Article open access publication

A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

Cancer Research, American Association for Cancer Research (AACR), ISSN 0008-5472

Volume 78, 18, 2018

DOI:10.1158/0008-5472.can-18-0951, Dimensions: pub.1105875095, PMC: PMC6139053, PMID: 30054336,

Authors

Wu, Lang (1)
Benitez, Javier (15) (16)
Bjorge, Line (17) (18)
Campbell, Ian (23) (24)
Cramer, Daniel W (29) (30)
deFazio, Anna (32) (33)
Fasching, Peter A (38) (39)
Friedman, Eitan (41) (42)
Giles, Graham G (23) (44) (45)
Heitz, Florian (51) (52)
Hulick, Peter J (55) (56)
Huntsman, David G (57) (58) (59)
James, Paul (23) (24)
Kjaer, Susanne K (64) (65)
Kwong, Ava (66) (67) (68)
Le, Nhu D (69)
Lesueur, Fabienne (70) (71) (72) (73)
Levine, Douglas A (74) (75)
Merritt, Melissa A (79) (80)
Osorio, Ana (16) (91)
Ramus, Susan J (98) (99)
Rennert, Gad (100)
Rossing, Mary Anne (104) (105)
Schmutzler, Rita K (108) (109)
Sieh, Weiva (111)
Teixeira, Manuel R (116) (117)
Teo, Soo H (118) (119)
Tischkowitz, Marc (14) (121)
Trichopoulou, Antonia (123) (124)
Tung, Nadine (125)
Vega, Ana (128)
White, Emily (104) (105)
Wolk, Alicja (129)
Wu, Anna H (110)
Gayther, Simon A (48) (110)

