Article open access publication

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 7, 1, 2016

DOI:10.1038/ncomms12675, Dimensions: pub.1041599895, PMC: PMC5023955, PMID: 27601076,

Authors

Lawrenson, Kate (1) (2)
Li, Qiyuan (5) (6)
Benitez, Javier (18) (19)
Bjorge, Line (22) (23)
Blot, William (25) (26)
Bojesen, Stig E. (29) (30)
Brauch, Hiltrud (11) (33) (34)
Burwinkel, Barbara (11) (39)
Butzow, Ralf (40) (41)
Ehrencrona, Hans (64) (65)
Fasching, Peter A. (17) (69)
Giles, Graham G (36) (81)
Guénel, Pascal (85) (86)
Hall, Per (54)
Hartman, Mikael (38) (88)
Heitz, Florian (91) (92)
Høgdall, Estrid (30) (94)
Ito, Hidemi (101)
Knight, Julia A. (8) (105)
Kosma, Veli-Matti (106) (107)
Kristensen, Vessela (31) (32) (108)
Kwong, Ava (109) (110)
Lambrechts, Diether (111) (112)
Le, Nhu (2)
Lu, Karen (12)
Mannermaa, Arto (106) (107)
Milne, Roger L. (36) (81)
Muir, Kenneth (68) (113)
Olah, Edith (125)
Orr, Nick (73)
Osorio, Ana (19) (128)
Poole, Elizabeth M (52) (133)
Pylkäs, Katri (134) (135)
Rennert, Gad (138)
Rossing, Mary Anne (141) (142)
Salvesen, Helga B. (22) (23)
Shen, Chen-Yang (146) (147)
Sieh, Weiva (148)
Sinilnikova, Olga M. (149) (150)
Teixeira, Manuel R. (155) (156)
Teo, Soo H. (89) (90)
Torres, Diana (11) (163)
Truong, Thérèse (85) (86)
Tung, Nadine (164)
Tworoger, Shelley S (52) (133)
Wang, Qin (3)
Winqvist, Robert (134) (135)
Yoon, Sook-Yee (167) (168)
Zheng, Wei (26)
Zheng, Ying (170)

