Article open access publication

Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

Gynecologic Oncology, Elsevier, ISSN 1095-6859

Volume 136, 3, 2015

DOI:10.1016/j.ygyno.2014.12.017, Dimensions: pub.1009433200, PMC: PMC4892108, PMID: 25528498,

Authors

Harter, Philipp (23) (24)
Heitz, Florian (23) (24)
du Bois, Andreas (23) (24)
Hogdall, Estrid (26) (27)
Kjaer, Susanne K. (27) (28)
Giles, Graham G (31) (32)
Wu, Xifeng (33)
Lu, Karen (33)
Poole, Elizabeth M (38) (39)
Bjorge, Line (41) (42)
Tangen, Ingvild L. (41) (42)
Salvesen, Helga B. (41) (42)
Krakstad, Camilla (41) (42)
Aben, Katja K H (43) (44)
Bean, Yukie (45) (46)
Pejovic, Tanja (45) (46)
Kellar, Melissa (45) (46)
Le, Nhu D. (47)
Kelemen, Linda E (49) (50)
Campbell, Ian G (6) (31)
Pike, Malcolm C (1) (35)
Rossing, Mary Anne (13) (66)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Southern California, grid.42505.36
  2. (2) University of Cambridge, grid.5335.0
  3. (3) Dartmouth College, grid.254880.3
  4. (4) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  5. (5) QIMR Berghofer Medical Research Institute, grid.1049.c
  6. (6) Peter MacCallum Cancer Centre, grid.1055.1
  7. (7) University of California, Los Angeles, grid.19006.3e
  8. (8) University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany
  9. (9) University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  10. (10) Universitair Ziekenhuis Leuven, grid.410569.f
  11. (11) Flanders Institute for Biotechnology, grid.11486.3a
  12. (12) Laboratory for Translational Genetics, Vesalius Research Center, VIB and KU Leuven, Belgium
  13. (13) Fred Hutchinson Cancer Research Center, grid.270240.3
  14. (14) German Cancer Research Center, grid.7497.d
  15. (15) University of Ulm, grid.6582.9
  16. (16) Roswell Park Cancer Institute, grid.240614.5
  17. (17) University of Hawaii at Manoa, grid.410445.0
  18. (18) Cedars-Sinai Medical Center, grid.50956.3f
  19. (19) Hannover Medical School, grid.10423.34
  20. (20) Friedrich Schiller University Jena, grid.9613.d
  21. (21) Helsinki University Central Hospital, grid.15485.3d
  22. (22) University of Pittsburgh, grid.21925.3d
  23. (23) Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  24. (24) Kliniken Essen-Mitte, grid.461714.1
  25. (25) Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
  26. (26) University of Copenhagen, grid.5254.6, KU
  27. (27) Danish Cancer Society, grid.417390.8
  28. (28) Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  29. (29) Mayo Clinic, grid.66875.3a
  30. (30) University of Kansas Medical Center, grid.412016.0
  31. (31) University of Melbourne, grid.1008.9
  32. (32) Cancer Council Victoria, grid.3263.4
  33. (33) The University of Texas MD Anderson Cancer Center, grid.240145.6
  34. (34) Texas Southern University, grid.264771.1
  35. (35) Memorial Sloan Kettering Cancer Center, grid.51462.34
  36. (36) Duke University Hospital, grid.189509.c
  37. (37) Duke University, grid.26009.3d
  38. (38) Harvard University, grid.38142.3c
  39. (39) Brigham and Women's Hospital, grid.62560.37
  40. (40) Rutgers, The State University of New Jersey, grid.430387.b
  41. (41) Haukeland University Hospital, grid.412008.f
  42. (42) University of Bergen, grid.7914.b
  43. (43) Radboud University Nijmegen Medical Centre, grid.10417.33
  44. (44) Comprehensive Cancer Center The Netherlands, Utrecht, The Netherlands
  45. (45) Knight Cancer Institute, Portland, OR, USA
  46. (46) Oregon Health & Science University, grid.5288.7
  47. (47) BC Cancer Agency, grid.248762.d
  48. (48) University of New Mexico, grid.266832.b
  49. (49) Alberta Health Services, grid.413574.0
  50. (50) University of Calgary, grid.22072.35
  51. (51) Simon Fraser University, grid.61971.38
  52. (52) Pomeranian Medical University, grid.107950.a
  53. (53) National Cancer Institute, grid.48336.3a
  54. (54) Deptartment of Pathology, Rigshospitalet, University of Copenhagen, Denmark
  55. (55) Princess Anne Hospital, grid.415216.5
  56. (56) Cancer Research UK Clinical Trials Unit, grid.470294.c
  57. (57) Glasgow Royal Infirmary, grid.411714.6
  58. (58) University of Glasgow, grid.8756.c
  59. (59) Stanford University, grid.168010.e
  60. (60) Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
  61. (61) Yale University, grid.47100.32
  62. (62) Moffitt Cancer Center, grid.468198.a
  63. (63) University of California, Irvine, grid.266093.8
  64. (64) University College London, grid.83440.3b
  65. (65) University of Pittsburgh Cancer Institute, grid.478063.e
  66. (66) University of Washington, grid.34477.33
  67. (67) The University of Texas Health Science Center at Houston, grid.267308.8
  68. (68) University of Michigan, grid.214458.e

Description

OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

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Times Cited: 10

Field Citation Ratio (FCR): 2.21

Relative Citation ratio (RCR): 0.54

Open Access Info

Green, Accepted