Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.
In: Nature genetics ; 52 ; 1 ; 56 ; 73 ; United Kingdom ; United States, 2020
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To access publisher's full text version of this article click on the hyperlink below ; 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 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 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 those potentially causal variants, using gene expression (expression quantitative trait loci), 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 highest-confidence target genes. ; European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant PERSPECTIVE project (Government of Canada through Genome Canada) Canadian Institutes of Health Research (CIHR) PERSPECTIVE project ('Ministere de l'Economie de la Science et de l'Innovation du Quebec' (Genome Quebec) PERSPECTIVE project (Quebec Breast Cancer Foundation) NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA Cancer Research UK European Community (EC) European Union (EU) Canadian Institutes of Health Research (CIHR) Ministry of Economic Development, Innovation and Export Trade of Quebec United States Department of Health & Human Services National Institutes of ...
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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.
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| Autor/in / Beteiligte Person: | Fachal, Laura ; Aschard, Hugues ; Beesley, Jonathan ; Barnes, Daniel R ; Allen, Jamie ; Kar, Siddhartha ; Pooley, Karen A ; Dennis, Joe ; Michailidou, Kyriaki ; Turman, Constance ; Soucy, Penny ; Lemaçon, Audrey ; Lush, Michael ; Tyrer, Jonathan P ; Ghoussaini, Maya ; Moradi Marjaneh, Mahdi ; Jiang, Xia ; Agata, Simona ; Aittomäki, Kristiina ; Alonso, M Rosario ; Andrulis, Irene L ; Anton-Culver, Hoda ; Antonenkova, Natalia N ; Arason, Adalgeir ; Arndt, Volker ; Aronson, Kristan J ; Arun, Banu K ; Auber, Bernd ; Auer, Paul L ; Azzollini, Jacopo ; Balmaña, Judith ; Barkardottir, Rosa B ; Barrowdale, Daniel ; Beeghly-Fadiel, Alicia ; Benitez, Javier ; Bermisheva, Marina ; Białkowska, Katarzyna ; Blanco, Amie M ; Blomqvist, Carl ; Blot, William ; Bogdanova, Natalia V ; Bojesen, Stig E ; Bolla, Manjeet K ; Bonanni, Bernardo ; Borg, Ake ; Bosse, Kristin ; Brauch, Hiltrud ; Brenner, Hermann ; Briceno, Ignacio ; Brock, Ian W ; Brooks-Wilson, Angela ; Brüning, Thomas ; Burwinkel, Barbara ; Buys, Saundra S ; Cai, Qiuyin ; Caldés, Trinidad ; Caligo, Maria A ; Camp, Nicola J ; Campbell, Ian ; Canzian, Federico ; Carroll, Jason S ; Carter, Brian D ; Castelao, Jose E ; Chiquette, Jocelyne ; Christiansen, Hans ; Chung, Wendy K ; Claes, Kathleen B M ; Clarke, Christine L ; Collée, J Margriet ; Cornelissen, Sten ; Couch, Fergus J ; Cox, Angela ; Cross, Simon S ; Cybulski, Cezary ; Czene, Kamila ; Daly, Mary B ; de la Hoya, Miguel ; Devilee, Peter ; Diez, Orland ; Ding, Yuan Chun ; Dite, Gillian S ; Domchek, Susan M ; Dörk, Thilo ; Dos-Santos-Silva, Isabel ; Droit, Arnaud ; Dubois, Stéphane ; Dumont, Martine ; Duran, Mercedes ; Durcan, Lorraine ; Dwek, Miriam ; Eccles, Diana M ; Engel, Christoph ; Eriksson, Mikael ; Evans, D Gareth ; Fasching, Peter A ; Fletcher, Olivia ; Floris, Giuseppe ; Flyger, Henrik ; Foretova, Lenka ; Foulkes, William D ; Friedman, Eitan ; Fritschi, Lin ; Frost, Debra ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Gambino, Gaetana ; Ganz, Patricia A ; Gapstur, Susan M ; Garber, Judy ; García-Sáenz, José A ; Gaudet, Mia M ; Georgoulias, Vassilios ; Giles, Graham G ; Glendon, Gord ; Godwin, Andrew K ; Goldberg, Mark S ; Goldgar, David E ; González-Neira, Anna ; Tibiletti, Maria Grazia ; Greene, Mark H ; Grip, Mervi ; Gronwald, Jacek ; Grundy, Anne ; Guénel, Pascal ; Hahnen, Eric ; Haiman, Christopher A ; Håkansson, Niclas ; Hall, Per ; Hamann, Ute ; Harrington, Patricia A ; Hartikainen, Jaana M ; Hartman, Mikael ; He, Wei ; Healey, Catherine S ; Heemskerk-Gerritsen ; Bernadette, A M ; Heyworth, Jane ; Hillemanns, Peter ; Hogervorst, Frans B L ; Hollestelle, Antoinette ; Hooning, Maartje J ; Hopper, John L ; Howell, Anthony ; Huang, Guanmengqian ; Hulick, Peter J ; Imyanitov, Evgeny N ; Isaacs, Claudine ; Iwasaki, Motoki ; Jager, Agnes ; Jakimovska, Milena ; Jakubowska, Anna ; James, Paul A ; Janavicius, Ramunas ; Jankowitz, Rachel C ; John, Esther M ; Johnson, Nichola ; Jones, Michael E ; Jukkola-Vuorinen, Arja ; Jung, Audrey ; 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201Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. 202Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark. 203Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark. 204Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. 205Genome Diagnostics Program, IFOM-the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy. 206ProCURE, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. 207Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland. 208Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland. 209Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy. 210School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. 211The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. 