Article open access publication

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Journal of Genetics and Genome Research, ClinMed International Library, ISSN 2378-3648

Volume 2, 2, 2015

DOI:10.23937/2378-3648/1410017, Dimensions: pub.1079216657, PMC: PMC4722961, PMID: 26807442,

Authors

Aben, Katja K H (4) (5)
Bjorge, Line (13) (14)
Campbell, Ian G (21) (22)
Carty, Karen (23) (24)
du Bois, Andreas (31) (32)
Fasching, Peter A. (11) (40)
Giles, Graham G (8) (22)
Harter, Philipp (31) (32)
Heitz, Florian (31) (32)
Hogdall, Estrid (48) (49)
Krakstad, Camilla (13) (14)
Kjaer, Susanne K. (47) (49)
Le, Nhu D. (18)
Lu, Karen (46)
Milne, Roger L. (8) (22)
Pike, Malcolm C (3) (12)
Schernhammer, Eva (27) (62)
Salvesen, Helga B. (13) (14)
Teo, Soo-Hwang (45) (68)
Tangen, Ingvild L. (13) (14)
Wu, Xifeng (46)
Zheng, Wei (66)
Amankwah, Ernest (1) (69)

Affiliations

Organisations

  1. (1) Moffitt Cancer Center, grid.468198.a
  2. (2) University of Cambridge, grid.5335.0
  3. (3) University of Southern California, grid.42505.36
  4. (4) Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
  5. (5) Radboud University Nijmegen Medical Centre, grid.10417.33
  6. (6) University of California, Irvine, grid.266093.8
  7. (7) Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus
  8. (8) Cancer Council Victoria, grid.3263.4
  9. (9) Rutgers, The State University of New Jersey, grid.430387.b
  10. (10) Oregon Health & Science University, grid.5288.7
  11. (11) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany
  12. (12) Memorial Sloan Kettering Cancer Center, grid.51462.34
  13. (13) Haukeland University Hospital, grid.412008.f
  14. (14) University of Bergen, grid.7914.b
  15. (15) Hannover Medical School, grid.10423.34
  16. (16) National Cancer Institute, grid.48336.3a
  17. (17) Simon Fraser University, grid.61971.38
  18. (18) BC Cancer Agency, grid.248762.d
  19. (19) University of Pittsburgh, grid.21925.3d
  20. (20) Helsinki University Central Hospital, grid.15485.3d
  21. (21) Peter MacCallum Cancer Centre, grid.1055.1
  22. (22) University of Melbourne, grid.1008.9
  23. (23) Glasgow Royal Infirmary, grid.411714.6
  24. (24) Beatson West of Scotland Cancer Centre, grid.422301.6
  25. (25) German Cancer Research Center, grid.7497.d
  26. (26) University of New Mexico, grid.266832.b
  27. (27) Harvard University, grid.38142.3c
  28. (28) Mayo Clinic, grid.66875.3a
  29. (29) Pomeranian Medical University, grid.107950.a
  30. (30) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  31. (31) Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  32. (32) Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany
  33. (33) Division of Gynecologic Oncology; Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium
  34. (34) Stanford University, grid.168010.e
  35. (35) Department of Epidemiology, Geisel School of Medicine, Dartmouth, Hanover, NH, USA
  36. (36) Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA
  37. (37) Friedrich Schiller University Jena, grid.9613.d
  38. (38) Princess Anne Hospital, grid.415216.5
  39. (39) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  40. (40) University of California, Los Angeles, grid.19006.3e
  41. (41) University of Kansas Medical Center, grid.412016.0
  42. (42) Shanghai Cancer Institute, grid.419087.3
  43. (43) University College London, grid.83440.3b
  44. (44) Cedars-Sinai Medical Center, grid.50956.3f
  45. (45) Cancer Research Initiatives Foundation, grid.427737.2
  46. (46) The University of Texas MD Anderson Cancer Center, grid.240145.6
  47. (47) Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  48. (48) University of Copenhagen, grid.5254.6, KU
  49. (49) Danish Cancer Society, grid.417390.8
  50. (50) Aichi Cancer Center, grid.410800.d
  51. (51) Duke University, grid.26009.3d
  52. (52) KU Leuven, grid.5596.f
  53. (53) Roswell Park Cancer Institute, grid.240614.5
  54. (54) Texas Southern University, grid.264771.1
  55. (55) Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  56. (56) Public Health Ontario, grid.415400.4
  57. (57) University of Pittsburgh Cancer Institute, grid.478063.e
  58. (58) Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  59. (59) The University of Texas Health Science Center at Houston, grid.267308.8
  60. (60) Duke University Hospital, grid.189509.c
  61. (61) University of Michigan, grid.214458.e
  62. (62) Brigham and Women's Hospital, grid.62560.37
  63. (63) Yale University, grid.47100.32
  64. (64) University of Toronto, grid.17063.33
  65. (65) Institut für Humangenetik, Wiesbaden, Germany
  66. (66) Vanderbilt University, grid.152326.1
  67. (67) University of Hawaii at Manoa, grid.410445.0
  68. (68) University Malaya Medical Centre, University of Malaya, Kuala Lumpur, Maylaysia
  69. (69) Clinical and Translational Research Organization, All Children’s Hospital Johns Hopkins Medicine, St Petersburg, FL
  70. (70) Medical University of South Carolina, grid.259828.c

Description

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

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Times Cited: 17

Field Citation Ratio (FCR): 2.28

Relative Citation ratio (RCR): 0.9

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