Article open access publication

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 5, 1, 2014

DOI:10.1038/ncomms5999, Dimensions: pub.1044808072, PMC: PMC4321900, PMID: 25248036,

Authors

Desai, Kinjal (5) (6)
Wang, Qin (1)
Dicks, Ed (1)
Guo, Qi (1)
Bojesen, Stig E. (9) (10) (11)
Nordestgaard, Børge G. (9) (10) (11)
Nielsen, Sune F. (10) (11)
Thienpont, Bernard (12) (13)
Neven, Patrick (13) (14)
Wildiers, Hans (13) (14)
Hall, Per (8)
Guénel, Pascal (26) (27)
Truong, Thérèse (26) (27)
Menegaux, Florence (26) (27)
Sanchez, Marie (26) (27)
Burwinkel, Barbara (16) (28)
Marme, Frederik (28) (29)
Wu, Anna H (30)
Benitez, Javier (31) (32)
Lu, Wei (36)
Andrulis, Irene L. (39) (40)
Knight, Julia A. (39) (41)
TEO, Soo Hwang (47) (48)
Shen, Chen-Yang (52) (53)
Wu, Pei-Ei (53)
Giles, Graham G (51) (57)
Milne, Roger L. (51) (57)
Muir, Kenneth (59) (60)
Hartman, Mikael (49) (62)
Miao, Hui (49) (62)
Teo, Yik Ying (49) (62)
Fasching, Peter A. (63) (64)
Orr, Nick (67)
Goldberg, Mark S (71) (72)
Brauch, Hiltrud (16) (76) (77)
Volorio, Sara (81) (83)
Mannermaa, Arto (85) (86)
Kosma, Veli-Matti (85) (86)
Torres, Diana (16) (94)
Zheng, Wei (35)
Lupien, Mathieu (5) (39) (42)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) University of Queensland, grid.1003.2
  4. (4) Oslo University Hospital, grid.55325.34
  5. (5) Princess Margaret Cancer Centre, grid.415224.4
  6. (6) Dartmouth College, grid.254880.3
  7. (7) Antoni van Leeuwenhoek Hospital, grid.430814.a
  8. (8) Karolinska Institute, grid.4714.6
  9. (9) University of Copenhagen, grid.5254.6, KU
  10. (10) Department of Clinical Biochemistry, Herlev Hospital Copenhagen University Hospital, 2730, Herlev, Copenhagen, Denmark
  11. (11) Herlev Hospital, grid.411900.d, Capital Region
  12. (12) Flanders Institute for Biotechnology, grid.11486.3a
  13. (13) KU Leuven, grid.5596.f
  14. (14) Universitair Ziekenhuis Leuven, grid.410569.f
  15. (15) Mayo Clinic, grid.66875.3a
  16. (16) German Cancer Research Center, grid.7497.d
  17. (17) University Medical Center Hamburg-Eppendorf, grid.13648.38
  18. (18) London School of Hygiene & Tropical Medicine, grid.8991.9
  19. (19) Helsinki University Central Hospital, grid.15485.3d
  20. (20) Department of Clinical Genetics, University of Helsinki Helsinki University Central Hospital, FI-00029, Helsinki, HUS, Finland
  21. (21) Department of Oncology, University of Helsinki, Helsinki University Central Hospital, FI-00029, Helsinki, HUS, Finland
  22. (22) Genome Institute of Singapore, grid.418377.e
  23. (23) Seoul National University, grid.31501.36
  24. (24) Kyushu University, grid.177174.3
  25. (25) Aichi Cancer Center, grid.410800.d
  26. (26) French Institute of Health and Medical Research, grid.7429.8
  27. (27) University of Paris-Sud, grid.5842.b
  28. (28) Heidelberg University, grid.7700.0
  29. (29) National Center for Tumor Diseases, University of Heidelberg, 69120, Heidelberg, Germany
  30. (30) University of Southern California, grid.42505.36
  31. (31) Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010, Valencia, Spain
  32. (32) Spanish National Cancer Research Centre, grid.7719.8
  33. (33) Hospital Universitario La Paz, grid.81821.32
  34. (34) Hospital Monte Naranco, grid.414858.4
  35. (35) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 37203, Nashville, Tennessee, USA
  36. (36) Shanghai Center for Disease Control and Prevention, 200336, Shanghai, China
  37. (37) Shanghai Cancer Institute, grid.419087.3
  38. (38) University of Sheffield, grid.11835.3e
  39. (39) University of Toronto, grid.17063.33
  40. (40) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  41. (41) Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
  42. (42) Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
  43. (43) King's College London, grid.13097.3c
