Article open access publication

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 97, 1, 2015

DOI:10.1016/j.ajhg.2015.05.002, Dimensions: pub.1047576567, PMC: PMC4572510, PMID: 26073781,

Authors

Nord, Silje (4) (5)
Wang, Qin (3)
Scott, Rodney J (10) (11)
Muir, Kenneth (12) (13)
Fasching, Peter A. (14) (16)
Burwinkel, Barbara (20) (21)
Marme, Frederik (20) (22)
Guénel, Pascal (23) (24)
Truong, Thérèse (23) (24)
Bojesen, Stig E. (25) (26)
Benitez, Javier (27) (28)
Schmutzler, Rita K. (33) (34) (35)
Brauch, Hiltrud (21) (37) (38)
Kosma, Veli-Matti (43) (44)
Mannermaa, Arto (43) (44)
Wu, Anna H (45)
Giles, Graham G (8) (51)
Milne, Roger L. (8) (51)
Goldberg, Mark S (55) (56)
Teo, Soo H. (58) (59)
Mariapun, Shivaani (58) (59)
Zheng, Wei (60)
Tamimi, Rulla (61) (62)
Winqvist, Robert (63) (64)
Andrulis, Irene L. (65) (66)
Knight, Julia A. (66) (67)
Hartman, Mikael (77) (78)
Lim, Wei Yen (77) (78)
Torres, Diana (21) (79)
Shen, Chen-Yang (85) (86)
Hall, Per (1)

* Corresponding author

Affiliations

Organisations

  1. (1) Karolinska Institute, grid.4714.6
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) University of Cambridge, grid.5335.0
  4. (4) K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway
  5. (5) Oslo University Hospital, grid.55325.34
  6. (6) Antoni van Leeuwenhoek Hospital, grid.430814.a
  7. (7) Mayo Clinic, grid.66875.3a
  8. (8) University of Melbourne, grid.1008.9
  9. (9) University of Western Australia, grid.1012.2
  10. (10) Hunter Medical Research Institute, grid.413648.c
  11. (11) University of Newcastle Australia, grid.266842.c
  12. (12) University of Warwick, grid.7372.1
  13. (13) University of Manchester, grid.5379.8
  14. (14) 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
  15. (15) Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  16. (16) University of California, Los Angeles, grid.19006.3e
  17. (17) London School of Hygiene & Tropical Medicine, grid.8991.9
  18. (18) University of Oxford, grid.4991.5
  19. (19) King's College London, grid.13097.3c
  20. (20) National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany
  21. (21) German Cancer Research Center, grid.7497.d
  22. (22) Heidelberg University, grid.7700.0
  23. (23) French Institute of Health and Medical Research, grid.7429.8
  24. (24) University of Paris-Sud, grid.5842.b
  25. (25) University of Copenhagen, grid.5254.6, KU
  26. (26) Herlev Hospital, grid.411900.d, Capital Region
  27. (27) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  28. (28) Spanish National Cancer Research Centre, grid.7719.8
  29. (29) University of California, Irvine, grid.266093.8
  30. (30) City Of Hope National Medical Center, grid.410425.6
  31. (31) Leipzig University, grid.9647.c
  32. (32) Technical University of Munich, grid.6936.a
  33. (33) Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne 50937, Germany
  34. (34) Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne 50937, Germany
  35. (35) University of Cologne, grid.6190.e
  36. (36) Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, 24105 Kiel, Germany
  37. (37) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  38. (38) University of Tübingen, grid.10392.39
  39. (39) Helsinki University Central Hospital, grid.15485.3d
  40. (40) Aichi Cancer Center, grid.410800.d
  41. (41) Kyushu University, grid.177174.3
  42. (42) Hannover Medical School, grid.10423.34
  43. (43) Kuopio University Hospital, grid.410705.7
  44. (44) University of Eastern Finland, grid.9668.1
  45. (45) University of Southern California, grid.42505.36
  46. (46) Universitair Ziekenhuis Leuven, grid.410569.f
  47. (47) Flanders Institute for Biotechnology, grid.11486.3a
  48. (48) KU Leuven, grid.5596.f
  49. (49) IFOM, the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 20139 Milan, Italy
  50. (50) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  51. (51) Cancer Council Victoria, grid.3263.4
  52. (52) The Alfred Hospital, grid.1623.6
  53. (53) University of Hawaii at Manoa, grid.410445.0
  54. (54) Dalhousie University, grid.55602.34
  55. (55) McGill University, grid.14709.3b
  56. (56) Royal Victoria Hospital, grid.416229.a
  57. (57) Centre Hospitalier Universitaire de Québec, grid.411081.d
  58. (58) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia
  59. (59) University Malaya Medical Centre, grid.413018.f
  60. (60) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
  61. (61) Brigham and Women's Hospital, grid.62560.37
  62. (62) Harvard University, grid.38142.3c
  63. (63) University of Oulu, grid.10858.34
  64. (64) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, 90220 Oulu, Finland
  65. (65) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  66. (66) University of Toronto, grid.17063.33
  67. (67) Mount Sinai Hospital, grid.416166.2
  68. (68) Leiden University Medical Center, grid.10419.3d
  69. (69) Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD 20850, USA
  70. (70) Breast Cancer Now, grid.458394.7
  71. (71) Institute of Cancer Research, grid.18886.3f
  72. (72) Erasmus University Medical Center, grid.5645.2
  73. (73) Genome Institute of Singapore, grid.418377.e
  74. (74) Shanghai Cancer Institute, grid.419087.3
  75. (75) University of Sheffield, grid.11835.3e
  76. (76) Seoul National University, grid.31501.36
  77. (77) National University Health System, grid.410759.e
  78. (78) National University of Singapore, grid.4280.e
  79. (79) Pontificia Universidad Javeriana, grid.41312.35
  80. (80) Pomeranian Medical University, grid.107950.a
  81. (81) International Agency For Research On Cancer, grid.17703.32
  82. (82) National Cancer Institute of Thailand, grid.419173.9
  83. (83) The Ohio State University, grid.261331.4
  84. (84) National Centre of Scientific Research Demokritos, grid.6083.d
  85. (85) China Medical University, grid.254145.3
  86. (86) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  87. (87) Tri-Service General Hospital, grid.278244.f
  88. (88) University of Oslo, grid.5510.1

Description

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

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Research area: Medicine

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Research area: Medicine

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Times Cited: 21

Field Citation Ratio (FCR): 4.85

Relative Citation ratio (RCR): 0.59

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