Article open access publication

Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Molecular Nutrition & Food Research, Wiley, ISSN 1613-4125

Volume 58, 10, 2014

DOI:10.1002/mnfr.201400068, Dimensions: pub.1033005608, PMC: PMC4197821, PMID: 25066213,


Goodman, Marc T (4) (5)
Dicks, Ed (12)
Aben, Katja K H (23) (24)
Giles, Graham G (27) (28) (29)
Kjær, Susanne (30) (31)
Høgdall, Estrid (30) (31)
Heitz, Florian (32) (33)
du Bois, Andreas (32) (33)
Harter, Philipp (32) (33)
Butzow, Ralf (35) (36)
Fasching, Peter A. (41) (42)
Wu, Anna H (16)
Pike, Malcolm C (16) (25)
Wu, Xifeng (57)
Lu, Karen (57)
Salvesen, Helga B. (61) (62)
Krakstad, Camilla (61) (62)
Bjorge, Line (61) (62)
Tangen, Ingvild L. (61) (62)
Campbell, Ian G (28) (66)
Cook, Linda S. (11) (73)
Le, Nhu D. (74)



  1. (1) University of Calgary, grid.22072.35
  2. (2) Brigham and Women's Hospital, grid.62560.37
  3. (3) Harvard University, grid.38142.3c
  4. (4) Cedars‐Sinai Medical Center Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute Los Angeles CA USA
  5. (5) Community and Population Health Research Institute, Cedars‐Sinai Medical Center Department of Biomedical Sciences Los Angeles CA USA
  6. (6) QIMR Berghofer Medical Research Institute, grid.1049.c
  7. (7) The State University of New Jersey Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey New Brunswick NJ USA
  8. (8) Stanford University, grid.168010.e
  9. (9) University of Washington, grid.34477.33
  10. (10) Fred Hutchinson Cancer Research Center Program in Epidemiology, Division of Public Health Sciences Seattle WA USA
  11. (11) Alberta Health Services, grid.413574.0
  12. (12) University of Cambridge, grid.5335.0
  13. (13) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  14. (14) Warsaw Medical University and Brodnowski Hospital Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine Warsaw Poland
  15. (15) Gynaecological Cancer Research Centre, University College London Department of Women's Cancer, Institute for Women's Health London UK
  16. (16) University of Southern California Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center Los Angeles CA USA
  17. (17) Women's College Hospital, grid.417199.3
  18. (18) Yale University, grid.47100.32
  19. (19) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  20. (20) Glasgow Royal Infirmary, grid.411714.6
  21. (21) Beatson West of Scotland Cancer Centre, grid.422301.6
  22. (22) Pomeranian Medical University International Hereditary Cancer Center, Department of Genetics and Pathology Szczecin Poland
  23. (23) Radboud University Nijmegen Medical Centre, grid.10417.33
  24. (24) Comprehensive Cancer Center Utrecht Netherlands
  25. (25) Memorial Sloan Kettering Cancer Center, grid.51462.34
  26. (26) Gynecology Service, Memorial Sloan‐Kettering Cancer Center Department of Surgery New York NY USA
  27. (27) Monash University, grid.1002.3
  28. (28) University of Melbourne, grid.1008.9
  29. (29) Cancer Council Victoria, grid.3263.4
  30. (30) Danish Cancer Society Research Center Department of Virus, Lifestyle and Genes Copenhagen Denmark
  31. (31) University of Copenhagen, grid.5254.6, KU
  32. (32) Helios Dr. Horst Schmidt Kliniken Wiesbaden, grid.491861.3
  33. (33) Kliniken Essen‐Mitte/Evang. Huyssens‐Stiftung/Knappschaft GmbH Department of Gynecology and Gynecologic Oncology Essen Germany
  34. (34) Praxis für Humangenetik Wiesbaden Germany
  35. (35) Helsinki University Central Hospital, grid.15485.3d
  36. (36) University of Helsinki, grid.7737.4
  37. (37) University of Hawaii at Manoa, grid.410445.0
  38. (38) KU Leuven, grid.5596.f
  39. (39) Vesalius Research Center Leuven VIB Belgium
  40. (40) Universitair Ziekenhuis Leuven, grid.410569.f
  41. (41) University of California, Los Angeles, grid.19006.3e
  42. (42) Comprehensive Cancer Center Erlangen‐EMN Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
  43. (43) Comprehensive Cancer Center Erlangen‐EMN Institute of Human Genetics, University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg Erlangen Germany
  44. (44) Dartmouth College, grid.254880.3
  45. (45) German Cancer Research Center, grid.7497.d
  46. (46) Hannover Medical School, grid.10423.34
  47. (47) Friedrich Schiller University Jena, grid.9613.d
  48. (48) Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N Minsk Belarus
  49. (49) Roswell Park Cancer Institute, grid.240614.5
  50. (50) University of Pittsburgh, grid.21925.3d
  51. (51) University of Pittsburgh Department of Epidemiology, University of Pittsburgh Graduate School of Public Health and Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute Pittsburgh PA USA
  52. (52) The University of Texas Health Science Center at Houston, grid.267308.8
  53. (53) Cedars-Sinai Medical Center, grid.50956.3f
  54. (54) University of Kansas Medical Center, grid.412016.0
  55. (55) Mayo Clinic Department of Health Sciences Research, Division of Biomedical Statistics and Informatics Rochester MN USA
  56. (56) Mayo Clinic Department of Laboratory Medicine and Pathology, Division of Experimental Pathology Rochester MN USA
  57. (57) The University of Texas MD Anderson Cancer Center, grid.240145.6
  58. (58) Texas Southern University, grid.264771.1
  59. (59) Duke University Hospital, grid.189509.c
  60. (60) Duke University, grid.26009.3d
  61. (61) Haukeland University Hospital, grid.412008.f
  62. (62) University of Bergen, grid.7914.b
  63. (63) Oregon Health & Science University, grid.5288.7
  64. (64) National Cancer Institute, grid.48336.3a
  65. (65) UK and Breakthrough Breast Cancer Research Centre Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton London UK
  66. (66) Peter MacCallum Cancer Centre Cancer Genetics Laboratory, Research Division East Melbourne Victoria Australia
  67. (67) University of Southampton, grid.5491.9
  68. (68) University of California, Irvine, grid.266093.8
  69. (69) Moffitt Cancer Center, grid.468198.a
  70. (70) Mayo Clinic Department of Health Sciences Research, Division of Epidemiology Rochester MN USA
  71. (71) Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency Vancouver BC Canada
  72. (72) Simon Fraser University, grid.61971.38
  73. (73) University of New Mexico, grid.266832.b
  74. (74) BC Cancer Agency, grid.248762.d


SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.


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Times Cited: 7

Field Citation Ratio (FCR): 1.42

Relative Citation ratio (RCR): 0.16

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Green, Accepted