Article open access publication

Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Scientific Reports, Springer Nature, ISSN 2045-2322

Volume 6, 1, 2016

DOI:10.1038/srep32512, Dimensions: pub.1012024644, PMC: PMC5013272, PMID: 27600471,

Authors

Wang, Qin (4)
Benitez, Javier (7) (13)
Bojesen, Stig E. (15) (16) (17)
Brauch, Hiltrud (11) (18) (19)
Burwinkel, Barbara (11) (22)
Fasching, Peter A. (12) (28)
Figueroa, Jonine (29) (30)
Galle, Eva (33) (34)
Giles, Graham G (35) (36)
Hartman, Mikael (40) (41)
Kosma, Veli-Matti (46) (47)
Kristensen, Vessela (5) (48) (49)
Lee, Soo Chin (40) (41)
Mannermaa, Arto (46) (47)
Milne, Roger L. (35) (36)
Muir, Kenneth (51) (55)
Orr, Nick (31)
Pylkäs, Katri (58) (59)
Surowy, Harald (11) (22)
Teo, Soo H. (66) (67)
Torres, Diana (11) (70)
Winqvist, Robert (58) (59)
Wu, Anna H (39)
Wu, Pei-Ei (64)
Zheng, Wei (65)
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) Laval University, grid.23856.3a
  4. (4) University of Cambridge, grid.5335.0
  5. (5) Oslo University Hospital, grid.55325.34
  6. (6) Cyprus Institute of Neurology and Genetics, grid.417705.0
  7. (7) Spanish National Cancer Research Centre, grid.7719.8
  8. (8) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  9. (9) University of Toronto, grid.17063.33
  10. (10) University of California, Irvine, grid.266093.8
  11. (11) German Cancer Research Center, grid.7497.d
  12. (12) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  13. (13) Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  14. (14) Hannover Medical School, grid.10423.34
  15. (15) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  16. (16) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  17. (17) University of Copenhagen, grid.5254.6, KU
  18. (18) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  19. (19) University of Tübingen, grid.10392.39
  20. (20) Antoni van Leeuwenhoek Hospital, grid.430814.a
  21. (21) Ruhr University Bochum, grid.5570.7
  22. (22) Heidelberg University, grid.7700.0
  23. (23) University Cancer Center Hamburg, grid.412315.0
  24. (24) Seoul National University, grid.31501.36
  25. (25) Mayo Clinic, grid.66875.3a
  26. (26) University of Sheffield, grid.11835.3e
  27. (27) Leiden University Medical Center, grid.10419.3d
  28. (28) University of California, Los Angeles, grid.19006.3e
  29. (29) University of Edinburgh, grid.4305.2
  30. (30) National Cancer Institute, grid.48336.3a
  31. (31) Institute of Cancer Research, grid.18886.3f
  32. (32) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  33. (33) KU Leuven, grid.5596.f
  34. (34) Vesalius Research Center, Leuven, Belgium
  35. (35) University of Melbourne, grid.1008.9
  36. (36) Cancer Council Victoria, grid.3263.4
  37. (37) McGill University, grid.14709.3b
  38. (38) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  39. (39) University of Southern California, grid.42505.36
  40. (40) National University Health System, grid.410759.e
  41. (41) National University of Singapore, grid.4280.e
  42. (42) Erasmus University Medical Center, grid.5645.2
  43. (43) Aichi Cancer Center, grid.410800.d
  44. (44) Pomeranian Medical University, grid.107950.a
  45. (45) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  46. (46) Kuopio University Hospital, grid.410705.7
  47. (47) University of Eastern Finland, grid.9668.1
  48. (48) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  49. (49) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  50. (50) University of Hawaii at Manoa, grid.410445.0
  51. (51) University of Warwick, grid.7372.1
  52. (52) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  53. (53) International Agency For Research On Cancer, grid.17703.32
  54. (54) Technical University of Munich, grid.6936.a
  55. (55) University of Manchester, grid.5379.8
  56. (56) City Of Hope National Medical Center, grid.410425.6
  57. (57) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  58. (58) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
  59. (59) University of Oulu, grid.10858.34
  60. (60) National Cancer Institute of Thailand, grid.419173.9
  61. (61) King's College London, grid.13097.3c
  62. (62) University Hospital Cologne, grid.411097.a
  63. (63) University of Cologne, grid.6190.e
  64. (64) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  65. (65) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  66. (66) Cancer Research Initiatives Foundation, grid.427737.2
  67. (67) University Malaya Medical Centre, grid.413018.f
  68. (68) McGill University and Génome Québec Innovation Centre, grid.411640.6
  69. (69) University of Oxford, grid.4991.5
  70. (70) Pontificia Universidad Javeriana, grid.41312.35

Description

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.

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