Affiliations

Organisations

  1. (1) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
  2. (2) Vanderbilt University Medical Center, grid.412807.8
  3. (3) University of Virginia, grid.27755.32
  4. (4) Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
  5. (5) Moffitt Cancer Center, grid.468198.a
  6. (6) Roswell Park Cancer Institute, grid.240614.5
  7. (7) Mount Sinai Hospital, grid.416166.2
  8. (8) University of Toronto, grid.17063.33
  9. (9) University of California, Irvine, grid.266093.8
  10. (10) The University of Texas MD Anderson Cancer Center, grid.240145.6
  11. (11) Rutgers, The State University of New Jersey, grid.430387.b
  12. (12) National University Hospital of Iceland, grid.410540.4
  13. (13) University of Iceland, grid.14013.37
  14. (14) University of Cambridge, grid.5335.0
  15. (15) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain,
  16. (16) Spanish National Cancer Research Centre, grid.7719.8
  17. (17) Haukeland University Hospital, grid.412008.f
  18. (18) University of Bergen, grid.7914.b
  19. (19) Cancer Research UK Cambridge Institute, grid.470869.4
  20. (20) Helsinki University Central Hospital, grid.15485.3d
  21. (21) Hospital Clínico San Carlos, grid.411068.a
  22. (22) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  23. (23) University of Melbourne, grid.1008.9
  24. (24) Peter MacCallum Cancer Centre, grid.1055.1
  25. (25) University Cancer Center Hamburg, grid.412315.0
  26. (26) German Cancer Research Center, grid.7497.d
  27. (27) Ghent University, grid.5342.0
  28. (28) Mayo Clinic, grid.66875.3a
  29. (29) Brigham and Women's Hospital, grid.62560.37
  30. (30) Harvard University, grid.38142.3c
  31. (31) Temple University Health System, grid.412530.1
  32. (32) University of Sydney, grid.1013.3
  33. (33) Westmead Hospital, grid.413252.3
  34. (34) Hospital Universitari Vall d'Hebron, grid.411083.f
  35. (35) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
  36. (36) Hannover Medical School, grid.10423.34
  37. (37) University of Southampton, grid.5491.9
  38. (38) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  39. (39) University of California, Los Angeles, grid.19006.3e
  40. (40) Aristotle University of Thessaloniki, grid.4793.9
  41. (41) Sheba Medical Center, grid.413795.d
  42. (42) Tel Aviv University, grid.12136.37
  43. (43) Dana-Farber Cancer Institute, grid.65499.37
  44. (44) Cancer Council Victoria, grid.3263.4
  45. (45) Monash University, grid.1002.3
  46. (46) University of Kansas Medical Center, grid.412016.0
  47. (47) University of Utah, grid.223827.e
  48. (48) Cedars-Sinai Medical Center, grid.50956.3f
  49. (49) National Cancer Institute, grid.48336.3a
  50. (50) Pomeranian Medical University, grid.107950.a
  51. (51) Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
  52. (52) Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang. Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany.
  53. (53) Department of Gynecology, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
  54. (54) Erasmus University Medical Center, grid.5645.2
  55. (55) University of Chicago, grid.170205.1
  56. (56) NorthShore University HealthSystem, grid.240372.0
  57. (57) Agriculture and Agriculture-Food Canada, grid.55614.33
  58. (58) University of British Columbia, grid.17091.3e
  59. (59) Vancouver General Hospital, grid.412541.7
  60. (60) Institute of Oncology NN Petrov, grid.465337.0
  61. (61) Georgetown University Medical Center, grid.411667.3
  62. (62) Medical University of South Carolina, grid.259828.c
  63. (63) Radboud University Nijmegen Medical Centre, grid.10417.33
  64. (64) Danish Cancer Society, grid.417390.8
  65. (65) Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark,
  66. (66) Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.
  67. (67) Hong Kong Hereditary Breast Cancer Family Registry, Happy Valley, Hong Kong.
  68. (68) University of Hong Kong, grid.194645.b
  69. (69) BC Cancer Agency, grid.248762.d
  70. (70) Genetic Epidemiology of Cancer team, Inserm U900, Paris, France.
  71. (71) Institute Curie, grid.418596.7
  72. (72) Mines ParisTech, grid.58140.38
  73. (73) PSL Research University, grid.440907.e
  74. (74) New York University Langone Medical Center, grid.240324.3
  75. (75) Memorial Sloan Kettering Cancer Center, grid.51462.34
  76. (76) University of Naples Federico II, grid.4691.a
  77. (77) Princess Margaret Cancer Centre, grid.415224.4
  78. (78) University of Glasgow, grid.8756.c
  79. (79) Imperial College London, grid.7445.2
  80. (80) University of Hawaii at Manoa, grid.410445.0
  81. (81) University of Pittsburgh, grid.21925.3d
  82. (82) University of Pittsburgh Cancer Institute, grid.478063.e
  83. (83) Istituto Oncologico Veneto, grid.419546.b
  84. (84) City Of Hope National Medical Center, grid.410425.6
  85. (85) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  86. (86) Latvian Biomedical Research and Study Centre, grid.419210.f
  87. (87) University of California, San Francisco, grid.266102.1
  88. (88) National Institute of Oncology, grid.419617.c
  89. (89) Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois.
  90. (90) Lund University, grid.4514.4
  91. (91) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  92. (92) Seoul National University, grid.31501.36
  93. (93) QIMR Berghofer Medical Research Institute, grid.1049.c
  94. (94) Julius Center for Health Sciences and Primary Care, UMC Utrecht, University Utrecht, Utrecht, The Netherlands.
  95. (95) Oregon Health & Science University, grid.5288.7
  96. (96) IFOM, the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
  97. (97) Catalan Institute of Oncology, grid.418701.b
  98. (98) The Kinghorn Cancer Centre, grid.410697.d
  99. (99) UNSW Sydney, grid.1005.4
  100. (100) Technion – Israel Institute of Technology, grid.6451.6
  101. (101) Yale University, grid.47100.32
  102. (102) International Agency For Research On Cancer, grid.17703.32
  103. (103) Antoni van Leeuwenhoek Hospital, grid.430814.a
  104. (104) Fred Hutchinson Cancer Research Center, grid.270240.3
  105. (105) University of Washington, grid.34477.33
  106. (106) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  107. (107) Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Maryland.
  108. (108) University Hospital Cologne, grid.411097.a
  109. (109) University of Cologne, grid.6190.e
  110. (110) University of Southern California, grid.42505.36
  111. (111) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  112. (112) Laval University, grid.23856.3a
  113. (113) Medical University of Vienna, grid.22937.3d
  114. (114) University of South Florida, grid.170693.a
  115. (115) Institute of Cancer Research, grid.18886.3f
  116. (116) Portuguese Oncology Institute, grid.418711.a
  117. (117) University of Porto, grid.5808.5
  118. (118) Cancer Research Malaysia, grid.507182.9
  119. (119) University Malaya Medical Centre, grid.413018.f
  120. (120) Odense University Hospital, grid.7143.1, Southern Denmark Region
  121. (121) McGill University, grid.14709.3b
  122. (122) The Ohio State University, grid.261331.4
  123. (123) Hellenic Health Foundation, grid.424637.0
  124. (124) National and Kapodistrian University of Athens, grid.5216.0
  125. (125) Beth Israel Deaconess Medical Center, grid.239395.7
  126. (126) University of Pretoria, grid.49697.35
  127. (127) Universitair Ziekenhuis Leuven, grid.410569.f
  128. (128) Fundación Pública Galega de Medicina Xenómica, grid.443929.1
  129. (129) Karolinska Institute, grid.4714.6
  130. (130) National Centre of Scientific Research Demokritos, grid.6083.d
  131. (131) Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  132. (132) Duke University Hospital, grid.189509.c
  133. (133) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. jirong.long@vanderbilt.edu.

Description

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

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Times Cited: 17

Field Citation Ratio (FCR): 7.6

Relative Citation ratio (RCR): 1.11

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