Article open access publication

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Clinical Cancer Research, American Association for Cancer Research (AACR), ISSN 1557-3265

Volume 21, 23, 2015

DOI:10.1158/1078-0432.ccr-15-0632, Dimensions: pub.1063224925, PMC: PMC4624261, PMID: 26152742,

Authors

Lu, Yi (1)
Gao, Bo (3) (4)
Rossing, Mary Anne (10) (11)
Campbell, Ian (23) (24)
Pearce, Celeste L. (29) (31)
Pike, Malcolm C (18) (29)
Wu, Anna H (29)
Heitz, Florian (34) (35)
du Bois, Andreas (34) (35)
Harter, Philipp (34) (35)
Høgdall, Estrid (40) (41)
Pejovic, Tanja (48) (49)
Bean, Yukie (48) (49)
Chiew, Yoke-Eng (3) (4)
deFazio, Anna (3) (4)

Affiliations

Organisations

  1. (1) QIMR Berghofer Medical Research Institute, grid.1049.c
  2. (2) University of Cambridge, grid.5335.0
  3. (3) Westmead Hospital, grid.413252.3
  4. (4) Westmead Institute for Medical Research, grid.452919.2
  5. (5) University of California, Los Angeles, grid.19006.3e
  6. (6) University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  7. (7) University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  8. (8) Flanders Institute for Biotechnology, grid.11486.3a
  9. (9) KU Leuven, grid.5596.f
  10. (10) Fred Hutchinson Cancer Research Center, grid.270240.3
  11. (11) University of Washington, grid.34477.33
  12. (12) Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
  13. (13) German Cancer Research Center, grid.7497.d
  14. (14) University of Pittsburgh, grid.21925.3d
  15. (15) University of Pittsburgh Cancer Institute, grid.478063.e
  16. (16) The University of Texas Health Science Center at Houston, grid.267308.8
  17. (17) Roswell Park Cancer Institute, grid.240614.5
  18. (18) Memorial Sloan Kettering Cancer Center, grid.51462.34
  19. (19) Radboud University Nijmegen Medical Centre, grid.10417.33
  20. (20) Pomeranian Medical University, grid.107950.a
  21. (21) National Cancer Institute, grid.48336.3a
  22. (22) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  23. (23) Peter MacCallum Cancer Centre, grid.1055.1
  24. (24) University of Melbourne, grid.1008.9
  25. (25) Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, Hampshire, United Kingdom
  26. (26) Stanford University, grid.168010.e
  27. (27) University of South Florida, grid.170693.a
  28. (28) University of California, Irvine, grid.266093.8
  29. (29) University of Southern California, grid.42505.36
  30. (30) University College London, grid.83440.3b
  31. (31) University of Michigan, grid.214458.e
  32. (32) Cedars-Sinai Medical Center, grid.50956.3f
  33. (33) University of Hawaii at Manoa, grid.410445.0
  34. (34) Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  35. (35) Kliniken Essen-Mitte, grid.461714.1
  36. (36) Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
  37. (37) Zentrum für Gynäkologische Onkologie, Kiel, Germany
  38. (38) Hannover Medical School, grid.10423.34
  39. (39) Mayo Clinic, grid.66875.3a
  40. (40) University of Copenhagen, grid.5254.6, KU
  41. (41) Danish Cancer Society, grid.417390.8
  42. (42) Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  43. (43) University of Kansas Medical Center, grid.412016.0
  44. (44) Duke University, grid.26009.3d
  45. (45) Duke University Hospital, grid.189509.c
  46. (46) Harvard University, grid.38142.3c
  47. (47) Rutgers, The State University of New Jersey, grid.430387.b
  48. (48) Knight Cancer Institute, Portland, Oregon
  49. (49) Oregon Health & Science University, grid.5288.7
  50. (50) Department of Gynaecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  51. (51) University of Glasgow, grid.8756.c
  52. (52) Cancer Research UK Clinical Trials Unit, grid.470294.c
  53. (53) Glasgow Royal Infirmary, grid.411714.6
  54. (54) Moffitt Cancer Center, grid.468198.a

Description

PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. RESULTS: Five SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)). CONCLUSIONS: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.

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Times Cited: 18

Field Citation Ratio (FCR): 3.97

Relative Citation ratio (RCR): 0.87

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