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

Jennifer B. Permuth, Moffitt Cancer Center
Brett Reid, Moffitt Cancer Center
Madalene Earp, Mayo Clinic
Y. Ann Chen, Moffitt Cancer Center
Alvaro N.A. Monteiro, Moffitt Cancer Center
Zhihua Chen, Moffitt Cancer Center
Georgia Chenevix-Trench, QIMR Berghofer Medical Research Institute
Peter A. Fasching, David Geffen School of Medicine at UCLA
Matthias W. Beckmann, Universitätsklinikum Erlangen
Diether Lambrechts, Flanders Interuniversity Institute for Biotechnology
Adriaan Vanderstichele, KU Leuven– University Hospital Leuven
Els Van Niewenhuyse, KU Leuven– University Hospital Leuven
Ignace Vergote, KU Leuven– University Hospital Leuven
Mary Anne Rossing, Fred Hutchinson Cancer Research Center
Jennifer Anne Doherty, Dartmouth College
Jenny Chang-Claude, German Cancer Research Center
Kirsten Moysich, Roswell Park Cancer Institute
Kunle Odunsi, Roswell Park Cancer Institute
Marc T. Goodman, Cedars-Sinai Medical Center
Yurii B. Shvetsov, University of Hawaiʻi Cancer Center
Lynne R. Wilkens, University of Hawaiʻi Cancer Center


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.