Preprint open access publication

Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

bioRxiv, Cold Spring Harbor Laboratory,

2019

DOI:10.1101/521054, Dimensions: pub.1111431857,

Authors

Aschard, Hugues (2) (3)
Andrulis, Irene L. (10) (11)
Arason, Adalgeir (14) (15)
Auer, Paul L. (20) (21)
Benitez, Javier (9) (25)
Blomqvist, Carl (29) (30)
Blot, William (24) (31)
Bojesen, Stig E. (32) (33) (34)
Borg, Ake (36)
Brauch, Hiltrud (16) (37) (38)
Briceno, Ignacio (39) (40)
Burwinkel, Barbara (16) (45)
Campbell, Ian (49) (50)
Droit, Arnaud (6) (69)
Evans, D. Gareth (75) (76)
Fasching, Peter A. (77) (78)
Friedman, Eitan (84) (85)
Giles, Graham G. (50) (70) (91)
Hahnen, Eric (98) (99)
Hall, Per (63) (101)
Hartikainen, Jaana M. (102) (103)
Hartman, Mikael (104) (105)
He, Wei (63)
Hulick, Peter J. (108) (109)
James, Paul (49) (50)
Kang, Daehee (118)
Khusnutdinova, Elza (26) (121)
Kirk, Judy (123)
Kosma, Veli-Matti (102) (103)
Kwong, Ava (128) (129) (130)
Lambrechts, Diether (131) (132)
Lee, Eunjung (100)
Lesueur, Fabienne (58) (59) (133)
Lindblom, Annika (63) (134)
Lo, Wing-Yee (37) (38)
Mannermaa, Arto (102) (103)
Margolin, Sara (63) (101)
Matsuo, Keitaro (136) (137)
Mebirouk, Noura (58) (59)
Middha, Pooja (16) (45)
Nassir, Rami (144)
Olah, Edith (148)
Orr, Nick (150)
Osorio, Ana (9) (25)
Papp, Janos (148)
Park, Sue K. (118)
Paul, James (152)
Pylkäs, Katri (156) (157)
Ramus, Susan J. (159) (160)
Rennert, Gad (161)
Robson, Mark (147)
Santamariña, Marta (25) (166) (167)
Schmidt, Daniel F. (50) (70)
Schöttker, Ben (16) (45)
Scott, Rodney J. (170) (171)
Shen, Chen-Yang (173) (174)
Spinelli, John J. (177) (178)
Stone, Jennifer (50) (106)
Tamimi, Rulla M. (3) (180)
Tan, Yen Yen (175)
Teixeira, Manuel R. (181) (182)
Tengström, Maria (102) (103)
Teo, Soo H. (183) (184)
Teulé, Alex (185)
Tomlinson, Ian (189) (190)
Torres, Diana (16) (40)
Tung, Nadine (193)
Vega, Ana (25) (166) (167)
Wang, Qin (1)
Winqvist, Robert (156) (157)
Wolk, Alicja (63) (198)
Wu, Anna H. (100)
Zhang, Yan (16)
Zheng, Wei (24)
Chang-Claude, Jenny (16) (138)
Milne, Roger L. (50) (70) (91)
Kraft, Peter * (3)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) Institut Pasteur, grid.428999.7
  3. (3) Harvard University, grid.38142.3c
  4. (4) QIMR Berghofer Medical Research Institute, grid.1049.c
  5. (5) Cyprus Institute of Neurology and Genetics, grid.417705.0
  6. (6) McGill University Health Centre, grid.63984.30
  7. (7) Istituto Oncologico Veneto, grid.419546.b
  8. (8) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland
  9. (9) Spanish National Cancer Research Centre, grid.7719.8
  10. (10) Mount Sinai Hospital, grid.416166.2
  11. (11) University of Toronto, grid.17063.33
  12. (12) University of California, Irvine, grid.266093.8
  13. (13) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, 223040, Belarus
  14. (14) National University Hospital of Iceland, grid.410540.4
  15. (15) University of Iceland, grid.14013.37
  16. (16) German Cancer Research Center, grid.7497.d
  17. (17) Department of Public Health Sciences, and Cancer Research Institute, QueenÕs University, Kingston, ON, K7L 3N6, Canada
  18. (18) The University of Texas MD Anderson Cancer Center, grid.240145.6
  19. (19) Hannover Medical School, grid.10423.34
  20. (20) University of Wisconsin–Milwaukee, grid.267468.9
  21. (21) Fred Hutchinson Cancer Research Center, grid.270240.3
  22. (22) Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori di Milano, Milan, 20133, Italy
  23. (23) Hospital Universitari Vall d'Hebron, grid.411083.f
  24. (24) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
  25. (25) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, 46010, Spain
  26. (26) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
  27. (27) Pomeranian Medical University, grid.107950.a
  28. (28) University of California, San Francisco, grid.266102.1
  29. (29) Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland
  30. (30) Örebro University Hospital, grid.412367.5
  31. (31) International Epidemiology Institute, grid.419344.f
  32. (32) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
  33. (33) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
  34. (34) University of Copenhagen, grid.5254.6, KU
  35. (35) European Institute of Oncology, grid.15667.33
  36. (36) Lund University, grid.4514.4
  37. (37) University of Tübingen, grid.10392.39
  38. (38) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  39. (39) University of La Sabana, grid.412166.6
  40. (40) Pontificia Universidad Javeriana, grid.41312.35
  41. (41) University of Sheffield, grid.11835.3e
  42. (42) BC Cancer Agency, grid.248762.d
  43. (43) Simon Fraser University, grid.61971.38
  44. (44) Ruhr University Bochum, grid.5570.7