* Corresponding author

Affiliations

Organisations

  1. (1) Cedars-Sinai Medical Center, grid.50956.3f
  2. (2) University of Southern California, grid.42505.36
  3. (3) University of Cambridge, grid.5335.0
  4. (4) QIMR Berghofer Medical Research Institute, grid.1049.c
  5. (5) Xiamen University, grid.12955.3a
  6. (6) Dana-Farber Cancer Institute, grid.65499.37
  7. (7) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, 00029 HUS, Helsinki, Finland
  8. (8) University of Toronto, grid.17063.33
  9. (9) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  10. (10) University of California, Irvine, grid.266093.8
  11. (11) German Cancer Research Center, grid.7497.d
  12. (12) The University of Texas MD Anderson Cancer Center, grid.240145.6
  13. (13) Karolinska University Hospital, grid.24381.3c
  14. (14) Rutgers, The State University of New Jersey, grid.430387.b
  15. (15) European Institute of Oncology, grid.15667.33
  16. (16) University of Iceland, grid.14013.37
  17. (17) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054, Erlangen, Germany
  18. (18) Centro de Investigación en Red de Enfermedades Raras, 28029, Valencia, Spain
  19. (19) Spanish National Cancer Research Centre, grid.7719.8
  20. (20) Duke University Hospital, grid.189509.c
  21. (21) Memorial Sloan Kettering Cancer Center, grid.51462.34
  22. (22) Haukeland University Hospital, grid.412008.f
  23. (23) University of Bergen, grid.7914.b
  24. (24) Department of Oncology, Helsinki University Hospital, University of Helsinki, FIN-00029, Helsinki, Finland
  25. (25) International Epidemiology Institute, grid.419344.f
  26. (26) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 37203, Nashville, Tennessee, USA
  27. (27) Hannover Medical School, grid.10423.34
  28. (28) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  29. (29) University of Copenhagen, grid.5254.6, KU
  30. (30) Herlev Hospital, grid.411900.d, Capital Region
  31. (31) Oslo University Hospital, grid.55325.34
  32. (32) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0310, Oslo, Norway
  33. (33) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  34. (34) University of Tübingen, grid.10392.39
  35. (35) International Agency For Research On Cancer, grid.17703.32
  36. (36) Cancer Council Victoria, grid.3263.4
  37. (37) Catalan Institute of Oncology, grid.418701.b
  38. (38) National University Health System, grid.410759.e
  39. (39) Heidelberg University, grid.7700.0
  40. (40) Helsinki University Central Hospital, grid.15485.3d
  41. (41) Hospital District of Helsinki and Uusimaa, grid.424664.6
  42. (42) University of Utah, grid.223827.e
  43. (43) Hospital Clínico San Carlos, grid.411068.a
  44. (44) Peter MacCallum Cancer Centre, grid.1055.1
  45. (45) Roswell Park Cancer Institute, grid.240614.5
  46. (46) University Cancer Center Hamburg, grid.412315.0
  47. (47) Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Centre de recherche FRSQ du Centre hospitalier affilié universitaire de Québec, G1J 1Z4, Québec City, Québec, Canada
  48. (48) Seoul National University, grid.31501.36
  49. (49) Ghent University, grid.5342.0
  50. (50) University of New Mexico, grid.266832.b
  51. (51) University of Sheffield, grid.11835.3e
  52. (52) Harvard University, grid.38142.3c
  53. (53) Pomeranian Medical University, grid.107950.a
  54. (54) Karolinska Institute, grid.4714.6
  55. (55) Temple University Health System, grid.412530.1
  56. (56) University of Lyon System, grid.25697.3f
  57. (57) Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, 44-101, Warsaw, Poland
  58. (58) Leiden University Medical Center, grid.10419.3d
  59. (59) Hospital Universitari Vall d'Hebron, grid.411083.f
  60. (60) Dartmouth College, grid.254880.3
  61. (61) University of Pennsylvania, grid.25879.31
  62. (62) University of Pretoria, grid.49697.35
  63. (63) Laval University, grid.23856.3a
  64. (64) Uppsala University, grid.8993.b
  65. (65) Skåne University Hospital, grid.411843.b
  66. (66) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, 2100, Copenhagen, Denmark
  67. (67) Leipzig University, grid.9647.c
  68. (68) University of Manchester, grid.5379.8
  69. (69) University of California, Los Angeles, grid.19006.3e
  70. (70) Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, 08908, Barcelona, Spain
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  72. (72) University Medical Center Hamburg-Eppendorf, grid.13648.38
  73. (73) Institute of Cancer Research, grid.18886.3f
  74. (74) Masaryk Memorial Cancer Institute, grid.419466.8
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  76. (76) McGill University, grid.14709.3b
  77. (77) University of Kansas Medical Center, grid.412016.0
  78. (78) Sheba Medical Center, grid.413795.d
  79. (79) Department of Laboratory Medicine, Section of Genetic Oncology, University and University Hospital of Pisa, 56126, Pisa, Italy
  80. (80) University College London, grid.83440.3b
  81. (81) University of Melbourne, grid.1008.9
  82. (82) Beatson West of Scotland Cancer Centre, grid.422301.6
  83. (83) Mayo Clinic, grid.66875.3a
  84. (84) National Institutes of Health, grid.94365.3d
  85. (85) French Institute of Health and Medical Research, grid.7429.8
  86. (86) University of Paris-Sud, grid.5842.b
  87. (87) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100, Copenhagen, Denmark
  88. (88) National University of Singapore, grid.4280.e
  89. (89) Cancer Research Initiatives Foundation, grid.427737.2
