Article open access publication

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Cancer Epidemiology Biomarkers & Prevention, American Association for Cancer Research (AACR), ISSN 1055-9965

Volume 24, 10, 2015

DOI:10.1158/1055-9965.epi-14-1270, Dimensions: pub.1003698597, PMC: PMC4592449, PMID: 26209509,

Authors

Aben, Katja K H (4) (5)
Bjørge, Line (15) (16)
Campbell, Ian (9) (22)
Cramer, Daniel (27) (28)
Dicks, Ed (1)
du Bois, Andreas (33) (34)
Edwards, Robert P. (36) (37)
Fasching, Peter A. (12) (39)
Harter, Philipp (33) (34)
Heitz, Florian (33) (34)
Hogdall, Estrid (46) (47)
Kjaer, Susanne K. (47) (48)
Krakstad, Camilla (15) (16)
Le, Nhu D. (20)
Lu, Karen (45)
Pike, Malcolm C (3) (14)
Poole, Elizabeth M (27) (65)
Rossing, Mary Anne (68) (69)
Salvesen, Helga B. (15) (16)
Tangen, Ingvild L. (15) (16)
Teo, Soo-Hwang (74) (75)
Terry, Kathryn L (27) (28)
Woo, Yin-Ling (75) (78)
Wu, Xifeng (45)
Wu, Anna (3)
Zheng, Wei (71)

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) Dana-Farber Cancer Institute, grid.65499.37
  3. (3) University of Southern California, grid.42505.36
  4. (4) Comprehensive Cancer Center The Netherlands, 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) QIMR Berghofer Medical Research Institute, grid.1049.c
  9. (9) Peter MacCallum Cancer Centre, grid.1055.1
  10. (10) Rutgers, The State University of New Jersey, grid.430387.b
  11. (11) Oregon Health & Science University, grid.5288.7
  12. (12) University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  13. (13) Duke University Hospital, grid.189509.c
  14. (14) Memorial Sloan Kettering Cancer Center, grid.51462.34
  15. (15) Haukeland University Hospital, grid.412008.f
  16. (16) University of Bergen, grid.7914.b
  17. (17) Hannover Medical School, grid.10423.34
  18. (18) National Cancer Institute, grid.48336.3a
  19. (19) Simon Fraser University, grid.61971.38
  20. (20) BC Cancer Agency, grid.248762.d
  21. (21) Helsinki University Central Hospital, grid.15485.3d
  22. (22) University of Melbourne, grid.1008.9
  23. (23) Beatson West of Scotland Cancer Centre, grid.422301.6
  24. (24) German Cancer Research Center, grid.7497.d
  25. (25) Moffitt Cancer Center, grid.468198.a
  26. (26) University of New Mexico, grid.266832.b
  27. (27) Harvard University, grid.38142.3c
  28. (28) Obstetrics and Gynecology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
  29. (29) Mayo Clinic, grid.66875.3a
  30. (30) Pomeranian Medical University, grid.107950.a
  31. (31) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  32. (32) Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
  33. (33) Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  34. (34) Kliniken Essen-Mitte, grid.461714.1
  35. (35) Department of Gynecology, Jena University Hospital, Friedrich Schiller University, Jena, Germany
  36. (36) Princess Anne Hospital, grid.415216.5
  37. (37) University of Pittsburgh, grid.21925.3d
  38. (38) University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  39. (39) University of California, Los Angeles, grid.19006.3e
  40. (40) University of Kansas Medical Center, grid.412016.0
  41. (41) Shanghai Cancer Institute, grid.419087.3
  42. (42) Women's Cancer, University College London Elizabeth Garrett Anderson Institute for Women's Health, London, United Kingdom
  43. (43) Cancer Council Victoria, grid.3263.4
  44. (44) Cedars-Sinai Medical Center, grid.50956.3f
  45. (45) The University of Texas MD Anderson Cancer Center, grid.240145.6
  46. (46) University of Copenhagen, grid.5254.6, KU
  47. (47) Danish Cancer Society, grid.417390.8
  48. (48) Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  49. (49) Aichi Cancer Center, grid.410800.d
  50. (50) Duke University, grid.26009.3d
  51. (51) Medical University of South Carolina, grid.259828.c
  52. (52) Flanders Institute for Biotechnology, grid.11486.3a
  53. (53) KU Leuven, grid.5596.f
  54. (54) Universitair Ziekenhuis Leuven, grid.410569.f
  55. (55) Roswell Park Cancer Institute, grid.240614.5
  56. (56) Texas Southern University, grid.264771.1
  57. (57) Kyushu University, grid.177174.3
  58. (58) Stanford University, grid.168010.e
  59. (59) Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  60. (60) University of Glasgow, grid.8756.c
  61. (61) University of Pittsburgh Cancer Institute, grid.478063.e
  62. (62) Women's College Hospital, grid.417199.3
  63. (63) Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  64. (64) The University of Texas Health Science Center at Houston, grid.267308.8
  65. (65) Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
  66. (66) Yale University, grid.47100.32
  67. (67) University of Toronto, grid.17063.33
  68. (68) University of Washington, grid.34477.33
  69. (69) Fred Hutchinson Cancer Research Center, grid.270240.3
  70. (70) Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
  71. (71) Vanderbilt University, grid.152326.1
  72. (72) University of Hawaii at Manoa, grid.410445.0
  73. (73) Glasgow Royal Infirmary, grid.411714.6
  74. (74) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  75. (75) University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  76. (76) Department of Obstetrics, Gynecology, and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland
  77. (77) University of Ulm, grid.6582.9
  78. (78) Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia

Description

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

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Times Cited: 21

Relative Citation ratio (RCR): 0.72

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