Article open access publication

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Cancer Epidemiology Biomarkers & Prevention, American Association for Cancer Research (AACR), ISSN 1055-9965

Volume 24, 11, 2015

DOI:10.1158/1055-9965.epi-15-0363, Dimensions: pub.1063224164, PMC: PMC4633342, PMID: 26354892,

Authors

Wang, Qin (2)
Milne, Roger L. (3) (4)
Benitez, Javier (11) (12)
Blot, William (1) (13)
Bojesen, Stig E. (15) (16)
Brauch, Hiltrud (9) (17) (18)
Cai, Hui (1)
Fasching, Peter A. (10) (28)
Giles, Graham G (3) (4)
Guénel, Pascal (33) (34)
Hartman, Mikael (36) (37)
Knight, Julia A. (7) (43)
Kosma, Veli-Matti (44) (45)
Mannermaa, Arto (44) (45)
Marme, Frederik (51) (52)
Muir, Kenneth (50) (56)
Nord, Silje (58) (59)
Orr, Nick (29)
Shen, Chen-Yang (39) (64)
Teo, Soo Hwang (65) (66)
Thienpont, Bernard (46) (47)
Truong, Thérèse (33) (34)
Winqvist, Robert (32) (69)
Wu, Anna (35)
Hall, Per (25)

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) University of Cambridge, grid.5335.0
  3. (3) Cancer Council Victoria, grid.3263.4
  4. (4) University of Melbourne, grid.1008.9
  5. (5) QIMR Berghofer Medical Research Institute, grid.1049.c
  6. (6) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  7. (7) University of Toronto, grid.17063.33
  8. (8) University of California, Irvine, grid.266093.8
  9. (9) German Cancer Research Center, grid.7497.d
  10. (10) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  11. (11) Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  12. (12) Spanish National Cancer Research Centre, grid.7719.8
  13. (13) International Epidemiology Institute, grid.419344.f
  14. (14) Hannover Medical School, grid.10423.34
  15. (15) University of Copenhagen, grid.5254.6, KU
  16. (16) Herlev Hospital, grid.411900.d, Capital Region
  17. (17) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  18. (18) University of Tübingen, grid.10392.39
  19. (19) National Cancer Institute, grid.48336.3a
  20. (20) Antoni van Leeuwenhoek Hospital, grid.430814.a
  21. (21) Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum, Germany
  22. (22) Seoul National University, grid.31501.36
  23. (23) Mayo Clinic, grid.66875.3a
  24. (24) University of Sheffield, grid.11835.3e
  25. (25) Karolinska Institute, grid.4714.6
  26. (26) Leiden University Medical Center, grid.10419.3d
  27. (27) Laval University, grid.23856.3a
  28. (28) University of California, Los Angeles, grid.19006.3e
  29. (29) Institute of Cancer Research, grid.18886.3f
  30. (30) National Centre of Scientific Research Demokritos, grid.6083.d
  31. (31) International Agency For Research On Cancer, grid.17703.32
  32. (32) University of Oulu, grid.10858.34
  33. (33) French Institute of Health and Medical Research, grid.7429.8
  34. (34) University of Paris-Sud, grid.5842.b
  35. (35) University of Southern California, grid.42505.36
  36. (36) National University of Singapore, grid.4280.e
  37. (37) National University Health System, grid.410759.e
  38. (38) Erasmus University Medical Center, grid.5645.2
  39. (39) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  40. (40) Aichi Cancer Center, grid.410800.d
  41. (41) Pomeranian Medical University, grid.107950.a
  42. (42) Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
  43. (43) Mount Sinai Hospital, grid.416166.2
  44. (44) Kuopio University Hospital, grid.410705.7
  45. (45) University of Eastern Finland, grid.9668.1
  46. (46) KU Leuven, grid.5596.f
  47. (47) Vesalius Research Center, Leuven, Belgium
  48. (48) University of Hawaii at Manoa, grid.410445.0
  49. (49) University of Warwick, grid.7372.1
  50. (50) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  51. (51) Heidelberg University, grid.7700.0
  52. (52) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  53. (53) Kyushu University, grid.177174.3
  54. (54) The Alfred Hospital, grid.1623.6
  55. (55) Technical University of Munich, grid.6936.a
  56. (56) University of Manchester, grid.5379.8
  57. (57) City Of Hope National Medical Center, grid.410425.6
  58. (58) K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien, Oslo, Norway
  59. (59) Oslo University Hospital, grid.55325.34
  60. (60) FIRC Institute of Molecular Oncology, grid.7678.e
  61. (61) National Cancer Institute of Thailand, grid.419173.9
  62. (62) King's College London, grid.13097.3c
  63. (63) University Hospital Cologne, grid.411097.a
  64. (64) China Medical University, grid.254145.3
  65. (65) Cancer Research Initiatives Foundation, grid.427737.2
  66. (66) University Malaya Medical Centre, grid.413018.f
  67. (67) The Ohio State University, grid.261331.4
  68. (68) University of Oxford, grid.4991.5
  69. (69) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  70. (70) Hospital Universitario La Paz, grid.81821.32
  71. (71) Shanghai Municipal Center For Disease Control Prevention, grid.430328.e
  72. (72) Peter MacCallum Cancer Centre, grid.1055.1

Description

BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

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Times Cited: 17

Field Citation Ratio (FCR): 3.76

Relative Citation ratio (RCR): 0.66

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