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

Jennifer B Permuth; Brett Reid; Madalene Earp; Y Ann Chen; Alvaro 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 Anne 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 Butzow; Heli Nevanlinna; Liisa Pelttari; Arto Leminen; Francesmary Modugno; Robert P Edwards; Roberta B Ness; Joseph Kelley; Florian Heitz; Beth Karlan; Jenny Lester; Susanne K Kjaer; Allan Jensen; Graham 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 Fridley; Julie Cunningham; Stacey J Winham; Sara H Olson; Irene Orlow; Line Bjorge; Lambertus A Kiemeney; Leon Massuger; Tanja Pejovic; Melissa Moffitt; Nhu Le; Linda S Cook; Angela Brooks-Wilson; Linda E Kelemen; Jacek Gronwald; Jan Lubinski; Nicolas Wentzensen; Louise A Brinton; Jolanta Lissowska; Hanna Yang; Estrid Hogdall; Claus Hogdall; Lene Lundvall; Paul D P Pharoah; Honglin Song; Ian Campbell; Diana Eccles; Iain McNeish; Alice Whittemore; Valerie McGuire; Weiva Sieh; Joseph Rothstein; Catherine M Phelan; Harvey Risch; Steven Narod; John McLaughlin; Hoda Anton-Culver; Argyrios Ziogas; Usha Menon; Simon Gayther; Susan J Ramus; Aleksandra Gentry-Maharaj; Celeste Leigh Pearce; Anna H Wu; Jolanta Kupryjanczyk; Agnieszka Dansonka-Mieszkowska; Joellen M Schildkraut; Jin Q Cheng; Ellen L Goode; Thomas A Sellers; AOCS Study Group

doi:10.18632/oncotarget.10546

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

Journal article

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Peer reviewed

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

Jennifer B Permuth, Brett Reid, Madalene Earp, Y Ann Chen, Alvaro N A Monteiro, Zhihua Chen, Georgia Chenevix-Trench, Peter A Fasching, Matthias W Beckmann, Diether Lambrechts, …

