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Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
Authors:Joseph S Baxter  Nichola Johnson  Katarzyna Tomczyk  Andrea Gillespie  Sarah Maguire  Rachel Brough  Laura Fachal  Kyriaki Michailidou  Manjeet K Bolla  Qin Wang  Joe Dennis  Thomas U Ahearn  Irene L Andrulis  Hoda Anton-Culver  Natalia N Antonenkova  Volker Arndt  Kristan J Aronson  Annelie Augustinsson  Olivia Fletcher
Institution:1. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK;2. Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Ireland BT7 1NN, UK;3. The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK;4. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK;5. Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus;6. Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus;7. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK;8. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA;9. Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada;10. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada;11. Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92617, USA;12. N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus;13. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;14. Department of Public Health Sciences, and Cancer Research Institute, Queen’s University, Kingston, ON K7L 3N6, Canada;15. Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund 222 42, Sweden;16. Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;17. Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen 91054, Germany;18. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;19. Biomedical Network on Rare Diseases (CIBERER), Madrid 28029, Spain;20. Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;21. Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa 450054, Russia;22. Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany;23. Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany;24. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark;25. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark;26. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark;27. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany;28. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;29. Department of Gynecology and Obstetrics, University of Tübingen, Tübingen 72076, Germany;30. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;31. Department of Biology, University of Pisa, Pisa 56126, Italy;32. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;33. Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo 36312, Spain;34. Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong;35. Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong;36. Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;37. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;38. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea;39. Cancer Research Institute, Seoul National University, Seoul 03080, Korea;40. Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul 03080, Korea;41. Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia;42. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway;43. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0450, Norway;44. Department of Research, Vestre Viken Hospital, Drammen 3019, Norway;45. Section for Breast and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Ullevål, Oslo 0450, Norway;46. Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo 0379, Norway;47. Department of Pathology, Akershus University Hospital, Lørenskog 1478, Norway;48. Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo 0379, Norway;49. Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway;50. National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway;51. Department of Oncology, Akershus University Hospital, Lørenskog 1478, Norway;52. Breast Cancer Research Consortium, Oslo University Hospital, Oslo 0379, Norway;53. Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA;54. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA;55. Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2TN, UK;56. Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK;57. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden;58. Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA;59. Department of Pathology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands;60. Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands;61. Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon 69372, France;62. School of Life Sciences, University of Westminster, London W1B 2HW, UK;63. Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK;64. Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany;65. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA;66. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;67. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany;68. LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany;69. David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA;70. Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh EH16 4UX, UK;71. Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh EH4 2XR, UK;72. Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark;73. Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela 15706, Spain;74. Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA;75. Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;76. Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid 28040, Spain;77. Open Targets, Core Genetics Team, Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK;78. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia;79. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia;80. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia;81. Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada;82. Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC H4A 3J1, Canada;83. Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif 94805, France;84. Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;85. Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg 69120, Germany;86. Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany;87. Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany;88. Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany;89. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;90. Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden;91. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany;92. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore;93. Department of Surgery, National University Hospital, Singapore 119228, Singapore;94. Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore;95. Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven Cancer Institute, Leuven 3000, Belgium;96. Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany;97. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam 3015 GD, the Netherlands;98. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany;99. University of Tübingen, Tübingen 72074, Germany;100. Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan;101. Research Department, Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia;102. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia;103. Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia;104. Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan;105. Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;106. Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan;107. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland;108. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin 71-252, Poland;109. Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm 89075, Germany;110. Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA;111. Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA;112. Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;113. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea;114. Division of Molecular Pathology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands;115. Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa 450000, Russia;116. Department of Surgery, Daerim Saint Mary’s Hospital, Seoul 07442, Korea;117. Translational Cancer Research Area, University of Eastern Finland, Kuopio 70210, Finland;118. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio 70210, Finland;119. Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland;120. Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0379, Norway;121. Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje 1000, Republic of North Macedonia;122. Department of Surgery, The University of Hong Kong, Hong Kong;123. Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong;124. Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA 91010, USA;125. City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA;126. VIB Center for Cancer Biology, Leuven 3001, Belgium;127. Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven 3000, Belgium;128. Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;129. Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden;130. Department of Surgical Sciences, Uppsala University, Uppsala 751 05, Sweden;131. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA;132. Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa 35254, Israel;133. Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore;134. Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK;135. Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan 20133, Italy;136. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm 118 83, Sweden;137. Department of Medical Oncology, University Hospital of Heraklion, Heraklion 711 10, Greece;138. Institute of Clinical Trials & Methodology, University College London, London WC1V 6LJ, UK;139. Breast Cancer Research Unit, University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;140. Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland;141. School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;142. Cancer Control Research, BC Cancer, Vancouver, BC V5Z 1L3, Canada;143. Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA;144. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;145. Convergence Graduate Program in Innovative Medical Science, Seoul National University College of Medicine, Seoul 03080, Korea;146. Department of Population Science, American Cancer Society, Atlanta, GA 30303, USA;147. Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan 20139, Italy;148. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK;149. Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, MASA, Skopje 1000, Republic of North Macedonia;150. Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu 90570, Finland;151. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu 90570, Finland;152. Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid 28222, Spain;153. Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe 76133, Germany;154. Department of Oncology, University Hospital of Larissa, Larissa 411 10, Greece;155. School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy’s Campus, King’s College London, London, UK;156. Division of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam 1066 CX, the Netherlands;157. National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg 69120, Germany;158. Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK;159. Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan;160. School of Public Health, China Medical University, Taichung, Taiwan;161. Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC G1V 4G2, Canada;162. Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia;163. Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, WA 6000, Australia;164. Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK;165. Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA;166. Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA;167. Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor 47500, Malaysia;168. Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;169. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA;170. Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA;171. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK;172. Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK;173. Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin 13125, Germany;174. Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA;175. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3015 GD, the Netherlands;176. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA;177. Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA
Abstract:
Keywords:breast cancer risk  functional annotation  risk locus
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