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Oncotarget. 2016 Nov 8;7(45):72381-72394. doi: 10.18632/oncotarget.10546.

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

Author information

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.

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.

KEYWORDS:

RNA editing; ovarian cancer risk; polymorphisms

PMID:
27911851
PMCID:
PMC5340123
DOI:
10.18632/oncotarget.10546
[Indexed for MEDLINE]
Free PMC Article

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