Article open access publication

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Breast Cancer Research, Springer Nature, ISSN 1465-5411

Volume 18, 1, 2016

DOI:10.1186/s13058-016-0718-0, Dimensions: pub.1052669138, PMC: PMC4962376, PMID: 27459855,

Authors

Milne, Roger L. (5) (6)
Wang, Qin (2)
Benitez, Javier (18) (19)
Blot, William J. (1) (22)
Bojesen, Stig E. (24) (25)
Brauch, Hiltrud (14) (30) (31)
Burwinkel, Barbara (14) (35)
Fasching, Peter A. (57) (58)
Giles, Graham G (5) (6)
Guénel, Pascal (72) (73)
Hartman, Mikael (79) (80)
John, Esther M (95) (96)
Khan, Sofia (100)
Khusnutdinova, Elza (20) (101)
Knight, Julia A. (9) (102)
Kwong, Ava (104) (105)
Lambrechts, Diether (106) (107)
Mannermaa, Arto (77) (78)
Marme, Frederik (35) (113)
Menegaux, Florence (72) (73)
Muir, Kenneth (111) (116)
Newcomb, Polly A (119) (120)
Olah, Edith (123)
Osorio, Ana (19) (125)
Papi, Laura (126)
Rennert, Gad (132)
Salani, Ritu (134)
Shen, Chen-Yang (137) (138)
Soucy, Penny (139)
Teixeira, Manuel R. (141) (142)
Teo, Soo H. (81) (82)
Teulé, Alex (144)
Tischkowitz, Marc (2) (147)
Tung, Nadine (148)
Winqvist, Robert (151) (152)
Wu, Anna H (74)
Hall, Per (29)
Zheng, Wei * (1)

