Article open access publication

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

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

Volume 23, 22, 2014

DOI:10.1093/hmg/ddu311, Dimensions: pub.1041169752, PMC: PMC4204770, PMID: 24943594,

Authors

Milne, Roger L. (1) (2) (3)
Wang, Qin (6)
Swerdlow, Anthony (10) (11)
Orr, Nick (12)
Brauch, Hiltrud (14) (15)
Andrulis, Irene L. (17) (18)
Knight, Julia A. (18) (19)
Brenner, Hermann (16) (26)
Hui, Miao (32) (33)
Yen Lim, Wei (32) (33)
Marme, Federick (5) (34)
Yang, Rongxi (5) (34)
Garcia-Closas, Montserrat (10) (11) (38) (39)
Bojesen, Stig E. (41) (42) (43)
Nordestgaard, Børge G. (41) (42) (43)
Zheng, Wei (48)
Kang, Dae Hee (57) (58)
Park, Sue K. (57) (58)
Goldberg, Mark S (60) (61)
Fasching, Peter A. (63) (64)
Tomlinson, Ian (71) (72)
Hwang Teo, Soo (75) (76)
Shen, Chen-Yang (77) (78)
Hou, Ming-Feng (80) (81)
Guénel, Pascal (82) (83)
Truong, Therese (82) (83)
Sanchez, Marie (82) (83)
Mulot, Claire (83) (84)
Wu, Anna H (88)
Bogdanova, Natalia (89) (90)
Muir, Kenneth (91) (92)
Mannermaa, Arto (94) (95) (96)
Kataja, Vesa (94) (97) (98)
Kosma, Veli-Matti (94) (95) (96)
Hartikainen, Jaana M (94) (95) (96)
Lu, Wei (99)
Gao, Yu-Tang (100)
Zhang, Ben (48)
Couch, Fergus J. (101) (102)
McKay, James (106)
Shah, Mitul (110)
Pharoah, Paul D P (6) (110)
Hall, Per (25)
Giles, Graham G (1) (2)
Easton, Douglas F. (6) (110)

