Article open access publication

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 48, 4, 2016

DOI:10.1038/ng.3521, Dimensions: pub.1029886099, PMC: PMC4938803, PMID: 26928228,

Authors

Dicks, Ed (1)
Jarosz, Monika (3) (4)
Drury, Suzie (3) (4)
Wang, Qin (1)
Muir, Kenneth (9) (10)
Fasching, Peter A (11) (12)
Tomlinson, Ian (15) (16)
Marme, Frederik (18) (19)
Guénel, Pascal (20) (21)
Truong, Thérèse (20) (21)
Bojesen, Stig E (22) (23)
Brauch, Hiltrud (17) (30) (31)
Kosma, Veli-Matti (38) (39)
Mannermaa, Arto (38) (39)
Wu, Anna H (27)
Giles, Graham G (8) (47)
Milne, Roger L (8) (47)
Teo, Soo H (49) (50)
Kristensen, Vessela (51) (52) (53)
Zheng, Wei (54)
Pylkäs, Katri (55) (56)
Winqvist, Robert (55) (56)
Andrulis, Irene L (57) (58)
Knight, Julia A (58) (59)
Blot, William (54) (65)
Lee, Soo Chin (67) (68)
Hartman, Mikael (67) (68)
Torres, Diana (17) (69)
Shen, Chen-Yang (75) (76)
Wu, Pei-Ei (76)
Orr, Nick (77)
Osorio, Ana (24) (89)
Benitez, Javier (24) (89)
Sinilnikova, Olga M (101) (104)
Kwong, Ava (109) (110)
Olah, Edith (111)
Diez, Orland (112)
Brunet, Joan (113)
Soucy, Penny (117)
Teixeira, Manuel R (119) (120)
Rennert, Gad (125) (126)
Yoon, Sook-Yee (49) (134)
Borg, Ake (136)
Ehrencrona, Hans (137) (138)
Arun, Banu K (142)
Mitchell, Gillian (8) (129)
Tamimi, Rulla (147) (148)
Dowsett, Mitch (3) (4)
Hall, Per (36)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) Royal Marsden Hospital, grid.424926.f
  4. (4) Breast Cancer Now, grid.458394.7
  5. (5) Stanford University, grid.168010.e
  6. (6) Massachusetts Institute of Technology, grid.116068.8
  7. (7) Antoni van Leeuwenhoek Hospital, grid.430814.a
  8. (8) University of Melbourne, grid.1008.9
  9. (9) University of Warwick, grid.7372.1
  10. (10) University of Manchester, grid.5379.8
  11. (11) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg Metropolitan Region, Erlangen, Germany
  12. (12) University of California, Los Angeles, grid.19006.3e
  13. (13) London School of Hygiene & Tropical Medicine, grid.8991.9
  14. (14) King's College London, grid.13097.3c
  15. (15) University of Oxford, grid.4991.5
  16. (16) Wellcome Centre for Human Genetics, grid.270683.8
  17. (17) German Cancer Research Center, grid.7497.d
  18. (18) Heidelberg University, grid.7700.0
  19. (19) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  20. (20) French Institute of Health and Medical Research, grid.7429.8
  21. (21) University of Paris-Sud, grid.5842.b
  22. (22) University of Copenhagen, grid.5254.6, KU
  23. (23) Herlev Hospital, grid.411900.d, Capital Region
  24. (24) Spanish National Cancer Research Centre, grid.7719.8
  25. (25) Hospital Monte Naranco, grid.414858.4
  26. (26) University of California, Irvine, grid.266093.8
  27. (27) University of Southern California, grid.42505.36
  28. (28) Technical University of Munich, grid.6936.a
  29. (29) University Hospital Cologne, grid.411097.a
  30. (30) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  31. (31) University of Tübingen, grid.10392.39
  32. (32) Helsinki University Central Hospital, grid.15485.3d
  33. (33) Department of Oncology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
  34. (34) Aichi Cancer Center, grid.410800.d
  35. (35) Hannover Medical School, grid.10423.34
  36. (36) Karolinska Institute, grid.4714.6
  37. (37) Karolinska University Hospital, grid.24381.3c
  38. (38) Kuopio University Hospital, grid.410705.7
  39. (39) University of Eastern Finland, grid.9668.1
  40. (40) KU Leuven, grid.5596.f
  41. (41) Vesalius Research Center, Leuven, Belgium
  42. (42) Universitair Ziekenhuis Leuven, grid.410569.f
  43. (43) University Cancer Center Hamburg, grid.412315.0
  44. (44) FIRC Institute of Molecular Oncology, grid.7678.e
  45. (45) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  46. (46) Mayo Clinic, grid.66875.3a
  47. (47) Cancer Council Victoria, grid.3263.4
  48. (48) McGill University, grid.14709.3b
  49. (49) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  50. (50) University Malaya Medical Centre, grid.413018.f
  51. (51) Oslo University Hospital, grid.55325.34
  52. (52) University of Oslo, grid.5510.1
  53. (53) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  54. (54) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  55. (55) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  56. (56) University of Oulu, grid.10858.34
  57. (57) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  58. (58) University of Toronto, grid.17063.33
  59. (59) Mount Sinai Hospital, grid.416166.2
  60. (60) Leiden University Medical Center, grid.10419.3d
  61. (61) Erasmus University Medical Center, grid.5645.2
  62. (62) National Cancer Institute, grid.48336.3a
  63. (63) Shanghai Cancer Institute, grid.419087.3
  64. (64) University of Sheffield, grid.11835.3e
  65. (65) International Epidemiology Institute, grid.419344.f
  66. (66) Seoul National University, grid.31501.36
  67. (67) National University Health System, grid.410759.e
  68. (68) National University of Singapore, grid.4280.e
  69. (69) Institute of Human Genetics, Pontificia Universidad Javerianar, Bogota, Colombia