  45. (45) Heidelberg University, grid.7700.0
  46. (46) Huntsman Cancer Institute, grid.479969.c
  47. (47) Hospital Clínico San Carlos, grid.411068.a
  48. (48) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  49. (49) Peter MacCallum Cancer Centre, grid.1055.1
  50. (50) University of Melbourne, grid.1008.9
  51. (51) Cancer Research UK Cambridge Institute, grid.470869.4
  52. (52) American Cancer Society, grid.422418.9
  53. (53) Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, 36312, Spain
  54. (54) CRCHU de Québec-oncologie, Québec, QC, G1S 4L8, Canada
  55. (55) Columbia University, grid.21729.3f
  56. (56) Ghent University, grid.5342.0
  57. (57) University of Sydney, grid.1013.3
  58. (58) Mines ParisTech, grid.58140.38
  59. (59) Institute Curie, grid.418596.7
  60. (60) Erasmus University Medical Center, grid.5645.2
  61. (61) Antoni van Leeuwenhoek Hospital, grid.430814.a
  62. (62) Mayo Clinic, grid.66875.3a
  63. (63) Karolinska Institute, grid.4714.6
  64. (64) Temple University Health System, grid.412530.1
  65. (65) Leiden University Medical Center, grid.10419.3d
  66. (66) City Of Hope National Medical Center, grid.410425.6
  67. (67) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
  68. (68) London School of Hygiene & Tropical Medicine, grid.8991.9
  69. (69) Laval University, grid.23856.3a
  70. (70) Monash University, grid.1002.3
  71. (71) University of Valladolid, grid.5239.d
  72. (72) University of Southampton, grid.5491.9
  73. (73) University of Westminster, grid.12896.34
  74. (74) Leipzig University, grid.9647.c
  75. (75) St Mary's Hospital, grid.416523.7
  76. (76) University of Manchester, grid.5379.8
  77. (77) Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
  78. (78) University of California, Los Angeles, grid.19006.3e
  79. (79) Institute of Cancer Research, grid.18886.3f
  80. (80) Universitair Ziekenhuis Leuven, grid.410569.f
  81. (81) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
  82. (82) Masaryk Memorial Cancer Institute, grid.419466.8
  83. (83) McGill University, grid.14709.3b
  84. (84) Tel Aviv University, grid.12136.37
  85. (85) Sheba Medical Center, grid.413795.d
  86. (86) Curtin University, grid.1032.0
  87. (87) Complejo Hospitalario Universitario de Santiago, grid.411048.8
  88. (88) University of California, San Diego, grid.266100.3
  89. (89) Dana-Farber Cancer Institute, grid.65499.37
  90. (90) University Hospital of Heraklion, grid.412481.a
  91. (91) Cancer Council Victoria, grid.3263.4
  92. (92) University of Kansas Medical Center, grid.412016.0
  93. (93) University of Utah, grid.223827.e
  94. (94) National Cancer Institute, grid.48336.3a
  95. (95) Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, 90220, Finland
  96. (96) University of Montreal, grid.14848.31
  97. (97) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, 94805, France
  98. (98) University Hospital Cologne, grid.411097.a
  99. (99) University of Cologne, grid.6190.e
  100. (100) University of Southern California, grid.42505.36
  101. (101) Stockholm South General Hospital, grid.416648.9
  102. (102) Kuopio University Hospital, grid.410705.7
  103. (103) University of Eastern Finland, grid.9668.1
  104. (104) National University Health System, grid.410759.e
  105. (105) National University of Singapore, grid.4280.e
  106. (106) University of Western Australia, grid.1012.2
  107. (107) Family Cancer Clinic, The Netherlands, Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, The Netherlands
  108. (108) NorthShore University HealthSystem, grid.240372.0
  109. (109) University of Chicago, grid.170205.1
  110. (110) Institute of Oncology NN Petrov, grid.465337.0
  111. (111) Georgetown University Medical Center, grid.411667.3
  112. (112) National Cancer Centre, grid.272242.3
  113. (113) Macedonian Academy of Sciences and Arts, grid.419383.4
  114. (114) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  115. (115) University of Pittsburgh, grid.21925.3d
  116. (116) Stanford University, grid.168010.e
  117. (117) Tampere University Hospital, grid.412330.7
  118. (118) Seoul National University, grid.31501.36
  119. (119) Cedars-Sinai Medical Center, grid.50956.3f
  120. (120) National University of Ireland, Galway, grid.6142.1
  121. (121) Bashkir State University, grid.77269.3d
  122. (122) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland
  123. (123) Familial Cancer Service, Weatmead Hospital, Wentworthville, New South Wales, 2145, Australia
  124. (124) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, 53177, Germany
  125. (125) National Centre of Scientific Research Demokritos, grid.6083.d
  126. (126) National Institutes of Health, grid.94365.3d
  127. (127) Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, 1000, Republic of Macedonia