Oncotarget, Vol.7(45), pp.72381-72394

11/08/2016

DOI: https://doi.org/10.18632/oncotarget.10546

PMCID: PMC5340123

PMID: 27911851

Abstract

Animals

Disease Susceptibility

Female

Genetic Variation - genetics

Humans

Middle Aged

Ovarian Neoplasms - genetics

Polymorphism, Single Nucleotide

RNA Editing - genetics

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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Title: Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration
Creators: Jennifer B Permuth - Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
Brett Reid - Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
Madalene Earp - Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
Y Ann Chen - Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
Alvaro N A Monteiro - Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
Zhihua Chen - Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
Georgia Chenevix-Trench - Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Queensland, Australia
Peter A Fasching - University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany
Matthias W Beckmann - University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany
Diether Lambrechts - Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
Adriaan Vanderstichele - Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
Els Van Niewenhuyse - Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
Ignace Vergote - Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
Mary Anne Rossing - Department of Epidemiology, University of Washington, Seattle, WA, USA
Jennifer Anne Doherty - Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NY, USA
Jenny Chang-Claude - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Kirsten Moysich - Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
Kunle Odunsi - Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
Marc T Goodman - Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Yurii B Shvetsov - Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
Lynne R Wilkens - Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
Pamela J Thompson - Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Thilo Dörk - Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
Natalia Bogdanova - Radiaton Oncology Research Unit, Hannover Medical School, Hannover, Germany
Ralf Butzow - Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Heli Nevanlinna - Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Liisa Pelttari - Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Arto Leminen - Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Francesmary Modugno - Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
Robert P Edwards - Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute & University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
Roberta B Ness - The University of Texas School of Public Health, Houston, TX, USA
Joseph Kelley - Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Florian Heitz - Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany
Beth Karlan - Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
Jenny Lester - Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
Susanne K Kjaer - Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Allan Jensen - Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
Graham Giles - Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
Michelle Hildebrandt - Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Dong Liang - College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA
Karen H Lu - Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Xifeng Wu - Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Douglas A Levine - Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Maria Bisogna - Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Andrew Berchuck - Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
Daniel W Cramer - Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Kathryn L Terry - Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Shelley S Tworoger - Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Elizabeth M Poole - Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Elisa V Bandera - Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
Brooke Fridley - Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
Julie Cunningham - Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
Stacey J Winham - Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
Sara H Olson - Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, USA
Irene Orlow - Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, USA
Line Bjorge - Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
Lambertus A Kiemeney - Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, Netherlands
Leon Massuger - Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gynaecology, Nijmegen, The Netherlands
Tanja Pejovic - Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA
Melissa Moffitt - Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA
Nhu Le - Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada
Linda S Cook - Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
Angela Brooks-Wilson - Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
Linda E Kelemen - Department of Public Health Sciences, Medical University of South Carolina College of Medicine, Charleston, SC, USA
Jacek Gronwald - International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Jan Lubinski - International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Nicolas Wentzensen - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Louise A Brinton - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Jolanta Lissowska - Department of Cancer Epidemiology and Prevention, The Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
Hanna Yang - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Estrid Hogdall - Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
Claus Hogdall - The Juliane Marie Centre, Department of Obstetrics and Gynecology, Rigshospitalet, Copenhagen, Denmark
Lene Lundvall - The Juliane Marie Centre, Department of Obstetrics and Gynecology, Rigshospitalet, Copenhagen, Denmark
Paul D P Pharoah - Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
Honglin Song - Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
Ian Campbell - Department of Pathology, University of Melbourne, Parkville, VIC, Australia
Diana Eccles - Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK
Iain McNeish - Institute of Cancer Sciences, Unversity of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK
Alice Whittemore - Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA
Valerie McGuire - Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA
Weiva Sieh - Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA
Joseph Rothstein - Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA
Catherine M Phelan - Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
Harvey Risch - Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
Steven Narod - Women's College Research Institute, University of Toronto, Toronto, ON, Canada
John McLaughlin - Public Health Ontario, Toronto, ON, Canada
Hoda Anton-Culver - Department of Epidemiology, Director of Genetic Epidemiology Research Institute, UCI School of Medicine, University of California Irvine, Irvine, CA, USA
Argyrios Ziogas - Department of Epidemiology, University of California Irvine, Irvine, CA, USA
Usha Menon - Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
Simon Gayther - Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
Susan J Ramus - Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
Aleksandra Gentry-Maharaj - Women's Cancer, Institute for Women's Health, University College London, London, UK
Celeste Leigh Pearce - Department of Epidemology,University of Michigan School of Public Health, Ann Arbor, MI, USA
Anna H Wu - Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
Jolanta Kupryjanczyk - Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
Agnieszka Dansonka-Mieszkowska - Department of Pathology and Laboratory Diagnostics, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
Joellen M Schildkraut - Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA
Jin Q Cheng - Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA
Ellen L Goode - Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
Thomas A Sellers - Ovarian Cancer Association Consortium
AOCS Study Group
Publication Details: Oncotarget, Vol.7(45), pp.72381-72394
Date published: 11/08/2016
Grant note: R03 CA113148 / NCI NIH HHS N01 CN025403 / NCI NIH HHS R01 CA058860 / NCI NIH HHS UM1 CA176726 / NCI NIH HHS K22 CA138563 / NCI NIH HHS R01 CA160669 / NCI NIH HHS 10119 / Cancer Research UK R01 CA063678 / NCI NIH HHS R03 CA115195 / NCI NIH HHS P30 CA015083 / NCI NIH HHS K07 CA095666 / NCI NIH HHS R01 CA112523 / NCI NIH HHS R01 CA149429 / NCI NIH HHS R01 CA114343 / NCI NIH HHS U01 CA069417 / NCI NIH HHS R01 CA063682 / NCI NIH HHS R01 CA058598 / NCI NIH HHS M01 RR000056 / NCRR NIH HHS P01 CA017054 / NCI NIH HHS 10124 / Cancer Research UK P50 CA159981 / NCI NIH HHS U19 CA148112 / NCI NIH HHS R01 CA067262 / NCI NIH HHS UL1 TR001863 / NCATS NIH HHS P50 CA105009 / NCI NIH HHS UL1 TR000124 / NCATS NIH HHS R01 CA083918 / NCI NIH HHS P30 CA076292 / NCI NIH HHS N01 PC067010 / NCI NIH HHS R01 CA054419 / NCI NIH HHS R01 CA095023 / NCI NIH HHS K07 CA080668 / NCI NIH HHS K07 CA143047 / NCI NIH HHS P30 CA016056 / NCI NIH HHS P30 CA008748 / NCI NIH HHS R01 CA087538 / NCI NIH HHS P50 CA136393 / NCI NIH HHS R01 CA122443 / NCI NIH HHS R01 CA126841 / NCI NIH HHS P30 CA014089 / NCI NIH HHS G0501974 / Medical Research Council P30 CA072720 / NCI NIH HHS
Academic Unit: Cancer Epidemiology and Health Outcomes
Language: English
Resource Type: Journal article
Identifiers: 991031665428704646