Article open access publication

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Human Molecular Genetics, Oxford University Press (OUP), ISSN 1460-2083

Volume 25, 17, 2016

DOI:10.1093/hmg/ddw223, Dimensions: pub.1059645955, PMC: PMC5216618, PMID: 27402876,

Authors

Yao, Song (2)
Wang, Qin (3)
Muir, Kenneth (7) (8)
Fasching, Peter A (10) (11)
Marme, Frederik (9) (15)
Guénel, Pascal (16) (17)
Truong, Thérèse (16) (17)
Benitez, Javier (19) (20)
Schmutzler, Rita K (23) (24)
Brauch, Hiltrud (25) (26)
Mannermaa, Arto (32) (33)
Kosma, Veli-Matti (32) (33)
Wu, Anna H (34)
Giles, Graham G (4) (42)
Milne, Roger L (4) (42)
Teo, Soo Hwang (44) (45)
Zheng, Wei (49)
Andrulis, Irene L (51) (52)
Knight, Julia A (52) (53)
Blot, William (49) (60)
Hartman, Mikael (46) (63)
Miao, Hui (46) (63)
Shen, Chen-Yang (69) (70)
Wu, Pei-Ei (70)
Orr, Nick (56)
Hall, Per (31)

Affiliations

Organisations

  1. (1) Dartmouth College, grid.254880.3
  2. (2) Roswell Park Cancer Institute, grid.240614.5
  3. (3) University of Cambridge, grid.5335.0
  4. (4) University of Melbourne, grid.1008.9
  5. (5) Antoni van Leeuwenhoek Hospital, grid.430814.a
  6. (6) University of Oxford, grid.4991.5
  7. (7) University of Manchester, grid.5379.8
  8. (8) University of Warwick, grid.7372.1
  9. (9) Heidelberg University, grid.7700.0
  10. (10) University of California, Los Angeles, grid.19006.3e
  11. (11) University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
  12. (12) London School of Hygiene & Tropical Medicine, grid.8991.9
  13. (13) King's College London, grid.13097.3c
  14. (14) German Cancer Research Center, grid.7497.d
  15. (15) National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany,
  16. (16) French Institute of Health and Medical Research, grid.7429.8
  17. (17) University of Paris-Sud, grid.5842.b
  18. (18) Herlev Hospital, grid.411900.d, Capital Region
  19. (19) Spanish National Cancer Research Centre, grid.7719.8
  20. (20) Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain,
  21. (21) City Of Hope National Medical Center, grid.410425.6
  22. (22) Technical University of Munich, grid.6936.a
  23. (23) University Hospital Cologne, grid.411097.a
  24. (24) University of Cologne, grid.6190.e
  25. (25) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  26. (26) University of Tübingen, grid.10392.39
  27. (27) Helsinki University Central Hospital, grid.15485.3d
  28. (28) Kyushu University, grid.177174.3
  29. (29) Aichi Cancer Center, grid.410800.d
  30. (30) Hannover Medical School, grid.10423.34
  31. (31) Karolinska Institute, grid.4714.6
  32. (32) Kuopio University Hospital, grid.410705.7
  33. (33) University of Eastern Finland, grid.9668.1
  34. (34) University of Southern California, grid.42505.36
  35. (35) Flanders Institute for Biotechnology, grid.11486.3a
  36. (36) KU Leuven, grid.5596.f
  37. (37) Universitair Ziekenhuis Leuven, grid.410569.f
  38. (38) University Cancer Center Hamburg, grid.412315.0
  39. (39) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  40. (40) FIRC Institute of Molecular Oncology, grid.7678.e
  41. (41) Mayo Clinic, grid.66875.3a
  42. (42) Cancer Council Victoria, grid.3263.4
  43. (43) Centre Hospitalier Universitaire de Québec, grid.411081.d
  44. (44) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Selangor, Malaysia.
  45. (45) University Malaya Medical Centre, grid.413018.f
  46. (46) National University of Singapore, grid.4280.e
  47. (47) Oslo University Hospital, grid.55325.34
  48. (48) University of Oslo, grid.5510.1
  49. (49) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA,
  50. (50) University of Oulu, grid.10858.34
  51. (51) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  52. (52) University of Toronto, grid.17063.33
  53. (53) Mount Sinai Hospital, grid.416166.2
  54. (54) Leiden University Medical Center, grid.10419.3d
  55. (55) Erasmus University Medical Center, grid.5645.2
  56. (56) Institute of Cancer Research, grid.18886.3f
  57. (57) National Cancer Institute, grid.48336.3a
  58. (58) Shanghai Cancer Institute, grid.419087.3
  59. (59) University of Sheffield, grid.11835.3e
  60. (60) International Epidemiology Institute, grid.419344.f
  61. (61) National Institutes of Health, grid.94365.3d
  62. (62) Seoul National University, grid.31501.36
  63. (63) National University Health System, grid.410759.e
  64. (64) Pomeranian Medical University, grid.107950.a
  65. (65) National Cancer Institute of Thailand, grid.419173.9
  66. (66) International Agency For Research On Cancer, grid.17703.32
  67. (67) The Ohio State University, grid.261331.4
  68. (68) National Centre of Scientific Research Demokritos, grid.6083.d
  69. (69) China Medical University, grid.254145.3
  70. (70) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  71. (71) QIMR Berghofer Medical Research Institute, grid.1049.c
  72. (72) Rutgers, The State University of New Jersey, grid.430387.b

Description

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 >0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

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Times Cited: 18

Field Citation Ratio (FCR): 3.72

Relative Citation ratio (RCR): 0.54

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