Article open access publication

Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

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

Volume 96, 1, 2015

DOI:10.1016/j.ajhg.2014.11.009, Dimensions: pub.1028616460, PMC: PMC4289692, PMID: 25529635,

Authors

Betts, Joshua A (1) (3)
Muir, Kenneth (7) (8)
Fasching, Peter A. (10) (11)
Wang, Qin (2)
Marme, Frederik (18) (19)
Yang, Rongxi (18) (20)
Surowy, Harald (18) (20)
Guénel, Pascal (21) (22)
Truong, Thérèse (21) (22)
Menegaux, Florence (21) (22)
Sanchez, Marie (21) (22)
Bojesen, Stig E. (23) (24)
Benitez, Javier (26) (27)
Schmutzler, Rita K. (34) (35) (36)
Brauch, Hiltrud (37) (38)
Network, The GENICA (20) (37) (38) (39) (40) (41)
Mannermaa, Arto (48) (49)
Kataja, Vesa (48) (49)
Kosma, Veli-Matti (48) (49)
Wu, Anna H (51)
Zhao, Hui (52) (53)
Capra, Fabio (56) (58)
Giles, Graham G (4) (60)
Milne, Roger L. (4) (60)
Goldberg, Mark S (64) (65)
Teo, Soo Hwang (67) (68)
Kristensen, Vessela (70) (71) (72)
Study, Norwegian Breast Cancer (71) (72) (73) (74) (75) (76) (77) (78) (79)
Zheng, Wei (80)
Andrulis, Irene L. (84) (85)
Knight, Julia A. (85) (86)
Hall, Per (47)
Lu, Wei (93)
Cai, Hui (80)
Blot, William (80) (96)
Hartman, Mikael (69) (99)
Miao, Hui (69) (99)
Lim, Wei Yen (69) (99)
Torres, Diana (20) (100)
McKay, James (103)
Shen, Chen-Yang (106) (107)
Wu, Pei-Ei (107)
Orr, Nick (14)
French, Juliet D * (1) (3)