Affiliations

Organisations

  1. (1) Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health
  2. (2) Cancer Council Victoria, grid.3263.4
  3. (3) Human Cancer Genetics Programme
  4. (4) Molecular Epidemiology Group
  5. (5) Department of Obstetrics and Gynecology
  6. (6) Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care
  7. (7) Hospital Monte Naranco, grid.414858.4
  8. (8) Hospital Universitario La Paz, grid.81821.32
  9. (9) Spanish National Cancer Research Centre, grid.7719.8
  10. (10) Institute of Cancer Research, grid.18886.3f
  11. (11) Division of Breast Cancer Research
  12. (12) Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research
  13. (13) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
  14. (14) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  15. (15) University of Tübingen, grid.10392.39
  16. (16) German Cancer Research Center, grid.7497.d
  17. (17) Department of Molecular Genetics
  18. (18) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
  19. (19) University of Toronto, grid.17063.33
  20. (20) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  21. (21) Kyushu University, grid.177174.3
  22. (22) Aichi Cancer Center, grid.410800.d
  23. (23) Mie University, grid.260026.0
  24. (24) Genome Institute of Singapore, grid.418377.e
  25. (25) Department of Medical Epidemiology and Biostatistics
  26. (26) Division of Clinical Epidemiology and Aging Research
  27. (27) Krebsregister Saarland, grid.482902.5
  28. (28) Flanders Institute for Biotechnology, grid.11486.3a
  29. (29) Universitair Ziekenhuis Leuven, grid.410569.f
  30. (30) Pomeranian Medical University, grid.107950.a
  31. (31) Saw Swee Hock School of Public Health, Department of Surgery, Yong Loo Lin School of Medicine
  32. (32) National University of Singapore, grid.4280.e
  33. (33) National University Health System, grid.410759.e
  34. (34) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  35. (35) Heidelberg University, grid.7700.0
  36. (36) Department of Molecular Medicine and Surgery
  37. (37) Karolinska Institute, grid.4714.6
  38. (38) National Cancer Institute, grid.48336.3a
  39. (39) Breakthrough Breast Cancer Research Centre
  40. (40) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  41. (41) Copenhagen General Population Study, Herlev Hospital
  42. (42) Department of Clinical Biochemistry, Herlev Hospital
  43. (43) University of Copenhagen, grid.5254.6, KU
  44. (44) Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  45. (45) Department of Medical Oncology
  46. (46) Erasmus University Medical Center, grid.5645.2
  47. (47) London School of Hygiene & Tropical Medicine, grid.8991.9
  48. (48) Vanderbilt University Medical Center, grid.412807.8
  49. (49) Institute for Medical Biometrics and Epidemiology
  50. (50) University Medical Center Hamburg-Eppendorf, grid.13648.38
  51. (51) University of Oulu, grid.10858.34
  52. (52) Department of Oncology
  53. (53) Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
  54. (54) CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology
  55. (55) University of Sheffield, grid.11835.3e
  56. (56) Antoni van Leeuwenhoek Hospital, grid.430814.a
  57. (57) Seoul National University, grid.31501.36
  58. (58) Department of Preventive Medicine
  59. (59) Laval University, grid.23856.3a
  60. (60) McGill University, grid.14709.3b
  61. (61) Royal Victoria Hospital, grid.416229.a
  62. (62) University of Montreal, grid.14848.31
  63. (63) University of California, Los Angeles, grid.19006.3e
  64. (64) University Breast Center Franconia, Department of Gynecology and Obstetrics
  65. (65) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  66. (66) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine
  67. (67) FIRC Institute of Molecular Oncology, grid.7678.e
  68. (68) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  69. (69) European Institute of Oncology, grid.15667.33
  70. (70) King's College London, grid.13097.3c
  71. (71) University of Oxford, grid.4991.5
  72. (72) Wellcome Centre for Human Genetics, grid.270683.8
  73. (73) National University of Ireland, Galway, grid.6142.1
  74. (74) University of Melbourne, grid.1008.9
  75. (75) University Malaya Medical Centre, grid.413018.f
  76. (76) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  77. (77) China Medical University, grid.254145.3
  78. (78) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  79. (79) Tri-Service General Hospital, grid.278244.f
  80. (80) Cancer Center
  81. (81) Kaohsiung Medical University Chung-Ho Memorial Hospital, grid.412027.2
  82. (82) University of Paris-Sud, grid.5842.b
  83. (83) French Institute of Health and Medical Research, grid.7429.8
  84. (84) Centre de Ressources Biologiques EPIGENETEC, Paris, France
  85. (85) Vanderbilt University, grid.152326.1
  86. (86) Helsinki University Central Hospital, grid.15485.3d
  87. (87) Department of Clinical Genetics
  88. (88) University of Southern California, grid.42505.36
  89. (89) Hannover Medical School, grid.10423.34
  90. (90) Department of Obstetrics and Gynaecology
  91. (91) University of Manchester, grid.5379.8
  92. (92) University of Warwick, grid.7372.1
  93. (93) Ministry of Public Health, grid.415836.d
  94. (94) Biocenter Kuopio
  95. (95) Department of Clinical Pathology
  96. (96) School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine
  97. (97) Kuopio University Hospital, grid.410705.7
  98. (98) University of Eastern Finland, grid.9668.1
  99. (99) Shanghai Center for Disease Control and Prevention, Shanghai, China
  100. (100) Shanghai Cancer Institute, grid.419087.3
  101. (101) Department of Laboratory Medicine and Pathology
  102. (102) Department of Health Sciences Research
  103. (103) The Ohio State University, grid.261331.4
  104. (104) National Centre of Scientific Research Demokritos, grid.6083.d
  105. (105) National Cancer Institute of Thailand, grid.419173.9
  106. (106) International Agency For Research On Cancer, grid.17703.32
  107. (107) University of Hawaii at Manoa, grid.410445.0
  108. (108) Department of Human Genetics, and
  109. (109) Leiden University Medical Center, grid.10419.3d
  110. (110) University of Cambridge, grid.5335.0
  111. (111) QIMR Berghofer Medical Research Institute, grid.1049.c

Description

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

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Times Cited: 42

Field Citation Ratio (FCR): 8.7

Relative Citation ratio (RCR): 1.98

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