  128. (128) Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
  129. (129) Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong
  130. (130) University of Hong Kong, grid.194645.b
  131. (131) Flanders Institute for Biotechnology, grid.11486.3a
  132. (132) KU Leuven, grid.5596.f
  133. (133) Genetic Epidemiology of Cancer team, Inserm U900, Paris, 75005, France
  134. (134) Karolinska University Hospital, grid.24381.3c
  135. (135) University of Warwick, grid.7372.1
  136. (136) Aichi Cancer Center, grid.410800.d
  137. (137) Nagoya University, grid.27476.30
  138. (138) University Cancer Center Hamburg, grid.412315.0
  139. (139) The Alfred Hospital, grid.1623.6
  140. (140) Ludwig Maximilian University of Munich, grid.5252.0
  141. (141) Roswell Park Cancer Institute, grid.240614.5
  142. (142) University Health Network, grid.231844.8
  143. (143) Radiation Oncology, Hospital Meixoeiro-XXI de Vigo, Vigo, 36214, Spain
  144. (144) University of California, Davis, grid.27860.3b
  145. (145) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark
  146. (146) Latvian Biomedical Research and Study Centre, grid.419210.f
  147. (147) Memorial Sloan Kettering Cancer Center, grid.51462.34
  148. (148) National Institute of Oncology, grid.419617.c
  149. (149) Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, 60637, USA
  150. (150) Queen's University Belfast, grid.4777.3
  151. (151) University of New Mexico, grid.266832.b
  152. (152) University of Glasgow, grid.8756.c
  153. (153) Aalborg Hospital, grid.27530.33, North Denmark Region
  154. (154) Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, 20139, Italy
  155. (155) Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, 08908, Spain
  156. (156) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, 90570, Finland
  157. (157) University of Oulu, grid.10858.34
  158. (158) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  159. (159) The Kinghorn Cancer Centre, grid.410697.d
  160. (160) UNSW Sydney, grid.1005.4
  161. (161) Technion – Israel Institute of Technology, grid.6451.6
  162. (162) Yale University, grid.47100.32
  163. (163) Hospital Universitario Puerta de Hierro Majadahonda, grid.73221.35
  164. (164) University Hospital of Larissa, grid.411299.6
  165. (165) National Institute of Environmental Health Sciences, grid.280664.e
  166. (166) Fundación Pública Galega de Medicina Xenómica, grid.443929.1
  167. (167) Instituto de Investigación Sanitaria de Santiago, grid.488911.d
  168. (168) King's College London, grid.13097.3c
  169. (169) University Hospital Heidelberg, grid.5253.1
  170. (170) John Hunter Hospital, grid.414724.0
  171. (171) University of Newcastle Australia, grid.266842.c
  172. (172) The Ohio State University, grid.261331.4
  173. (173) China Medical University, grid.254145.3
  174. (174) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  175. (175) Medical University of Vienna, grid.22937.3d
  176. (176) Saints Cyril and Methodius University of Skopje, grid.7858.2
  177. (177) Population Oncology, BC Cancer, Vancouver, BC, V5Z 1G1, Canada
  178. (178) University of British Columbia, grid.17091.3e
  179. (179) Paris Descartes University, grid.10992.33
  180. (180) Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
  181. (181) Portuguese Oncology Institute, grid.418711.a
  182. (182) University of Porto, grid.5808.5
  183. (183) Cancer Research Malaysia, grid.507182.9
  184. (184) University Malaya Medical Centre, grid.413018.f
  185. (185) Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, 08908, Spain
  186. (186) Odense University Hospital, grid.7143.1, Southern Denmark Region
  187. (187) Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
  188. (188) University of Insubria, grid.18147.3b
  189. (189) University of Birmingham, grid.6572.6
  190. (190) University of Oxford, grid.4991.5
  191. (191) Instituto Nacional de Salud Pública, grid.415771.1
  192. (192) University of North Carolina at Chapel Hill, grid.10698.36
  193. (193) Beth Israel Deaconess Medical Center, grid.239395.7
  194. (194) Klinikum Mittelbaden, grid.506801.a
  195. (195) University of Pretoria, grid.49697.35
  196. (196) Centro di Riferimento Oncologico, grid.418321.d
  197. (197) Department of Pathology, Netherlands Cancer Institute, 1006 BE
  198. (198) Uppsala University, grid.8993.b
  199. (199) Division of Psychosocial Research and Epidemiology, The Netherlands, Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, The Netherlands
  200. (200) Oslo University Hospital, grid.55325.34
  201. (201) University of Oslo, grid.5510.1

Description

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

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