  90. (90) University Malaya Medical Centre, grid.413018.f
  91. (91) Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, 65199, Wiesbaden, Germany
  92. (92) Kliniken Essen-Mitte, grid.461714.1
  93. (93) Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, 91010, Duarte, California, USA
  94. (94) Danish Cancer Society, grid.417390.8
  95. (95) Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
  96. (96) Antoni van Leeuwenhoek Hospital, grid.430814.a
  97. (97) Erasmus University Medical Center, grid.5645.2
  98. (98) NorthShore University HealthSystem, grid.240372.0
  99. (99) Institute of Oncology NN Petrov, grid.465337.0
  100. (100) Georgetown University Medical Center, grid.411667.3
  101. (101) Aichi Cancer Center, grid.410800.d
  102. (102) State Research Institute Centre for Innovative Medicine, grid.493509.2
  103. (103) Cancer Prevention Institute of California, grid.280669.3
  104. (104) Radboud University Nijmegen Medical Centre, grid.10417.33
  105. (105) Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
  106. (106) Kuopio University Hospital, grid.410705.7
  107. (107) University of Eastern Finland, grid.9668.1
  108. (108) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, 1478, Oslo, Norway
  109. (109) Hong Kong Sanatorium and Hospital, grid.414329.9
  110. (110) University of Hong Kong, grid.194645.b
  111. (111) Flanders Institute for Biotechnology, grid.11486.3a
  112. (112) KU Leuven, grid.5596.f
  113. (113) University of Warwick, grid.7372.1
  114. (114) Department of Preventive and Predictive Medicine, Unit of Medical Genetics, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), 20133, Milan, Italy
  115. (115) University of Hawaii at Manoa, grid.410445.0
  116. (116) Kyushu University, grid.177174.3
  117. (117) The Alfred Hospital, grid.1623.6
  118. (118) University of Glasgow, grid.8756.c
  119. (119) Technical University of Munich, grid.6936.a
  120. (120) Istituti di Ricovero e Cura a Carattere Scientifico, grid.414603.4
  121. (121) University Health Network, grid.231844.8
  122. (122) The University of Texas Health Science Center at Houston, grid.267308.8
  123. (123) City Of Hope National Medical Center, grid.410425.6
  124. (124) University of California, San Francisco, grid.266102.1
  125. (125) National Institute of Oncology, grid.419617.c
  126. (126) University of Chicago Medical Center, grid.412578.d
  127. (127) The Ohio State University, grid.261331.4
  128. (128) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  129. (129) Oregon Health & Science University, grid.5288.7
  130. (130) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 16 20139, Milan, Italy
  131. (131) Medical University of Vienna, grid.22937.3d
  132. (132) Moffitt Cancer Center, grid.468198.a
  133. (133) Brigham and Women's Hospital, grid.62560.37
  134. (134) Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014, Oulu, Finland
  135. (135) University of Oulu, grid.10858.34
  136. (136) Department of Preventive and Predictive Medicine, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), 20133, Milan, Italy
  137. (137) Shaukat Khanum Memorial Cancer Hospital and Research Center, grid.415662.2
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  140. (140) Yale University, grid.47100.32
  141. (141) Fred Hutchinson Cancer Research Center, grid.270240.3
  142. (142) University of Washington, grid.34477.33
  143. (143) National Cancer Institute of Thailand, grid.419173.9
  144. (144) King's College London, grid.13097.3c
  145. (145) Duke University, grid.26009.3d
  146. (146) China Medical University, grid.254145.3
  147. (147) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  148. (148) Stanford University, grid.168010.e
  149. (149) Cancer Center of Lyon, grid.462282.8
  150. (150) Centre Léon Bérard, grid.418116.b
  151. (151) Linköping University, grid.5640.7
  152. (152) Institute Curie, grid.418596.7
  153. (153) Paris Descartes University, grid.10992.33
  154. (154) Department of Human Genetics, Institute of Human Genetics, University Hospital Heidelberg, 69120, Heidelberg, Germany
  155. (155) Portuguese Oncology Institute, grid.418711.a
  156. (156) University of Porto, grid.5808.5
  157. (157) Columbia University, grid.21729.3f
  158. (158) Odense University Hospital, grid.7143.1, Southern Denmark Region
  159. (159) University of Insubria, grid.18147.3b
  160. (160) Latvian Biomedical Research and Study Centre, grid.419210.f
  161. (161) Istituto Oncologico Veneto, grid.419546.b
  162. (162) University of Oxford, grid.4991.5
  163. (163) Pontificia Universidad Javeriana, grid.41312.35
  164. (164) Beth Israel Deaconess Medical Center, grid.239395.7
  165. (165) Universitair Ziekenhuis Leuven, grid.410569.f
  166. (166) 89069, University Hospital UlmUlm, Germany
  167. (167) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500, Subang Jaya, Malaysia
  168. (168) University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 59100, Kuala Lumpur, Malaysia
  169. (169) Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, 114, Taipei, Taiwan
  170. (170) Shanghai Center for Disease Control and Prevention, Shanghai, China

Description

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

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Research area: Medicine

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Times Cited: 39

Field Citation Ratio (FCR): 10.35

Relative Citation ratio (RCR): 1.83

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