Article open access publication

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

Oncotarget, Impact Journals, LLC, ISSN 1949-2553

Volume 5, 0, 2016

DOI:10.18632/oncotarget.10546, Dimensions: pub.1021420810, PMC: PMC5340123, PMID: 27911851,

Authors

Rossing, Mary Anne (10) (11)
Edwards, Robert P. (20) (21)
Heitz, Florian (23) (24)
Kjaer, Susanne K. (25) (26)
Giles, Graham (27) (28) (29)
Wu, Xifeng (30)
Cramer, Daniel W. (34) (35)
Terry, Kathryn L (34) (35)
Bjorge, Line (38) (39)
Le, Nhu (42)
Campbell, Ian (3) (29)
Wu, Anna H (58)

Affiliations

Organisations

  1. (1) Moffitt Cancer Center, grid.468198.a
  2. (2) Mayo Clinic, grid.66875.3a
  3. (3) Peter MacCallum Cancer Centre, grid.1055.1
  4. (4) QIMR Berghofer Medical Research Institute, grid.1049.c
  5. (5) University of California, Los Angeles, grid.19006.3e
  6. (6) 7, University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany
  7. (7) Flanders Institute for Biotechnology, grid.11486.3a
  8. (8) KU Leuven, grid.5596.f
  9. (9) Universitair Ziekenhuis Leuven, grid.410569.f
  10. (10) Fred Hutchinson Cancer Research Center, grid.270240.3
  11. (11) University of Washington, grid.34477.33
  12. (12) Dartmouth College, grid.254880.3
  13. (13) German Cancer Research Center, grid.7497.d
  14. (14) University Cancer Center Hamburg, grid.412315.0
  15. (15) Roswell Park Cancer Institute, grid.240614.5
  16. (16) Cedars-Sinai Medical Center, grid.50956.3f
  17. (17) University of Hawaii at Manoa, grid.410445.0
  18. (18) Hannover Medical School, grid.10423.34
  19. (19) Helsinki University Central Hospital, grid.15485.3d
  20. (20) University of Pittsburgh Cancer Institute, grid.478063.e
  21. (21) University of Pittsburgh, grid.21925.3d
  22. (22) The University of Texas Health Science Center at Houston, grid.267308.8
  23. (23) 29, Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
  24. (24) Helios Dr. Horst Schmidt Kliniken Wiesbaden, grid.491861.3
  25. (25) 33, Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  26. (26) Danish Cancer Society, grid.417390.8
  27. (27) 34, Cancer Epidemiology Centre, Melbourne, Australia
  28. (28) Monash University, grid.1002.3
  29. (29) University of Melbourne, grid.1008.9
  30. (30) The University of Texas MD Anderson Cancer Center, grid.240145.6
  31. (31) Texas Southern University, grid.264771.1
  32. (32) Memorial Sloan Kettering Cancer Center, grid.51462.34
  33. (33) Duke University Hospital, grid.189509.c
  34. (34) Harvard University, grid.38142.3c
  35. (35) Brigham and Women's Hospital, grid.62560.37
  36. (36) Rutgers, The State University of New Jersey, grid.430387.b
  37. (37) University of Kansas Medical Center, grid.412016.0
  38. (38) Haukeland University Hospital, grid.412008.f
  39. (39) University of Bergen, grid.7914.b
  40. (40) Radboud University Nijmegen Medical Centre, grid.10417.33
  41. (41) Oregon Health & Science University, grid.5288.7
  42. (42) BC Cancer Agency, grid.248762.d
  43. (43) University of New Mexico, grid.266832.b
  44. (44) Simon Fraser University, grid.61971.38
  45. (45) 58, Department of Public Health Sciences, Medical University of South Carolina College of Medicine, Charleston, SC, USA
  46. (46) Pomeranian Medical University, grid.107950.a
  47. (47) National Cancer Institute, grid.48336.3a
  48. (48) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  49. (49) Rigshospitalet, grid.475435.4, Capital Region
  50. (50) University of Cambridge, grid.5335.0
  51. (51) 66, Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK
  52. (52) Beatson Institute, grid.23636.32
  53. (53) Stanford University, grid.168010.e
  54. (54) Yale University, grid.47100.32
  55. (55) University of Toronto, grid.17063.33
  56. (56) Public Health Ontario, grid.415400.4
  57. (57) University of California, Irvine, grid.266093.8
  58. (58) University of Southern California, grid.42505.36
  59. (59) University College London, grid.83440.3b
  60. (60) University of Michigan, grid.214458.e
  61. (61) Duke University, grid.26009.3d
  62. (62) 81, Ovarian Cancer Association Consortium

Description

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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Times Cited: 9

Field Citation Ratio (FCR): 2.34

Relative Citation ratio (RCR): 0.32

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