Article open access publication

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

British Journal of Cancer, Springer Nature, ISSN 0007-0920

Volume 116, 4, 2017

DOI:10.1038/bjc.2016.426, Dimensions: pub.1017700835, PMC: PMC5318969, PMID: 28103614,

Authors

Campbell, Ian (11) (12)
Heitz, Florian (27) (28)
Høgdall, Estrid (30) (31)
Huntsman, David G (33) (34) (35)
Kjaer, Susanne K (31) (38)
Li, Qiyuan (42) (43)
Pike, Malcolm C (2) (41)
Rossing, Mary Anne (55) (56)
Salvesen, Helga B (57) (58)
Terry, Kathryn L (17) (61)
Zheng, Wei (62)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) University of Southern California, grid.42505.36
  3. (3) Cedars-Sinai Medical Center, grid.50956.3f
  4. (4) University of California, Irvine, grid.266093.8
  5. (5) Rutgers, The State University of New Jersey, grid.430387.b
  6. (6) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Universitaetsstrasse 21-23, 91054, Erlangen, Germany
  7. (7) Duke University Hospital, grid.189509.c
  8. (8) Hannover Medical School, grid.10423.34
  9. (9) National Cancer Institute, grid.48336.3a
  10. (10) Helsinki University Central Hospital, grid.15485.3d
  11. (11) Peter MacCallum Cancer Centre, grid.1055.1
  12. (12) University of Melbourne, grid.1008.9
  13. (13) Beatson West of Scotland Cancer Centre, grid.422301.6
  14. (14) German Cancer Research Center, grid.7497.d
  15. (15) University Cancer Center Hamburg, grid.412315.0
  16. (16) University of New Mexico, grid.266832.b
  17. (17) Brigham and Women's Hospital, grid.62560.37
  18. (18) Mayo Clinic, grid.66875.3a
  19. (19) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  20. (20) Dartmouth College, grid.254880.3
  21. (21) Friedrich Schiller University Jena, grid.9613.d
  22. (22) University of Southampton, grid.5491.9
  23. (23) University of California, Los Angeles, grid.19006.3e
  24. (24) Imperial College London, grid.7445.2
  25. (25) University College London, grid.83440.3b
  26. (26) Pomeranian Medical University, grid.107950.a
  27. (27) Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany
  28. (28) Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen 45136, Germany
  29. (29) The University of Texas MD Anderson Cancer Center, grid.240145.6
  30. (30) University of Copenhagen, grid.5254.6, KU
  31. (31) Danish Cancer Society, grid.417390.8
  32. (32) Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
  33. (33) Agriculture and Agriculture-Food Canada, grid.55614.33
  34. (34) University of British Columbia, grid.17091.3e
  35. (35) Vancouver General Hospital, grid.412541.7
  36. (36) Medical University of South Carolina, grid.259828.c
  37. (37) Radboud University Nijmegen Medical Centre, grid.10417.33
  38. (38) Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
  39. (39) Flanders Institute for Biotechnology, grid.11486.3a
  40. (40) KU Leuven, grid.5596.f
  41. (41) Memorial Sloan Kettering Cancer Center, grid.51462.34
  42. (42) Xiamen University, grid.12955.3a
  43. (43) Dana-Farber Cancer Institute, grid.65499.37
  44. (44) Stanford University, grid.168010.e
  45. (45) University of Glasgow, grid.8756.c
  46. (46) University of Pittsburgh, grid.21925.3d
  47. (47) University of Pittsburgh Cancer Institute, grid.478063.e
  48. (48) Moffitt Cancer Center, grid.468198.a
  49. (49) Roswell Park Cancer Institute, grid.240614.5
  50. (50) The University of Texas Health Science Center at Houston, grid.267308.8
  51. (51) University of Michigan, grid.214458.e
  52. (52) Oregon Health & Science University, grid.5288.7
  53. (53) UNSW Sydney, grid.1005.4
  54. (54) Yale University, grid.47100.32
  55. (55) Fred Hutchinson Cancer Research Center, grid.270240.3
  56. (56) University of Washington, grid.34477.33
  57. (57) Haukeland University Hospital, grid.412008.f
  58. (58) University of Bergen, grid.7914.b
  59. (59) Duke University, grid.26009.3d
  60. (60) Glasgow Royal Infirmary, grid.411714.6
  61. (61) Harvard University, grid.38142.3c
  62. (62) Vanderbilt University Medical Center, grid.412807.8
  63. (63) Broad Institute, grid.66859.34

Description

BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

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Research area: Medicine

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Research area: Medicine

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Times Cited: 15

Field Citation Ratio (FCR): 5.43

Relative Citation ratio (RCR): 0.77

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