  44. (44) Wellcome Centre for Human Genetics, grid.270683.8
  45. (45) University Hospital Galway, grid.412440.7
  46. (46) University of Hawaii at Manoa, grid.410445.0
  47. (47) University Malaya Medical Centre, grid.413018.f
  48. (48) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500, Subang JayaSelangor, Malaysia
  49. (49) National University of Singapore, grid.4280.e
  50. (50) Erasmus University Medical Center, grid.5645.2
  51. (51) University of Melbourne, grid.1008.9
  52. (52) College of Public Health, China Medical University, 40402, Taichung, Taiwan, China
  53. (53) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  54. (54) Tri-Service General Hospital, grid.278244.f
  55. (55) Changhua Christian Hospital, grid.413814.b
  56. (56) University of Oslo, grid.5510.1
  57. (57) Cancer Council Victoria, grid.3263.4
  58. (58) The Alfred Hospital, grid.1623.6
  59. (59) University of Manchester, grid.5379.8
  60. (60) University of Warwick, grid.7372.1
  61. (61) Ministry of Public Health, grid.415836.d
  62. (62) National University Health System, grid.410759.e
  63. (63) University of California, Los Angeles, grid.19006.3e
  64. (64) Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054, Erlangen, Germany
  65. (65) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
  66. (66) Krebsregister Saarland, grid.482902.5
  67. (67) Institute of Cancer Research, grid.18886.3f
  68. (68) National Cancer Institute, grid.48336.3a
  69. (69) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  70. (70) Laval University, grid.23856.3a
  71. (71) Royal Victoria Hospital, grid.416229.a
  72. (72) McGill University, grid.14709.3b
  73. (73) University of Montreal, grid.14848.31
  74. (74) Department of Clinical Chemistry and Biocenter Oulu, Laboratory of Cancer Genetics and Tumor Biology, NordLab Oulu/Oulu University Hospital University of Oulu, FI-90220, Oulu, Finland
  75. (75) Department of Oncology, Oulu University Hospital, University of Oulu, FI-90220, Oulu, Finland
  76. (76) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  77. (77) University of Tübingen, grid.10392.39
  78. (78) Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789, Bochum, Germany
  79. (79) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113, Bonn, Germany
  80. (80) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  81. (81) FIRC Institute of Molecular Oncology, grid.7678.e
  82. (82) European Institute of Oncology, grid.15667.33
  83. (83) Cogentech Cancer Genetic Test Laboratory, 20133, Milan, Italy
  84. (84) Hannover Medical School, grid.10423.34
  85. (85) University of Eastern Finland, grid.9668.1
  86. (86) Kuopio University Hospital, grid.410705.7
  87. (87) Leiden University Medical Center, grid.10419.3d
  88. (88) Pomeranian Medical University, grid.107950.a
  89. (89) The Ohio State University, grid.261331.4
  90. (90) Roswell Park Cancer Institute, grid.240614.5
  91. (91) National Centre of Scientific Research Demokritos, grid.6083.d
  92. (92) National Cancer Institute of Thailand, grid.419173.9
  93. (93) International Agency For Research On Cancer, grid.17703.32
  94. (94) Pontificia Universidad Javeriana, grid.41312.35
  95. (95) University of California, Irvine, grid.266093.8
  96. (96) Department of Population Sciences, Beckman Research Institute of City of Hope, 92697, Duarte, California, USA
  97. (97) McGill University and Génome Québec Innovation Centre, grid.411640.6

Description

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

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Research area: Medicine

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Research area: Medicine

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Times Cited: 77

Field Citation Ratio (FCR): 8.8

Relative Citation ratio (RCR): 2.22

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