziogas A 6 , Lee AW 78 , Pearce CL 79 , Berchuck A 80 , Schildkraut JM 81 , Ramus SJ 82 , Monteiro ANA 4 , Narod SA 83 , Sellers TA 4 , Gayther SA 84 , Kelemen LE 85 , Chenevix-Trench G 86 , Risch HA 87 , Pharoah PDP 2 , Goode EL 1 , Phelan CM 4

Affiliations 

  • 1 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
  • 2 Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom
  • 3 Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, United States of America
  • 4 Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, United States of America
  • 5 Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
  • 6 Genetic Epidemiology Research Institute, UCI Center for Cancer Genetics Research and Prevention, School of Medicine, Department of Epidemiology, University of California Irvine, Irvine, CA, United States of America
  • 7 Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus
  • 8 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States of America
  • 9 Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, United States of America
  • 10 University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
  • 11 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
  • 12 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 13 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
  • 14 Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada
  • 15 Cancer Epidemiology & Intelligence Division, The Cancer Council Victoria, Melbourne, Australia
  • 16 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States of America
  • 17 Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
  • 18 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
  • 19 CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
  • 20 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 21 Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, United States of America
  • 22 Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
  • 23 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
  • 24 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 25 Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  • 26 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
  • 27 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
  • 28 Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  • 29 Department of Gynecology, Friedrich Schiller University, Jena, Germany
  • 30 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 31 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
  • 32 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
  • 33 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • 34 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America
  • 35 Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom
  • 36 Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States of America
  • 37 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
  • 38 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 39 Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 40 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
  • 41 Department of Statistics, Duke University, Durham, NC, United States of America
  • 42 Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
  • 43 Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
  • 44 Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  • 45 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
  • 46 Division of Gynecologic Oncology; Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium
  • 47 Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada
  • 48 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, United States of America
  • 49 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America
  • 50 College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States of America
  • 51 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
  • 52 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
  • 53 Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
  • 54 Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, United States of America
  • 55 Public Health Ontario, Toronto, ON, Canada
  • 56 The University of Texas School of Public Health, Houston, TX, United States of America
  • 57 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • 58 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, United States of America
  • 59 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America
  • 60 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
  • 61 Department of Gynecology-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 62 Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
  • 63 Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
  • 64 Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
  • 65 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States of America
  • 66 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America
  • 67 Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  • 68 Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland
  • 69 Division of Cancer Etiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America
  • 70 Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States of America
  • 71 Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 72 Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegan, The Netherlands
  • 73 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 74 Department of Health Research and Policy, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, United States of America
  • 75 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America
  • 76 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
  • 77 Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
  • 78 Department of Health Science, California State University, Fullerton, Fullerton, CA, United States of America
  • 79 Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States of America
  • 80 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, United States of America
  • 81 Department of Public Health Sciences, The University of Virginia, Charlottesville, VA, United States of America
  • 82 School of Women's and Children's Health, University of New South Wales, Sydney, Australia
  • 83 Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada
  • 84 Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
  • 85 Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, United States of America
  • 86 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 87 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, United States of America
PLoS ONE, 2018;13(7):e0197561.
PMID: 29979793 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.