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PLoS One. 2018 Jul 6;13(7):e0197561. doi: 10.1371/journal.pone.0197561. eCollection 2018.

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

Earp M1, Tyrer JP2, Winham SJ1, Lin HY3,4, Chornokur G5, Dennis J2, Aben KKH6,7, Anton-Culver H8, Antonenkova N9, Bandera EV10, Bean YT11,12, Beckmann MW13, Bjorge L14,15, Bogdanova N16, Brinton LA17, Brooks-Wilson A18,19, Bruinsma F20, Bunker CH21, Butzow R22,23, Campbell IG24,25,26, Carty K27,28, Chang-Claude J29,30, Cook LS31, Cramer DW32, Cunningham JM33, Cybulski C34, Dansonka-Mieszkowska A35, Despierre E36, Doherty JA37,38, Dörk T16, du Bois A39,40, Dürst M41, Easton DF42,43, Eccles DM44, Edwards RP45, Ekici AB46, Fasching PA13,47, Fridley BL48, Gentry-Maharaj A49, Giles GG20,50, Glasspool R27, Goodman MT51, Gronwald J34, Harter P39,40, Hein A13, Heitz F39,40, Hildebrandt MAT52, Hillemanns P16, Hogdall CK53, Høgdall E54,55, Hosono S56, Iversen ES57, Jakubowska A34, Jensen A54, Ji BT17, Jung AY29, Karlan BY58, Kellar M11,12, Kiemeney LA7, Kiong Lim B59, Kjaer SK54,60, Krakstad C14, Kupryjanczyk J35, Lambrechts D61,62, Lambrechts S63, Le ND64, Lele S65, Lester J58, Levine DA66, Li Z1,67, Liang D68, Lissowska J69, Lu K70, Lubinski J34, Lundvall L53, Massuger LFAG71, Matsuo K56, McGuire V72, McLaughlin JR73, McNeish I73, Menon U49, Milne RL20,50, Modugno F21,45,74, Moysich KB65, Ness RB75, Nevanlinna H23, Odunsi K76, Olson SH77, Orlow I77, Orsulic S58, Paul J27, Pejovic T11,12, Pelttari LM23, Permuth JB5, Pike MC77, Poole EM78,79, Rosen B80, Rossing MA37, Rothstein JH81, Runnebaum IB41, Rzepecka IK35, Schernhammer E78,79, Schwaab I82, Shu XO83, Shvetsov YB84, Siddiqui N84, Sieh W81, Song H4, Southey MC26, Spiewankiewicz B85, Sucheston-Campbell L65, Tangen IL14, Teo SH86,87, Terry KL79,88, Thompson PJ51, Thomsen L89, Tworoger SS5,78,79, van Altena AM90, Vergote I63, Vestrheim Thomsen LC14, Vierkant RA1, Walsh CS58, Wang-Gohrke S91, Wentzensen N17, Whittemore AS92, Wicklund KG37, Wilkens LR84, Woo YL59,93, Wu AH94, Wu X52, Xiang YB95, Yang H17, Zheng W96, Ziogas A8, Lee AW97, Pearce CL88, Berchuck A98, Schildkraut JM99, Ramus SJ100,101, Monteiro ANA5, Narod SA102, Sellers TA5, Gayther SA103, Kelemen LE104, Chenevix-Trench G105, Risch HA106, Pharoah PDP2,107, Goode EL1, Phelan CM5.

Author information

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
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America.
5
Division of Population Sciences, Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, United States of America.
6
Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands.
7
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
8
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.
9
Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.
10
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States of America.
11
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, United States of America.
12
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States of America.
13
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany.
14
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
15
Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
16
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
17
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.
18
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
19
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
20
Cancer Epidemiology & Intelligence Division, The Cancer Council Victoria, Melbourne, Australia.
21
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States of America.
22
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
23
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
24
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
25
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
26
Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
27
CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
28
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, United Kingdom.
29
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
30
University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
31
Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, United States of America.
32
Obstetrics and Gynecology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
33
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America.
34
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
35
Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
36
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
37
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
38
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States of America.
39
Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
40
Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany.
41
Department of Gynecology, Friedrich Schiller University, Jena, Germany.
42
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
43
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
44
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
45
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.
46
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
47
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, United States of America.
48
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
49
Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
50
Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
51
Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States of America.
52
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
53
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
54
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
55
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
56
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.
57
Department of Statistics, Duke University, Durham, NC, United States of America.
58
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
59
Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
60
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
61
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
62
Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium.
63
Division of Gynecologic Oncology; Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
64
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
65
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, United States of America.
66
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.
67
Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China.
68
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, United States of America.
69
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland.
70
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
71
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
72
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, United States of America.
73
Public Health Ontario, Toronto, ON, Canada.
74
Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States of America.
75
The University of Texas School of Public Health, Houston, TX, United States of America.
76
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, United States of America.
77
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States of America.
78
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
79
Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States of America.
80
Department of Gynecology-Oncology, Princess Margaret Hospital, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
81
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.
82
Institut für Humangenetik Wiesbaden, Wiesbaden, Germany.
83
Epidemiology Center and Vanderbilt, Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
84
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States of America.
85
Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland.
86
Division of Cancer Etiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.
87
University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
88
Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States of America.
89
Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
90
Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegan, The Netherlands.
91
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
92
Department of Health Research and Policy, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, United States of America.
93
Cancer Research Malaysia, Subang Jaya Selangor, Malaysia.
94
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America.
95
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
96
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
97
Department of Health Science, California State University, Fullerton, Fullerton, CA, United States of America.
98
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, United States of America.
99
Department of Public Health Sciences, The University of Virginia, Charlottesville, VA, United States of America.
100
School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
101
The Garvan Institute, Sydney, New South Wales, Australia.
102
Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.
103
Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
104
Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, United States of America.
105
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
106
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, United States of America.
107
Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom.

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.

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