* Corresponding author

Affiliations

Organisations

  1. (1) QIMR Berghofer Medical Research Institute, grid.1049.c
  2. (2) University of Cambridge, grid.5335.0
  3. (3) University of Queensland, grid.1003.2
  4. (4) Antoni van Leeuwenhoek Hospital, grid.430814.a
  5. (5) University of Melbourne, grid.1008.9
  6. (6) Sanquin, grid.417732.4
  7. (7) University of Manchester, grid.5379.8
  8. (8) University of Warwick, grid.7372.1
  9. (9) Ministry of Public Health, grid.415836.d
  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 of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  12. (12) Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  13. (13) London School of Hygiene & Tropical Medicine, grid.8991.9
  14. (14) Institute of Cancer Research, grid.18886.3f
  15. (15) King's College London, grid.13097.3c
  16. (16) Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford OX3 7BN, UK
  17. (17) University Hospital Galway, grid.412440.7
  18. (18) Heidelberg University, grid.7700.0
  19. (19) National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany
  20. (20) German Cancer Research Center, grid.7497.d
  21. (21) Centre for research in epidemiology and population health, grid.463845.8
  22. (22) University of Paris-Sud, grid.5842.b
  23. (23) University of Copenhagen, grid.5254.6, KU
  24. (24) Herlev Hospital, grid.411900.d, Capital Region
  25. (25) Spanish National Cancer Research Centre, grid.7719.8
  26. (26) Centro de Investigación en Red de Enfermedades Raras, 46010 Valencia, Spain
  27. (27) Human Genetics Group, Spanish National Cancer Centre and Biomedical Network on Rare Diseases, 28029 Madrid, Spain
  28. (28) Hospital Universitario La Paz, grid.81821.32
  29. (29) Hospital Monte Naranco, grid.414858.4
  30. (30) University of California, Irvine, grid.266093.8
  31. (31) City Of Hope National Medical Center, grid.410425.6
  32. (32) Krebsregister Saarland, grid.482902.5
  33. (33) Technical University of Munich, grid.6936.a
  34. (34) Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, 50937 Cologne, Germany
  35. (35) University Hospital Cologne, grid.411097.a
  36. (36) University of Cologne, grid.6190.e
  37. (37) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  38. (38) University of Tübingen, grid.10392.39
  39. (39) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113 Bonn, Germany
  40. (40) Ruhr University Bochum, grid.5570.7
  41. (41) University Medical Center Hamburg-Eppendorf, grid.13648.38
  42. (42) Hospital District of Helsinki and Uusimaa, grid.424664.6
  43. (43) Helsinki University Central Hospital, grid.15485.3d
  44. (44) Kyushu University, grid.177174.3
  45. (45) Aichi Cancer Center, grid.410800.d
  46. (46) Hannover Medical School, grid.10423.34
  47. (47) Karolinska Institute, grid.4714.6
  48. (48) Kuopio University Hospital, grid.410705.7
  49. (49) University of Eastern Finland, grid.9668.1
  50. (50) Peter MacCallum Cancer Centre, grid.1055.1
  51. (51) University of Southern California, grid.42505.36
  52. (52) Flanders Institute for Biotechnology, grid.11486.3a
  53. (53) KU Leuven, grid.5596.f
  54. (54) Universitair Ziekenhuis Leuven, grid.410569.f
  55. (55) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  56. (56) Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy
  57. (57) European Institute of Oncology, grid.15667.33
  58. (58) Cogentech Cancer Genetic Test Laboratory, 20139 Milan, Italy
  59. (59) Mayo Clinic, grid.66875.3a
  60. (60) Cancer Council Victoria, grid.3263.4
  61. (61) The Alfred Hospital, grid.1623.6
  62. (62) University of Hawaii at Manoa, grid.410445.0
  63. (63) Centre Hospitalier Universitaire de Québec, grid.411081.d
  64. (64) McGill University, grid.14709.3b
  65. (65) Royal Victoria Hospital, grid.416229.a
  66. (66) University of Montreal, grid.14848.31
  67. (67) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia
  68. (68) University Malaya Medical Centre, grid.413018.f
  69. (69) National University of Singapore, grid.4280.e
  70. (70) Department of Clinical Molecular Biology, University of Oslo, 0450 Oslo, Norway
  71. (71) Oslo University Hospital, grid.55325.34
  72. (72) University of Oslo, grid.5510.1
  73. (73) Akershus University Hospital, grid.411279.8
  74. (74) Department of Clinical Molecular Biology, Institute of Clinical Medicine, Akershus University Hospital, University of Oslo, 1478 Lørenskog, Norway
  75. (75) Haukeland University Hospital, grid.412008.f
  76. (76) National Resource Centre for Long-Term Studies after Cancer, Rikshospitalet-Radiumhospitalet Cancer Clinic, Montebello, 0310 Oslo, Norway
  77. (77) The Arctic University of Norway, grid.10919.30
  78. (78) University Hospital of North Norway, grid.412244.5
  79. (79) University of Bergen, grid.7914.b
  80. (80) Vanderbilt University, grid.152326.1
  81. (81) Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu, Oulu University Hospital, 90210 Oulu, Finland
  82. (82) Department of Oncology, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland
  83. (83) Department of Pathology, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland
  84. (84) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  85. (85) University of Toronto, grid.17063.33
  86. (86) Mount Sinai Hospital, grid.416166.2
  87. (87) Leiden University Medical Center, grid.10419.3d
  88. (88) National Cancer Institute, grid.48336.3a
  89. (89) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  90. (90) Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, 3075 EA Rotterdam, the Netherlands
  91. (91) Erasmus University Medical Center, grid.5645.2
  92. (92) Genome Institute of Singapore, grid.418377.e
  93. (93) Shanghai Center for Disease Control and Prevention, Changning, Shanghai 200336, China
  94. (94) Shanghai Cancer Institute, grid.419087.3
  95. (95) University of Sheffield, grid.11835.3e
  96. (96) International Epidemiology Institute, grid.419344.f
  97. (97) Seoul National University, grid.31501.36
  98. (98) Department of Surgery, Seoul National University, Bundang Hospital, Seongnam 110-744, Korea
  99. (99) National University Health System, grid.410759.e
  100. (100) Pontificia Universidad Javeriana, grid.41312.35
  101. (101) Pomeranian Medical University, grid.107950.a
  102. (102) National Cancer Institute of Thailand, grid.419173.9
  103. (103) International Agency For Research On Cancer, grid.17703.32
  104. (104) The Ohio State University, grid.261331.4
  105. (105) National Centre of Scientific Research Demokritos, grid.6083.d
  106. (106) China Medical University, grid.254145.3
  107. (107) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  108. (108) Tri-Service General Hospital, grid.278244.f
  109. (109) Cancer Center and Department of Surgery, Kaohsiung Medical University, Chung-Ho Memorial Hospital, Kaohsiung 807, Taiwan
  110. (110) McGill University and Génome Québec Innovation Centre, grid.411640.6

Description

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

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Times Cited: 53

Field Citation Ratio (FCR): 11.68

Relative Citation ratio (RCR): 1.75

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