Article open access publication

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Carcinogenesis, Oxford University Press (OUP), ISSN 0143-3334

Volume 36, 11, 2015

DOI:10.1093/carcin/bgv138, Dimensions: pub.1059454489, PMC: PMC4635670, PMID: 26424751,

Authors

Aben, Katja K H (8) (9)
Bjorge, Line (16) (17)
Campbell, Ian G (24) (25)
Chen, Ann (29)
Dicks, Ed (3)
du Bois, Andreas (5) (36)
Edwards, Robert P. (37) (38)
Fasching, Peter A. (14) (40)
Giles, Graham G (22) (25)
Harter, Philipp (36) (44)
Heitz, Florian (36) (44)
Hogdall, Estrid (47) (48)
Krakstad, Camilla (16) (17)
Le, Nhu D. (21)
Lu, Karen (46)
Pike, Malcolm C (2) (15)
Poole, Elizabeth M (31) (68)
Rossing, Mary Anne (71) (72)
Salvesen, Helga B. (16) (17)
Tangen, Ingvild L. (16) (17)
Teo, Soo-Hwang (46) (77)
Woo, Yin-Ling (66) (77)
Wu, Xifeng (46)
Zheng, Wei (74)

Affiliations

Organisations

  1. (1) Cedars-Sinai Medical Center, grid.50956.3f
  2. (2) Duke University, grid.26009.3d
  3. (3) University of Cambridge, grid.5335.0
  4. (4) Duke University Hospital, grid.189509.c
  5. (5) University of Florida, grid.15276.37
  6. (6) University of Southern California, grid.42505.36
  7. (7) Xiamen University, grid.12955.3a
  8. (8) Department for Health Evidence, Nijmegen 6500 HB, The Netherlands,
  9. (9) Comprehensive Cancer Center, Utrecht 3542 EG, The Netherlands,
  10. (10) University of California, Irvine, grid.266093.8
  11. (11) Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk 223052, Belarus,
  12. (12) Rutgers, The State University of New Jersey, grid.430387.b
  13. (13) Oregon Health & Science University, grid.5288.7
  14. (14) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany,
  15. (15) Memorial Sloan Kettering Cancer Center, grid.51462.34
  16. (16) Haukeland University Hospital, grid.412008.f
  17. (17) University of Bergen, grid.7914.b
  18. (18) Hannover Medical School, grid.10423.34
  19. (19) National Cancer Institute, grid.48336.3a
  20. (20) Simon Fraser University, grid.61971.38
  21. (21) BC Cancer Agency, grid.248762.d
  22. (22) Cancer Council Victoria, grid.3263.4
  23. (23) Helsinki University Central Hospital, grid.15485.3d
  24. (24) Peter MacCallum Cancer Centre, grid.1055.1
  25. (25) University of Melbourne, grid.1008.9
  26. (26) Beatson West of Scotland Cancer Centre, grid.422301.6
  27. (27) German Cancer Research Center, grid.7497.d
  28. (28) QIMR Berghofer Medical Research Institute, grid.1049.c
  29. (29) Moffitt Cancer Center, grid.468198.a
  30. (30) University of New Mexico, grid.266832.b
  31. (31) Harvard University, grid.38142.3c
  32. (32) Mayo Clinic, grid.66875.3a
  33. (33) Pomeranian Medical University, grid.107950.a
  34. (34) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  35. (35) Dartmouth College, grid.254880.3
  36. (36) Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany,
  37. (37) Princess Anne Hospital, grid.415216.5
  38. (38) University of Pittsburgh, grid.21925.3d
  39. (39) Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, Germany,
  40. (40) University of California, Los Angeles, grid.19006.3e
  41. (41) University of Kansas Medical Center, grid.412016.0
  42. (42) Shanghai Cancer Institute, grid.419087.3
  43. (43) University College London, grid.83440.3b
  44. (44) Kliniken Essen-Mitte, grid.461714.1
  45. (45) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya 47500, Malaysia,
  46. (46) The University of Texas MD Anderson Cancer Center, grid.240145.6
  47. (47) University of Copenhagen, grid.5254.6, KU
  48. (48) Danish Cancer Society, grid.417390.8
  49. (49) Rigshospitalet, grid.475435.4, Capital Region
  50. (50) Aichi Cancer Center, grid.410800.d
  51. (51) Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark,
  52. (52) Medical University of South Carolina, grid.259828.c
  53. (53) Radboud University Nijmegen Medical Centre, grid.10417.33
  54. (54) Flanders Institute for Biotechnology, grid.11486.3a
  55. (55) Laboratory for Translational Genetics, Department of Oncology, University of Leuven3000, Belgium,
  56. (56) Universitair Ziekenhuis Leuven, grid.410569.f
  57. (57) Roswell Park Cancer Institute, grid.240614.5
  58. (58) Texas Southern University, grid.264771.1
  59. (59) Kyushu University, grid.177174.3
  60. (60) Stanford University, grid.168010.e
  61. (61) Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,
  62. (62) University of Glasgow, grid.8756.c
  63. (63) University of Pittsburgh Cancer Institute, grid.478063.e
  64. (64) Women's College Hospital, grid.417199.3
  65. (65) The University of Texas Health Science Center at Houston, grid.267308.8
  66. (66) Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur50603, Malaysia,
  67. (67) University of Michigan, grid.214458.e
  68. (68) Brigham and Women's Hospital, grid.62560.37
  69. (69) Yale University, grid.47100.32
  70. (70) University of Toronto, grid.17063.33
  71. (71) Fred Hutchinson Cancer Research Center, grid.270240.3
  72. (72) University of Washington, grid.34477.33
  73. (73) Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena D-07743, Germany,
  74. (74) Vanderbilt University, grid.152326.1
  75. (75) University of Hawaii at Manoa, grid.410445.0
  76. (76) Glasgow Royal Infirmary, grid.411714.6
  77. (77) University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur 50603, Malaysia,
  78. (78) Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw 03-242, Poland,
  79. (79) University of Ulm, grid.6582.9
  80. (80) Dana-Farber Cancer Institute, grid.65499.37

Description

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

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2015: Unused

Research area: Medicine

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2015: Level 2

Research area: Medicine

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Times Cited: 20

Field Citation Ratio (FCR): 4.41

Relative Citation ratio (RCR): 0.88

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