TY - JOUR
T1 - Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility
T2 - Results from a large-scale collaboration
AU - AOCS study group
AU - AOCS study group
AU - Permuth, Jennifer B.
AU - Reid, Brett
AU - Earp, Madalene
AU - Chen, Y. Ann
AU - Monteiro, Alvaro N.A.
AU - Chen, Zhihua
AU - Chenevix-Trench, Georgia
AU - Fasching, Peter A.
AU - Beckmann, Matthias W.
AU - Lambrechts, Diether
AU - Vanderstichele, Adriaan
AU - Van Niewenhuyse, Els
AU - Vergote, Ignace
AU - Rossing, Mary Anne
AU - Doherty, Jennifer Anne
AU - Chang-Claude, Jenny
AU - Moysich, Kirsten
AU - Odunsi, Kunle
AU - Goodman, Marc T.
AU - Shvetsov, Yurii B.
AU - Wilkens, Lynne R.
AU - Thompson, Pamela J.
AU - Dörk, Thilo
AU - Bogdanova, Natalia
AU - Butzow, Ralf
AU - Nevanlinna, Heli
AU - Pelttari, Liisa
AU - Leminen, Arto
AU - Modugno, Francesmary
AU - Edwards, Robert P.
AU - Ness, Roberta B.
AU - Kelley, Joseph
AU - Heitz, Florian
AU - Karlan, Beth
AU - Lester, Jenny
AU - Kjaer, Susanne K.
AU - Jensen, Allan
AU - Giles, Graham
AU - Hildebrandt, Michelle
AU - Liang, Dong
AU - Lu, Karen H.
AU - Wu, Xifeng
AU - Levine, Douglas A.
AU - Bisogna, Maria
AU - Berchuck, Andrew
AU - Cramer, Daniel W.
AU - Terry, Kathryn L.
AU - Cunningham, Julie
AU - Winham, Stacey J.
AU - Goode, Ellen L.
N1 - Funding Information:
Funding for this study was supported in part by the US National Institute of Health (R01-CA-11343 and R01-CA114343-S1) and the Genetic Associations and Mechanisms in Oncology (GAME-ON), a NCI Cancer Post-GWAS Initiative (U19-CA148112). In addition, we acknowledge the following: AUS: U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia, Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia (199600 and 400281). The Australian Ovarian Cancer Study Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) and ACS Investigators (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all the clinical and scientific collaborators (see http://www.aocstudy.org/) and the women for their contribution. GCT & PW are supported by Fellowships from NHMRC; AP is funded by a Medical Research Council studentship; BAV: ELAN funds of the University of Erlangen-Nuremberg. BEL: Nationaal Kankerplan, we would like to thank Gilian Peuteman, Thomas Van Brussel, Annick Van den Broeck and Joke De Roover for technical assistance; DOV: U.S. National Institutes of Health R01-CA112523 and R01-CA87538; GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ). GRR: Roswell Park Cancer Institute Alliance Foundation, P30 CA016056. HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); HJO and HMO: Intramural funding; Rudolf-Bartling Foundation; HOC: Helsinki University Research Fund; HOP: DOD DAMD17-02-1-0669 and NCI K07-CA080668, R01-CA95023, P50-CA159981; NIH/National Center for Research Resources/General Clinical Research Center grant M01-RR000056; R01-CA126841; LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; MAL: Funding for this study was provided by research grant R01-CA61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project.; MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393), Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MCC: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database;; MDA: DOD Ovarian Cancer Research Program (W81XWH-07-0449); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH-10-1-02802; NHS: National Institute of Health (UM1-CA176726, and R01-CA67262). The NHS would like to thank the participants and staff for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey, and NCI CCSG award (P30-CA008748); NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP-86727) and by NIH/NCI 1 R01CA160669-01A1; POC: Pomeranian Medical University; POL: Intramural Research Program of the NCI; PVD: Herlev Hospitals Forskningsrad, Direktor Jacob Madsens og Hustru Olga Madsens fond, Arvid Nilssons fond, Gangsted fonden, Herlev Hospitals Forskningsrad and Danish Cancer Society; RMH: Cancer Research UK (no grant number is available); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy; SRO: Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589) and to thank all members of Scottish Gynaecological Clinical Trials group and COTROC1 investigators; STA: US National Institutes of Health U01-CA71966, R01-CA16056, K07-CA143047, and U01-CA69417 for recruitment of controls by the Cancer Prevention Institute of California; TOR: NIH grants R01 CA063678, CA063682, and CA149429; UCI: NIH R01-CA058860, and the Lon V Smith Foundation grant VLS-39420; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We particularly thank I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study; UKR: Cancer Research UK (C490/A6187); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; USC: P01-CA17054, P30-CA14089, R01-CA61132, N01-PC67010, R03-CA113148, R03-CA115195, N01-CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200). WOC: National Science Centren (N N301 5645 40) The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. This study was supported in part by the Biostatistics and Cancer Informatics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292).
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Ovarian cancer risk
KW - Polymorphisms
KW - RNA editing
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U2 - 10.18632/oncotarget.10546
DO - 10.18632/oncotarget.10546
M3 - Article
C2 - 27911851
AN - SCOPUS:84995776558
SN - 1949-2553
VL - 7
SP - 72381
EP - 72394
JO - Oncotarget
JF - Oncotarget
IS - 45
ER -