학술논문
Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration
Document Type
article
Author
Permuth, Jennifer B; Reid, Brett; Earp, Madalene; Chen, Y Ann; Monteiro, Alvaro NA; Chen, Zhihua; Group, AOCS Study; Chenevix-Trench, Georgia; Fasching, Peter A; Beckmann, Matthias W; Lambrechts, Diether; Vanderstichele, Adriaan; Van Niewenhuyse, Els; Vergote, Ignace; Rossing, Mary Anne; Doherty, Jennifer Anne; Chang-Claude, Jenny; Moysich, Kirsten; Odunsi, Kunle; Goodman, Marc T; Shvetsov, Yurii B; Wilkens, Lynne R; Thompson, Pamela J; Dörk, Thilo; Bogdanova, Natalia; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa; Leminen, Arto; Modugno, Francesmary; Edwards, Robert P; Ness, Roberta B; Kelley, Joseph; Heitz, Florian; Karlan, Beth; Lester, Jenny; Kjaer, Susanne K; Jensen, Allan; Giles, Graham; Hildebrandt, Michelle; Liang, Dong; Lu, Karen H; Wu, Xifeng; Levine, Douglas A; Bisogna, Maria; Berchuck, Andrew; Cramer, Daniel W; Terry, Kathryn L; Tworoger, Shelley S; Poole, Elizabeth M; Bandera, Elisa V; Fridley, Brooke; Cunningham, Julie; Winham, Stacey J; Olson, Sara H; Orlow, Irene; Bjorge, Line; Kiemeney, Lambertus A; Massuger, Leon; Pejovic, Tanja; Moffitt, Melissa; Le, Nhu; Cook, Linda S; Brooks-Wilson, Angela; Kelemen, Linda E; Gronwald, Jacek; Lubinski, Jan; Wentzensen, Nicolas; Brinton, Louise A; Lissowska, Jolanta; Yang, Hanna; Hogdall, Estrid; Hogdall, Claus; Lundvall, Lene; Pharoah, Paul DP; Song, Honglin; Campbell, Ian; Eccles, Diana; McNeish, Iain; Whittemore, Alice; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph; Phelan, Catherine M; Risch, Harvey; Narod, Steven; McLaughlin, John; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Gayther, Simon; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Pearce, Celeste Leigh; Wu, Anna H; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Schildkraut, Joellen M; Cheng, Jin Q; Goode, Ellen L
Source
Oncotarget. 5
Subject
Language
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