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Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

2016; Impact Journals LLC; Volume: 7; Issue: 45 Linguagem: Inglês

10.18632/oncotarget.10546

1949-2553

Jennifer B. Permuth, Brett M. Reid, Madalene A. Earp, Y. Ann Chen, Álvaro N.A. Monteiro, Zhihua Chen, Georgia Chenevix‐Trench, Peter A. Fasching, Matthias W. Beckmann, Diether Lambrechts, Adriaan Vanderstichele, Els Van Niewenhuyse, Ignace Vergote, Mary Anne Rossing, Jennifer A. Doherty, Jenny Chang‐Claude, Kirsten Moysich, Kunle Odunsi, Marc T. Goodman, Yurii B. Shvetsov, Lynne R. Wilkens, Pamela J. Thompson, Thilo Dörk, Natalia Bogdanova, Ralf Bützow, Heli Nevanlinna, Liisa M. Pelttari, Arto Leminen, Francesmary Modugno, Robert P. Edwards, Roberta B. Ness, Joseph L. Kelley, Florian Heitz, Beth Y. Karlan, Jenny Lester, Susanne K. Kjær, Allan Jensen, Graham G. Giles, Michelle Hildebrandt, Dong Liang, Karen H. Lu, Xifeng Wu, Douglas A. Levine, Maria Bisogna, Andrew Berchuck, Daniel W. Cramer, Kathryn L. Terry, Shelley S. Tworoger, Elizabeth M. Poole, Elisa V. Bandera, Brooke L. Fridley, Julie M. Cunningham, Stacey J. Winham, Sara H. Olson, Irene Orlow, Line Bjørge, Lambertus A. Kiemeney, Leon F.A.G. Massuger, Tanja Pejović, Melissa Moffitt, Nhu Le, Linda S. Cook, Angela Brooks‐Wilson, Linda E. Kelemen, Jacek Gronwald, Jan Lubiński, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Hanna Yang, Estrid Høgdall, Claus Høgdall, Lene Lundvall, Paul D.P. Pharoah, Honglin Song, Ian Campbell, Diana Eccles, Iain A. McNeish, Alice S. Whittemore, Valerie McGuire, Weiva Sieh, Joseph H. Rothstein, Catherine M. Phelan, Harvey A. Risch, Steven A. Narod, Esther M. John, Hoda Anton‐Culver, Argyrios Ziogas, Usha Menon, Simon A. Gayther, Susan J. Ramus, Aleksandra Gentry‐Maharaj, Celeste Leigh Pearce, Anna H. Wu, Jolanta Kupryjańczyk, Agnieszka Dansonka‐Mieszkowska, Joellen M. Schildkraut, Jin Q. Cheng, Ellen L. Goode, Thomas A. Sellers,

Cancer-related molecular mechanisms research

// Jennifer B. Permuth 1 , Brett Reid 1 , Madalene Earp 2 , Y. Ann Chen 3 , Alvaro N.A. Monteiro 1 , Zhihua Chen 3 , AOCS Study Group 4,5 , Georgia Chenevix-Trench 4 , Peter A. Fasching 6,7 , Matthias W. Beckmann 7 , Diether Lambrechts 8,9 , Adriaan Vanderstichele 10 , Els Van Niewenhuyse 10 , Ignace Vergote 10 , Mary Anne Rossing 11,12 , Jennifer Anne Doherty 13 , Jenny Chang-Claude 14,15 , Kirsten Moysich 16 , Kunle Odunsi 17 , Marc T. Goodman 18,19 , Yurii B. Shvetsov 20 , Lynne R. Wilkens 20 , Pamela J. Thompson 18,19 , Thilo Dörk 21 , Natalia Bogdanova 22 , Ralf Butzow 23 , Heli Nevanlinna 24 , Liisa Pelttari 24 , Arto Leminen 24 , Francesmary Modugno 25,26,27 , Robert P. Edwards 25,26 , Roberta B. Ness 28 , Joseph Kelley 25 , Florian Heitz 29,30 , Beth Karlan 31 , Jenny Lester 31 , Susanne K. Kjaer 32,33 , Allan Jensen 32 , Graham Giles 34,35,36 , Michelle Hildebrandt 37 , Dong Liang 38 , Karen H. Lu 39 , Xifeng Wu 37 , Douglas A. Levine 40 , Maria Bisogna 40 , Andrew Berchuck 41 , Daniel W. Cramer 42,43 , Kathryn L. Terry 42,43 , Shelley S. Tworoger 43,44 , Elizabeth M. Poole 44 , Elisa V. Bandera 45 , Brooke Fridley 46 , Julie Cunningham 2 , Stacey J. Winham 2 , Sara H. Olson 47 , Irene Orlow 47 , Line Bjorge 48,49 , Lambertus A. Kiemeney 50 , Leon Massuger 51 , Tanja Pejovic 52,53 , Melissa Moffitt 52,53 , Nhu Le 54 , Linda S. Cook 55 , Angela Brooks-Wilson 56,57 , Linda E. Kelemen 58 , Jacek Gronwald 59 , Jan Lubinski 59 , Nicolas Wentzensen 60 , Louise A. Brinton 60 , Jolanta Lissowska 61 , Hanna Yang 60 , Estrid Hogdall 32 , Claus Hogdall 62 , Lene Lundvall 62 , Paul D.P. Pharoah 63,64 , Honglin Song 64 , Ian Campbell 5,65 , Diana Eccles 66 , Iain McNeish 67 , Alice Whittemore 68 , Valerie McGuire 68 , Weiva Sieh 68 , Joseph Rothstein 68 , Catherine M. Phelan 1 , Harvey Risch 69 , Steven Narod 70 , John McLaughlin 71 , Hoda Anton-Culver 72 , Argyrios Ziogas 73 , Usha Menon 69 , Simon Gayther 74 , Susan J. Ramus 74 , Aleksandra Gentry-Maharaj 75 , Celeste Leigh Pearce 74,76 , Anna H. Wu 74 , Jolanta Kupryjanczyk 77 , Agnieszka Dansonka-Mieszkowska 77 , Joellen M. Schildkraut 78,79 , Jin Q. Cheng 80 , Ellen L. Goode 2 and Thomas A. Sellers 1,81 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 P AML =0.022 and P SKAT-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.