  70. (70) Pomeranian Medical University, grid.107950.a
  71. (71) International Agency For Research On Cancer, grid.17703.32
  72. (72) National Cancer Institute of Thailand, grid.419173.9
  73. (73) Roswell Park Cancer Institute, grid.240614.5
  74. (74) The Ohio State University, grid.261331.4
  75. (75) China Medical University, grid.254145.3
  76. (76) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  77. (77) Institute of Cancer Research, grid.18886.3f
  78. (78) Cancer Prevention Institute of California, grid.280669.3
  79. (79) Columbia University, grid.21729.3f
  80. (80) Temple University Health System, grid.412530.1
  81. (81) University of Utah, grid.223827.e
  82. (82) State Research Institute Centre for Innovative Medicine, grid.493509.2
  83. (83) Latvian Biomedical Research and Study Centre, grid.419210.f
  84. (84) Beth Israel Deaconess Medical Center, grid.239395.7
  85. (85) University of Pretoria, grid.49697.35
  86. (86) City Of Hope National Medical Center, grid.410425.6
  87. (87) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  88. (88) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  89. (89) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  90. (90) European Institute of Oncology, grid.15667.33
  91. (91) University of Florence, grid.8404.8
  92. (92) Sapienza University of Rome, grid.7841.a
  93. (93) National Centre of Scientific Research Demokritos, grid.6083.d
  94. (94) Dana-Farber Cancer Institute, grid.65499.37
  95. (95) Shaukat Khanum Memorial Cancer Hospital and Research Center, grid.415662.2
  96. (96) National Health Service, grid.451052.7
  97. (97) University of Kansas Medical Center, grid.412016.0
  98. (98) Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian Albrechts University Kiel, Kiel, Germany
  99. (99) Heinrich Heine University Düsseldorf, grid.411327.2
  100. (100) University of Bonn, grid.10388.32
  101. (101) University of Lyon System, grid.25697.3f
  102. (102) Institute Curie, grid.418596.7
  103. (103) Paris Descartes University, grid.10992.33
  104. (104) Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon–Centre Léon Bérard, Lyon, France
  105. (105) Georgetown University Medical Center, grid.411667.3
  106. (106) Ghent University, grid.5342.0
  107. (107) Hospital Clínico San Carlos, grid.411068.a
  108. (108) Radboud University Nijmegen Medical Centre, grid.10417.33
  109. (109) Hong Kong Sanatorium and Hospital, grid.414329.9
  110. (110) University of Hong Kong, grid.194645.b
  111. (111) National Institute of Oncology, grid.419617.c
  112. (112) Hospital Universitari Vall d'Hebron, grid.411083.f
  113. (113) Catalan Institute of Oncology, grid.418701.b
  114. (114) Breast Cancer and Systems Biology Unit, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  115. (115) University of Iceland, grid.14013.37
  116. (116) Laval University, grid.23856.3a
  117. (117) Centre Hospitalier Universitaire de Québec, grid.411081.d
  118. (118) Istituto Oncologico Veneto, grid.419546.b
  119. (119) Portuguese Oncology Institute, grid.418711.a
  120. (120) University of Porto, grid.5808.5
  121. (121) Masaryk University, grid.10267.32
  122. (122) Memorial Sloan Kettering Cancer Center, grid.51462.34
  123. (123) Medical University of Vienna, grid.22937.3d
  124. (124) Moffitt Cancer Center, grid.468198.a
  125. (125) Clalit National Israeli Cancer Control Center, Haifa, Israel
  126. (126) Technion – Israel Institute of Technology, grid.6451.6
  127. (127) Institute of Oncology NN Petrov, grid.465337.0
  128. (128) NorthShore University HealthSystem, grid.240372.0
  129. (129) Peter MacCallum Cancer Centre, grid.1055.1
  130. (130) University Health Network, grid.231844.8
  131. (131) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  132. (132) Odense University Hospital, grid.7143.1, Southern Denmark Region
  133. (133) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  134. (134) University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia
  135. (135) Sheba Medical Center, grid.413795.d
  136. (136) Lund University, grid.4514.4
  137. (137) Skåne University Hospital, grid.411843.b
  138. (138) Uppsala University, grid.8993.b
  139. (139) University of Chicago Medical Center, grid.412578.d
  140. (140) University of California, San Francisco, grid.266102.1
  141. (141) University of Pennsylvania, grid.25879.31
  142. (142) The University of Texas MD Anderson Cancer Center, grid.240145.6
  143. (143) Cedars-Sinai Medical Center, grid.50956.3f
  144. (144) University of Hawaii at Manoa, grid.410445.0
  145. (145) Dalhousie University, grid.55602.34
  146. (146) University of Western Australia, grid.1012.2
  147. (147) Brigham and Women's Hospital, grid.62560.37
  148. (148) Harvard University, grid.38142.3c

Description

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

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Times Cited: 68

Field Citation Ratio (FCR): 17.45

Relative Citation ratio (RCR): 3.01

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