* Corresponding author

Affiliations

Organisations

  1. (1) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, 37203-1738, Nashville, TN, USA
  2. (2) University of Cambridge, grid.5335.0
  3. (3) Laval University, grid.23856.3a
  4. (4) St Vincent's Hospital, grid.413105.2
  5. (5) University of Melbourne, grid.1008.9
  6. (6) Cancer Council Victoria, grid.3263.4
  7. (7) Istituti di Ricovero e Cura a Carattere Scientifico, grid.414603.4
  8. (8) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  9. (9) University of Toronto, grid.17063.33
  10. (10) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  11. (11) University of California, Irvine, grid.266093.8
  12. (12) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
  13. (13) University of Iceland, grid.14013.37
  14. (14) German Cancer Research Center, grid.7497.d
  15. (15) The University of Texas MD Anderson Cancer Center, grid.240145.6
  16. (16) Karolinska University Hospital, grid.24381.3c
  17. (17) McGill University and Génome Québec Innovation Centre, grid.411640.6
  18. (18) Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  19. (19) Spanish National Cancer Research Centre, grid.7719.8
  20. (20) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
  21. (21) Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  22. (22) International Epidemiology Institute, grid.419344.f
  23. (23) Hannover Medical School, grid.10423.34
  24. (24) University of Copenhagen, grid.5254.6, KU
  25. (25) Herlev Hospital, grid.411900.d, Capital Region
  26. (26) European Institute of Oncology, grid.15667.33
  27. (27) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  28. (28) Oslo University Hospital, grid.55325.34
  29. (29) Karolinska Institute, grid.4714.6
  30. (30) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  31. (31) University of Tübingen, grid.10392.39
  32. (32) International Agency For Research On Cancer, grid.17703.32
  33. (33) Antoni van Leeuwenhoek Hospital, grid.430814.a
  34. (34) Ruhr University Bochum, grid.5570.7
  35. (35) Heidelberg University, grid.7700.0
  36. (36) University of Utah, grid.223827.e
  37. (37) Hospital Clínico San Carlos, grid.411068.a
  38. (38) Peter MacCallum Cancer Centre, grid.1055.1
  39. (39) University of Sydney, grid.1013.3
  40. (40) University Cancer Center Hamburg, grid.412315.0
  41. (41) Seoul National University, grid.31501.36
  42. (42) Ghent University, grid.5342.0
  43. (43) University of Sheffield, grid.11835.3e
  44. (44) Temple University Health System, grid.412530.1
  45. (45) Leiden University Medical Center, grid.10419.3d
  46. (46) Hospital Universitari Vall d'Hebron, grid.411083.f
  47. (47) University of Pennsylvania, grid.25879.31
  48. (48) National Cancer Institute, grid.48336.3a
  49. (49) University of Pretoria, grid.49697.35
  50. (50) London School of Hygiene & Tropical Medicine, grid.8991.9
  51. (51) University of Westminster, grid.12896.34
  52. (52) University of Bonn, grid.10388.32
  53. (53) Moffitt Cancer Center, grid.468198.a
  54. (54) Sahlgrenska University Hospital, grid.1649.a
  55. (55) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  56. (56) Manchester University NHS Foundation Trust, grid.498924.a
  57. (57) University of California, Los Angeles, grid.19006.3e
  58. (58) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  59. (59) ANZ GOTG Coordinating Centre, Australia New Zealand GOG, Camperdown, NSW, Australia
  60. (60) Sheba Medical Center, grid.413795.d
  61. (61) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  62. (62) Shanghai Cancer Institute, grid.419087.3
  63. (63) Dana-Farber Cancer Institute, grid.65499.37
  64. (64) Institute of Cancer Research, grid.18886.3f
  65. (65) University of Würzburg, grid.8379.5
  66. (66) University of Lyon System, grid.25697.3f
  67. (67) Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, 75248, Paris, France
  68. (68) Institute Curie, grid.418596.7
  69. (69) Paris Descartes University, grid.10992.33
  70. (70) GEMO study: National Cancer Genetics Network, UNICANCER Genetic Group, ᅟ, France
  71. (71) University of Kansas Medical Center, grid.412016.0
  72. (72) French Institute of Health and Medical Research, grid.7429.8
  73. (73) University of Paris-Sud, grid.5842.b
  74. (74) University of Southern California, grid.42505.36
  75. (75) Mayo Clinic, grid.66875.3a
  76. (76) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  77. (77) Kuopio University Hospital, grid.410705.7
  78. (78) University of Eastern Finland, grid.9668.1
  79. (79) National University Health System, grid.410759.e
  80. (80) National University of Singapore, grid.4280.e
  81. (81) Cancer Research Initiatives Foundation, grid.427737.2
  82. (82) University Malaya Medical Centre, grid.413018.f
  83. (83) QIMR Berghofer Medical Research Institute, grid.1049.c
  84. (84) Care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA
  85. (85) Suburban Hospital, grid.416674.6
  86. (86) Erasmus University Medical Center, grid.5645.2
  87. (87) NorthShore University HealthSystem, grid.240372.0
  88. (88) Harvard University, grid.38142.3c
  89. (89) Institute of Oncology NN Petrov, grid.465337.0
  90. (90) Georgetown University Medical Center, grid.411667.3
  91. (91) Aichi Cancer Center, grid.410800.d
  92. (92) Pomeranian Medical University, grid.107950.a
  93. (93) State Research Institute Centre for Innovative Medicine, grid.493509.2
  94. (94) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  95. (95) Cancer Prevention Institute of California, grid.280669.3
  96. (96) Stanford University, grid.168010.e
  97. (97) Cedars-Sinai Medical Center, grid.50956.3f
  98. (98) Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland
  99. (99) National University of Ireland, Galway, grid.6142.1
  100. (100) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  101. (101) Bashkir State University, grid.77269.3d
  102. (102) Mount Sinai Hospital, grid.416166.2
  103. (103) National Centre of Scientific Research Demokritos, grid.6083.d
  104. (104) Hong Kong Sanatorium and Hospital, grid.414329.9
  105. (105) University of Hong Kong, grid.194645.b
  106. (106) KU Leuven, grid.5596.f
  107. (107) Vesalius Research Center, Leuven, Belgium
  108. (108) Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  109. (109) University of Hawaii at Manoa, grid.410445.0
  110. (110) Soonchunhyang University Hospital, grid.412678.e
  111. (111) University of Warwick, grid.7372.1
  112. (112) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  113. (113) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  114. (114) Kyushu University, grid.177174.3
  115. (115) Technical University of Munich, grid.6936.a
  116. (116) University of Manchester, grid.5379.8
  117. (117) University Health Network, grid.231844.8
  118. (118) City Of Hope National Medical Center, grid.410425.6
  119. (119) Fred Hutchinson Cancer Research Center, grid.270240.3
  120. (120) University of Wisconsin–Madison, grid.14003.36
  121. (121) University of California, San Francisco, grid.266102.1
  122. (122) Memorial Sloan Kettering Cancer Center, grid.51462.34
  123. (123) National Institute of Oncology, grid.419617.c
  124. (124) University of Chicago Medical Center, grid.412578.d
  125. (125) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  126. (126) University of Florence, grid.8404.8
  127. (127) Uppsala University, grid.8993.b
  128. (128) Universitair Ziekenhuis Leuven, grid.410569.f
  129. (129) IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy
  130. (130) Medical University of Vienna, grid.22937.3d
  131. (131) Shaukat Khanum Memorial Cancer Hospital and Research Center, grid.415662.2
  132. (132) Technion – Israel Institute of Technology, grid.6451.6
  133. (133) University Hospital Cologne, grid.411097.a
  134. (134) The Ohio State University, grid.261331.4
  135. (135) National Cancer Institute of Thailand, grid.419173.9
  136. (136) King's College London, grid.13097.3c
  137. (137) China Medical University, grid.254145.3
  138. (138) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  139. (139) Centre Hospitalier Universitaire de Québec, grid.411081.d
  140. (140) National Human Genome Research Institute, grid.280128.1
  141. (141) Portuguese Oncology Institute, grid.418711.a
  142. (142) University of Porto, grid.5808.5
  143. (143) Columbia University, grid.21729.3f
  144. (144) Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  145. (145) Odense University Hospital, grid.7143.1, Southern Denmark Region
  146. (146) Latvian Biomedical Research and Study Centre, grid.419210.f
  147. (147) McGill University, grid.14709.3b
  148. (148) Beth Israel Deaconess Medical Center, grid.239395.7
  149. (149) University of Ulm, grid.6582.9
  150. (150) Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA
  151. (151) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  152. (152) University of Oulu, grid.10858.34
  153. (153) Aristotle University of Thessaloniki, grid.4793.9
  154. (154) National Taiwan University Hospital, grid.412094.a
  155. (155) Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia

Description

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

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Times Cited: 16

Field Citation Ratio (FCR): 4.14

Relative Citation ratio (RCR): 0.66

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