212Clinical Genetics, Karolinska Institutet, Stockholm, Sweden. 213Clalit National Israeli Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel. 214Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA. 215Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain. 216Department of Oncology, University Hospital of Larissa, Larissa, Greece. 217Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. 218Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain. 219Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain. 220School of Medicine, University of Western Australia, Perth, Western Australia, Australia. 221Research Oncology, Guy's Hospital, King's College London, London, UK. 222Faculty of Information Technology, Monash University, Melbourne, Victoria, Australia. 223National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany. 224Network Aging Research, University of Heidelberg, Heidelberg, Germany. 225Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia. 226Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia. 227Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia. 228Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. 229Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA. 230Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 231School of Public Health, China Medical University, Taichung, Taiwan. 232Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 233Clinical Cancer Genomics, City of Hope, Duarte, CA, USA. 234University Clinic of Radiotherapy and Oncology, Medical Faculty, Ss. Cyril and Methodius University in Skopje, Skopje, Republic of North Macedonia. 235Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia. 236Population Oncology, BC Cancer, Vancouver, British Columbia, Canada. 237School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada. 238The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia. 239Service de Génétique, Institut Curie, Paris, France. 240Université Paris Descartes, Paris, France. 241Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 242Division of Breast Cancer Research, The Institute of Cancer Research, London, UK. 243Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 244Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria. 245Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. 246Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. 247Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal. 248Cancer Center, Kuopio University Hospital, Kuopio, Finland. 249Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland. 250Breast Cancer Research Programme, Cancer Research Malaysia, Kuala Lumpur, Malaysia. 251Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. 252Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. 253Hereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain. 254Department of Clinical Genetics, Odense University Hospital, Odence, Denmark. 255Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 256Department of Medical Genetics, University of Cambridge, Cambridge, UK. 257Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA. 258Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. 259Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. 260Wellcome Trust Centre for Human Genetics and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. 261Center for Population Health Research, National Institute of Public Health, Cuernavaca, Mexico. 262Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 263Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. 264Department of Pathology, University Hospital of Heraklion, Heraklion, Greece. 265Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany. 266Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA. 267Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands. 268Department of Genetics, University of Pretoria, Pretoria, South Africa. 269Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain. 270Division of Functional Onco-genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy. 271Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, USA. 272Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. 273Nuffield Department of Population Health, University of Oxford, Oxford, UK. 274Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK. 275Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. 276Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway. 277Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. 278The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Coordinating Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 279Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia. 280Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. pkraft@hsph.harvard.edu. 281Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. pkraft@hsph.harvard.edu. 282Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. amd24@medschl.cam.ac.uk. |
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| Zeitschrift: | Nature genetics ; 52 ; 1 ; 56 ; 73 ; United Kingdom ; United States, 2020 |
| Veröffentlichung: | NATURE PUBLISHING GROUP, 2020 |
| Medientyp: | academicJournal |
| ISSN: | 1546-1718 (print) |
| DOI: | 10.1038/s41588-019-0537-1 |
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