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Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration
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Abstract
Jennifer B. Permuth1, Brett Reid1, Madalene Earp2, Y. Ann Chen3, Alvaro N.A. Monteiro1, Zhihua Chen3, AOCS Study Group4,5, Georgia Chenevix-Trench4, Peter A. Fasching6,7, Matthias W. Beckmann7, Diether Lambrechts8,9, Adriaan Vanderstichele10, Els Van Niewenhuyse10, Ignace Vergote10, Mary Anne Rossing11,12, Jennifer Anne Doherty13, Jenny Chang-Claude14,15, Kirsten Moysich16, Kunle Odunsi17, Marc T. Goodman18,19, Yurii B. Shvetsov20, Lynne R. Wilkens20, Pamela J. Thompson18,19, Thilo Dörk21, Natalia Bogdanova22, Ralf Butzow23, Heli Nevanlinna24, Liisa Pelttari24, Arto Leminen24, Francesmary Modugno25,26,27, Robert P. Edwards25,26, Roberta B. Ness28, Joseph Kelley25, Florian Heitz29,30, Beth Karlan31, Jenny Lester31, Susanne K. Kjaer32,33, Allan Jensen32, Graham Giles34,35,36, Michelle Hildebrandt37, Dong Liang38, Karen H. Lu39, Xifeng Wu37, Douglas A. Levine40, Maria Bisogna40, Andrew Berchuck41, Daniel W. Cramer42,43, Kathryn L. Terry42,43, Shelley S. Tworoger43,44, Elizabeth M. Poole44, Elisa V. Bandera45, Brooke Fridley46, Julie Cunningham2, Stacey J. Winham2, Sara H. Olson47, Irene Orlow47, Line Bjorge48,49, Lambertus A. Kiemeney50, Leon Massuger51, Tanja Pejovic52,53, Melissa Moffitt52,53, Nhu Le54, Linda S. Cook55, Angela Brooks-Wilson56,57, Linda E. Kelemen58, Jacek Gronwald59, Jan Lubinski59, Nicolas Wentzensen60, Louise A. Brinton60, Jolanta Lissowska61, Hanna Yang60, Estrid Hogdall32, Claus Hogdall62, Lene Lundvall62, Paul D.P. Pharoah63,64, Honglin Song64, Ian Campbell5,65, Diana Eccles66, Iain McNeish67, Alice Whittemore68, Valerie McGuire68, Weiva Sieh68, Joseph Rothstein68, Catherine M. Phelan1, Harvey Risch69, Steven Narod70, John McLaughlin71, Hoda Anton-Culver72, Argyrios Ziogas73, Usha Menon69, Simon Gayther74, Susan J. Ramus74, Aleksandra Gentry-Maharaj75, Celeste Leigh Pearce74,76, Anna H. Wu74, Jolanta Kupryjanczyk77, Agnieszka Dansonka-Mieszkowska77, Joellen M. Schildkraut78,79, Jin Q. Cheng80, Ellen L. Goode2 and Thomas A. Sellers1,81
1 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
2 Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
3 Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
4 Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Queensland, Australia
5 Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
6 David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA
7 University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany
8 Vesalius Research Center, VIB, Leuven, Belgium
9 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
10 Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
11 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
12 Department of Epidemiology, University of Washington, Seattle, WA, USA
13 Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NY, USA
14 German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany
15 University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
16 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
17 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
18 Cancer Prevention and Control, Samuel Oshin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
19 Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
20 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
21 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
22 Radiaton Oncology Research Unit, Hannover Medical School, Hannover, Germany
23 Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
24 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
25 Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
26 Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute & University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
27 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
28 The University of Texas School of Public Health, Houston, TX, USA
29 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
30 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany
31 Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
32 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
33 Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
34 Cancer Epidemiology Centre, Melbourne, Australia
35 Centre for Epidemiology and Biostatistics, University of Melbourne, Australia
36 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
37 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
38 College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA
39 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
40 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
41 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
42 Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital, Boston, MA, USA
43 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
44 Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
45 Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
46 Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
47 Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, USA
48 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
49 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
50 Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, Netherlands
51 Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gynaecology, Nijmegen, The Netherlands
52 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA
53 Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA
54 Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada
55 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
56 Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver BC, Canada
57 Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
58 Department of Public Health Sciences, Medical University of South Carolina College of Medicine, Charleston, SC, USA
59 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
60 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
61 Department of Cancer Epidemiology and Prevention, The Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
62 The Juliane Marie Centre, Department of Obstetrics and Gynecology, Rigshospitalet, Copenhagen, Denmark
63 Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
64 Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
65 Department of Pathology, University of Melbourne, Parkville, VIC, Australia
66 Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK
67 Institute of Cancer Sciences, Unversity of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK
68 Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA
69 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
70 Women’s College Research Institute, University of Toronto, Toronto, ON, Canada
71 Public Health Ontario, Toronto, ON, Canada
72 Department of Epidemiology, Director of Genetic Epidemiology Research Institute, UCI School of Medicine, University of California Irvine, Irvine, CA, USA
73 Department of Epidemiology, University of California Irvine, Irvine, CA, USA
74 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
75 Women’s Cancer, Institute for Women’s Health, University College London, London, UK
76 Department of Epidemology,University of Michigan School of Public Health, Ann Arbor, MI, USA
77 Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
78 Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA
79 Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA
80 Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA
81 Ovarian Cancer Association Consortium
Correspondence to:
Jennifer B. Permuth, email:
Keywords: polymorphisms, RNA editing, ovarian cancer risk
Received: April 08, 2016 Accepted: June 13, 2016 Published: July 12, 2016
Abstract
RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3’ untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.
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