Article open access publication

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

PLoS ONE, Public Library of Science (PLoS), ISSN 1932-6203

Volume 13, 7, 2018

DOI:10.1371/journal.pone.0197561, Dimensions: pub.1105333977, PMC: PMC6034790, PMID: 29979793,

Authors

Lin, Hui-Yi (3) (4)
Aben, Katja K H (5) (6)
Bjorge, Line (12) (13)
Campbell, Ian G (21) (22)
Carty, Karen (23) (24)
du Bois, Andreas (34) (35)
Fasching, Peter A. (11) (39)
Giles, Graham G (18) (22)
Harter, Philipp (34) (35)
Heitz, Florian (34) (35)
Høgdall, Estrid (44) (45)
Kjaer, Susanne K. (45) (49)
Le, Nhu D. (17)
Li, Zheng (1) (54)
Lu, Karen (42)
Milne, Roger L. (18) (22)
Poole, Elizabeth M (28) (60)
Schernhammer, Eva (28) (60)
Teo, Soo-Hwang (15) (66)
Terry, Kathryn L. (28) (67)
Tworoger, Shelley S (4) (28) (60)
Woo, Yin-Ling (48) (69)
Wu, Anna H (70)
Wu, Xifeng (42)
Zheng, Wei (64)
Ramus, Susan J (75) (76)

* Corresponding author

Affiliations

Organisations

  1. (1) Mayo Clinic, grid.66875.3a
  2. (2) University of Cambridge, grid.5335.0
  3. (3) Louisiana State University Health Sciences Center New Orleans, grid.279863.1
  4. (4) Moffitt Cancer Center, grid.468198.a
  5. (5) Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands
  6. (6) Radboud University Nijmegen Medical Centre, grid.10417.33
  7. (7) University of California, Irvine, grid.266093.8
  8. (8) Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus
  9. (9) Rutgers, The State University of New Jersey, grid.430387.b
  10. (10) Oregon Health & Science University, grid.5288.7
  11. (11) University Hospital Erlangen, grid.411668.c
  12. (12) University of Bergen, grid.7914.b
  13. (13) Haukeland University Hospital, grid.412008.f
  14. (14) Hannover Medical School, grid.10423.34
  15. (15) National Cancer Institute, grid.48336.3a
  16. (16) Simon Fraser University, grid.61971.38
  17. (17) BC Cancer Agency, grid.248762.d
  18. (18) Cancer Council Victoria, grid.3263.4
  19. (19) University of Pittsburgh, grid.21925.3d
  20. (20) Helsinki University Central Hospital, grid.15485.3d
  21. (21) Peter MacCallum Cancer Centre, grid.1055.1
  22. (22) University of Melbourne, grid.1008.9
  23. (23) Glasgow Royal Infirmary, grid.411714.6
  24. (24) Beatson West of Scotland Cancer Centre, grid.422301.6
  25. (25) University Cancer Center Hamburg, grid.412315.0
  26. (26) German Cancer Research Center, grid.7497.d
  27. (27) University of New Mexico, grid.266832.b
  28. (28) Harvard University, grid.38142.3c
  29. (29) Pomeranian Medical University, grid.107950.a
  30. (30) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  31. (31) Universitair Ziekenhuis Leuven, grid.410569.f
  32. (32) University of Utah Health Care, grid.412722.0
  33. (33) Fred Hutchinson Cancer Research Center, grid.270240.3
  34. (34) Department of Gynaecology and Gynaecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  35. (35) Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany
  36. (36) Friedrich Schiller University Jena, grid.9613.d
  37. (37) Princess Anne Hospital, grid.415216.5
  38. (38) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  39. (39) University of California, Los Angeles, grid.19006.3e
  40. (40) University College London, grid.83440.3b
  41. (41) Cedars-Sinai Medical Center, grid.50956.3f
  42. (42) The University of Texas MD Anderson Cancer Center, grid.240145.6
  43. (43) Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  44. (44) University of Copenhagen, grid.5254.6, KU
  45. (45) Danish Cancer Society, grid.417390.8
  46. (46) Aichi Cancer Center, grid.410800.d
  47. (47) Duke University, grid.26009.3d
  48. (48) Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  49. (49) Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  50. (50) KU Leuven, grid.5596.f
  51. (51) Division of Gynecologic Oncology; Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Leuven, Belgium
  52. (52) Roswell Park Cancer Institute, grid.240614.5
  53. (53) Memorial Sloan Kettering Cancer Center, grid.51462.34
  54. (54) Yan'an Hospital Affiliated To Kunming Medical University, grid.452826.f
  55. (55) Texas Southern University, grid.264771.1
  56. (56) Stanford University, grid.168010.e
  57. (57) Public Health Ontario, grid.415400.4
  58. (58) University of Pittsburgh Cancer Institute, grid.478063.e
  59. (59) The University of Texas Health Science Center at Houston, grid.267308.8
  60. (60) Brigham and Women's Hospital, grid.62560.37
  61. (61) University of Toronto, grid.17063.33
  62. (62) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  63. (63) Institut für Humangenetik Wiesbaden, Wiesbaden, Germany
  64. (64) Vanderbilt University, grid.152326.1
  65. (65) University of Hawaii at Manoa, grid.410445.0
  66. (66) University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  67. (67) University of Michigan, grid.214458.e
  68. (68) Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  69. (69) Cancer Research Malaysia, grid.507182.9
  70. (70) University of Southern California, grid.42505.36
  71. (71) Shanghai Cancer Institute, grid.419087.3
  72. (72) California State University, Fullerton, grid.253559.d
  73. (73) Duke University Hospital, grid.189509.c
  74. (74) University of Virginia, grid.27755.32
  75. (75) Garvan Institute of Medical Research, grid.415306.5
  76. (76) UNSW Sydney, grid.1005.4
  77. (77) Hollings Cancer Center, grid.467988.c
  78. (78) QIMR Berghofer Medical Research Institute, grid.1049.c
  79. (79) Yale University, grid.47100.32

Description

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

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Times Cited: 7

Field Citation Ratio (FCR): 2.58

Relative Citation ratio (RCR): 0.92

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