Article open access publication

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Human Genetics, Springer Nature, ISSN 0340-6717

Volume 135, 7, 2016

DOI:10.1007/s00439-016-1663-9, Dimensions: pub.1037515608, PMC: PMC4976079, PMID: 27075448,

Authors

Lu, Yi (1)
Rossing, Mary Anne (10) (11)
Edwards, Robert P. (20) (21)
Høgdall, Estrid (24) (25)
Giles, Graham G (27) (28) (29)
Kjaer, Susanne K. (25) (26)
Wu, Xifeng (30)
Dao, Fanny (32)
Terry, Kathryn L (33) (34)
Stampfer, Meir (33) (34)
Missmer, Stacey (33) (34)
Bjorge, Line (35) (36)
Salvesen, Helga B. (35) (36)
Bischof, Katharina (35) (36)
Aben, Katja K H (37) (38)
Le, Nhu D. (40)
Wu, Anna H (54)
Pearce, Celeste L. (54) (62)

* Corresponding author

Affiliations

Organisations

  1. (1) QIMR Berghofer Medical Research Institute, grid.1049.c
  2. (2) University of Queensland, grid.1003.2
  3. (3) Peter MacCallum Cancer Centre, grid.1055.1
  4. (4) University of California, Los Angeles, grid.19006.3e
  5. (5) Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Universitaetsstrasse 21-23, 91054, Erlangen, Germany
  6. (6) Flanders Institute for Biotechnology, grid.11486.3a
  7. (7) KU Leuven, grid.5596.f
  8. (8) Universitair Ziekenhuis Leuven, grid.410569.f
  9. (9) Dartmouth College, grid.254880.3
  10. (10) Fred Hutchinson Cancer Research Center, grid.270240.3
  11. (11) University of Washington, grid.34477.33
  12. (12) University Cancer Center Hamburg, grid.412315.0
  13. (13) German Cancer Research Center, grid.7497.d
  14. (14) University of Ulm, grid.6582.9
  15. (15) Cedars-Sinai Medical Center, grid.50956.3f
  16. (16) Hannover Medical School, grid.10423.34
  17. (17) Friedrich Schiller University Jena, grid.9613.d
  18. (18) N.N. Alexandrov National Cancer Centre, grid.477553.7
  19. (19) Helsinki University Central Hospital, grid.15485.3d
  20. (20) University of Pittsburgh, grid.21925.3d
  21. (21) University of Pittsburgh Cancer Institute, grid.478063.e
  22. (22) Roswell Park Cancer Institute, grid.240614.5
  23. (23) The University of Texas Health Science Center at Houston, grid.267308.8
  24. (24) University of Copenhagen, grid.5254.6, KU
  25. (25) Danish Cancer Society, grid.417390.8
  26. (26) Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  27. (27) Monash University, grid.1002.3
  28. (28) University of Melbourne, grid.1008.9
  29. (29) Cancer Council Victoria, grid.3263.4
  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) Brigham and Women's Hospital, grid.62560.37
  34. (34) Harvard University, grid.38142.3c
  35. (35) Haukeland University Hospital, grid.412008.f
  36. (36) University of Bergen, grid.7914.b
  37. (37) Netherlands Comprehensive Cancer Organisation, grid.470266.1
  38. (38) Radboud University Nijmegen Medical Centre, grid.10417.33
  39. (39) Simon Fraser University, grid.61971.38
  40. (40) BC Cancer Agency, grid.248762.d
  41. (41) Stanford University, grid.168010.e
  42. (42) University of New Mexico, grid.266832.b
  43. (43) University of British Columbia, grid.17091.3e
  44. (44) Pomeranian Medical University, grid.107950.a
  45. (45) Rzeszów University, grid.13856.39
  46. (46) University of Cambridge, grid.5335.0
  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) Public Health Ontario, grid.415400.4
  50. (50) University of Toronto, grid.17063.33
  51. (51) Moffitt Cancer Center, grid.468198.a
  52. (52) University of California, Irvine, grid.266093.8
  53. (53) University of Southampton, grid.5491.9
  54. (54) University of Southern California, grid.42505.36
  55. (55) University College London, grid.83440.3b
  56. (56) Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland
  57. (57) Mayo Clinic, grid.66875.3a
  58. (58) University of Kansas, grid.266515.3
  59. (59) Rutgers, The State University of New Jersey, grid.430387.b
  60. (60) Oregon Health & Science University, grid.5288.7
  61. (61) University of Virginia, grid.27755.32
  62. (62) University of Michigan, grid.214458.e
  63. (63) Duke University, grid.26009.3d
  64. (64) Yale University, grid.47100.32

Description

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

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University of Copenhagen

Danish Open Access Indicator

2016: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2016: Level 1

Research area: Medicine

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Times Cited: 16

Field Citation Ratio (FCR): 4.14

Relative Citation ratio (RCR): 1

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Green, Accepted