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=1.0×10−4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0×10−4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0×10−4). 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.
Highlights
Over the past decade it has been recognized that the complexity of higher organisms is related to the information stored in non-protein-coding regions of the genome
Such complexity may be attributed to a range of processing events and post-transcriptional modifications that affect the fate of RNA, including alternative splicing, 5’ capping, 3’ polyadenylation, and RNA editing [1,2,3]
The most common type of RNA editing in eukaryotes is site-selective hydrolytic deamination of adenosine into inosine (A-to-I) within double-stranded RNAs, and recent bioinformatic analyses and high-throughput sequencing efforts have revealed that A-to-I editing is widespread and alters non-coding and protein-coding sequences throughout the genome [4]
Summary
Over the past decade it has been recognized that the complexity of higher organisms is related to the information stored in non-protein-coding regions of the genome. Such complexity may be attributed to a range of processing events and post-transcriptional modifications that affect the fate of RNA, including alternative splicing, 5’ capping, 3’ polyadenylation, and RNA editing [1,2,3]. A-to-I editing is mediated by a family of adenosine deaminases acting on RNA (ADARs), and this process modulates expression of genes and biological pathways via several mechanisms [4]. Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States [5], and ADAR expression levels have been reported to be significantly higher in serum and peritoneal fluid from patients with EOCs compared with benign ovarian tumors [6, 7], suggesting ADARs may be useful biomarkers for the diagnosis and management of EOC
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