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

Publication ,  Journal Article
Permuth, JB; Reid, B; Earp, M; Chen, YA; Monteiro, ANA; Chen, Z; AOCS Study Group, ; Chenevix-Trench, G; Fasching, PA; Beckmann, MW; Vergote, I ...
Published in: Oncotarget
November 8, 2016

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.

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Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

November 8, 2016

Volume

7

Issue

45

Start / End Page

72381 / 72394

Location

United States

Related Subject Headings

  • RNA Editing
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Middle Aged
  • Humans
  • Genetic Variation
  • Female
  • Disease Susceptibility
  • Animals
  • 3211 Oncology and carcinogenesis
 

Citation

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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://doi.org/10.18632/oncotarget.10546
Permuth, Jennifer B., Brett Reid, Madalene Earp, Y Ann Chen, Alvaro N. A. Monteiro, Zhihua Chen, Zhihua AOCS Study Group, et al. “Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration.Oncotarget 7, no. 45 (November 8, 2016): 72381–94. https://doi.org/10.18632/oncotarget.10546.
Permuth JB, Reid B, Earp M, Chen YA, Monteiro ANA, Chen Z, et al. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration. Oncotarget. 2016 Nov 8;7(45):72381–94.
Permuth, Jennifer B., et al. “Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration.Oncotarget, vol. 7, no. 45, Nov. 2016, pp. 72381–94. Pubmed, doi:10.18632/oncotarget.10546.
Permuth JB, Reid B, Earp M, Chen YA, Monteiro ANA, Chen Z, AOCS Study Group, Chenevix-Trench G, Fasching PA, Beckmann MW, 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, Dörk 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. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration. Oncotarget. 2016 Nov 8;7(45):72381–72394.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

November 8, 2016

Volume

7

Issue

45

Start / End Page

72381 / 72394

Location

United States

Related Subject Headings

  • RNA Editing
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Middle Aged
  • Humans
  • Genetic Variation
  • Female
  • Disease Susceptibility
  • Animals
  • 3211 Oncology and carcinogenesis