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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 NA. Monteiro, Zhihua Chen, AOCS Study Group, 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 DP 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

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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.

Author Information

Jennifer B. Permuth
Primary Contact  _

Brett Reid

Madalene Earp

Y. Ann Chen

Alvaro NA. Monteiro

Zhihua Chen

AOCS Study Group

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 DP 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


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