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

Permuth JB, Reid B, Earp M, Chen YA, Monteiro ANA, Chen Z, Chenevix-Trench G, Fasching P, Beckmann M, Lambrechts D, Vanderstichele A, Van Niewenhuyse E, Vergote I, Rossing MA, Doherty JA, Chang-Claude J, Moysich K, Odunsi K, Goodman MT, Shvetsov YB, Wilkens LR, Thompson PJ, Doerk T, Bogdanova N, Butzow R, Nevanlinna H, Pelttari L, Leminen A, Modugno F, Edwards RP, Ness RB, Kelley J, Heitz F, Karlan B, Lester J, Kjaer SK, Jensen A, Giles G, Hildebrandt M, Liang D, Lu KH, Wu X, Levine DA, Bisogna M, Berchuck A, Cramer DW, Terry KL, Tworoger SS, Poole EM, Bandera EV, Fridley B, Cunningham J, Winham SJ, Olson SH, Orlow I, Bjorge L, Kiemeney LA, Massuger L, Pejovic T, Moffitt M, Le N, Cook LS, Brooks-Wilson A, Kelemen LE, Gronwald J, Lubinski J, Wentzensen N, Brinton LA, Lissowska J, Yang H, Hogdall E, Hogdall C, Lundvall L, Pharoah PDP, Song H, Campbell I, Eccles D, Mcneish I, Whittemore A, Mcguire V, Sieh W, Rothstein J, Phelan CM, Risch H, Narod S, Mclaughlin J, Anton-Culver H, Ziogas A, Menon U, Gayther S, Ramus SJ, Gentry-Maharaj A, Pearce CL, Wu AH, Kupryjanczyk J, Dansonka-Mieszkowska A, Schildkraut JM, Cheng JQ, Goode EL, Sellers TA (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 7

Pages Range: 72381-72394

Journal Issue: 45

DOI: 10.18632/oncotarget.10546

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.

Authors with CRIS profile

Involved external institutions

Mayo Clinic United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Danish Cancer Society Denmark (DK) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Helsingin yliopisto / University of Helsinki Finland (FI) University of Cambridge United Kingdom (GB) University of Glasgow United Kingdom (GB) Memorial Sloan Kettering Cancer Center United States (USA) (US) Radboud University Nijmegen Netherlands (NL) Dartmouth College United States (USA) (US) Fred Hutchinson Cancer Research Center Canada (CA) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of California Irvine United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Harvard University United States (USA) (US) Duke University United States (USA) (US) University of Southampton United Kingdom (GB) Kliniken Essen-Mitte Germany (DE) Roswell Park Cancer Institute United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) University of Kansas (KU) United States (USA) (US) Rigshospitalet Denmark (DK) University of Southern California (USC) United States (USA) (US) Yale University United States (USA) (US) University of Toronto Canada (CA) Peter MacCallum Cancer Centre Australia (AU) The University of Melbourne Australia (AU) University of Hawaii (U.H.) United States (USA) (US) Stanford University United States (USA) (US) University of Pittsburgh United States (USA) (US) Oregon Health and Science University (OSHU) United States (USA) (US) Public Health Ontario Canada (CA) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Brigham and Women's Hospital (BWH) United States (USA) (US) University College London (UCL) United Kingdom (GB) University of Texas MD Anderson Cancer Center United States (USA) (US) British Columbia Cancer Agency Canada (CA) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Texas Southern University (TSU) United States (USA) (US) Rutgers Cancer Institute of New Jersey United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of Bergen / Universitetet i Bergen Norway (NO) Medical University of South Carolina (MUSC) United States (USA) (US)

How to cite

APA:

Permuth, J.B., Reid, B., Earp, M., Chen, Y.A., Monteiro, A.N.A., Chen, Z.,... Sellers, T.A. (2016). Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration. Oncotarget, 7(45), 72381-72394. https://dx.doi.org/10.18632/oncotarget.10546

MLA:

Permuth, Jennifer B., et al. "Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration." Oncotarget 7.45 (2016): 72381-72394.

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