A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
Nature Communications, vol. 11, pp. 312
Abstract
Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
Authors 99
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
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University of Cambridge · NIHR Cambridge Biomedical Research Centre
Affiliation as printed
Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, UK
Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
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Mount Sinai Hospital · University of Toronto · Lunenfeld-Tanenbaum Research Institute
Affiliation as printed
Department of Molecular Genetics, University of Toronto, Toronto, Canada
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
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University of California, Irvine
Affiliation as printed
Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA
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Affiliation as printed
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
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University of California, San Francisco · UCSF Helen Diller Family Comprehensive Cancer Center
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UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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Fred Hutch Cancer Center · University of Wisconsin–Milwaukee
Affiliation as printed
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
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University of Eastern Finland · Kuopio University Hospital
Affiliation as printed
Cancer Center, Kuopio University Hospital, Kuopio, Finland
Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen · Comprehensive Cancer Center Erlangen
Affiliation as printed
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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Affiliation as printed
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Spanish National Cancer Research Centre · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain
Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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Russian Academy of Sciences · Institute of Biochemistry and Genetics of Ufa Scientific Centre
Affiliation as printed
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia
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University of Helsinki · Helsinki University Hospital · Örebro University Hospital
Affiliation as printed
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
Department of Oncology, Örebro University Hospital, Örebro, Sweden
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Vanderbilt University · International Epidemiology Institute · Vanderbilt-Ingram Cancer Center
Affiliation as printed
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
International Epidemiology Institute, Rockville, MD, USA
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Medizinische Hochschule Hannover · N.N. Alexandrov National Cancer Centre
Affiliation as printed
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
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University of Copenhagen · Herlev Hospital · Copenhagen University Hospital · Gentofte Hospital
Affiliation as printed
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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German Cancer Research Center · Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · Deutsches Konsortium für Translationale Krebsforschung · University of Tübingen
Affiliation as printed
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
iFIT-Cluster of Excellence, University of Tuebingen, Tuebingen, Germany
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German Cancer Research Center · National Center for Tumor Diseases · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
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Affiliation as printed
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany
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German Cancer Research Center · Heidelberg University
Affiliation as printed
Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany
Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany
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University of Cambridge · Cancer Research UK · Cambridge University Hospitals NHS Foundation Trust · Cancer Research UK Cambridge Center
Affiliation as printed
Breast Cancer Programme, CRUK Cambridge Cancer Centre and NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Cancer Research UK Cambridge Institute, Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
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Affiliation as printed
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · University Medical Center Hamburg-Eppendorf · University Cancer Center Hamburg
Affiliation as printed
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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National Institutes of Health · National Cancer Institute · Division of Cancer Epidemiology and Genetics
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Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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University of Cambridge · Cancer Research UK
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Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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The University of Sydney · Westmead Institute for Medical Research
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Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
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Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Affiliation as printed
Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK
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Affiliation as printed
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
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Affiliation as printed
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
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Peter Devilee Aachen Department of Human Genetics Department of Pathology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK
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Affiliation as printed
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
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Affiliation as printed
Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK
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University of Cambridge · NIHR Cambridge Biomedical Research Centre
Affiliation as printed
Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, UK
Department of Oncology, University of Cambridge, Cambridge, UK
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Affiliation as printed
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
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Brigham and Women's Hospital · Harvard University
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Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Affiliation as printed
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
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Manchester Academic Health Science Centre · University of Manchester · St Mary's Hospital · Manchester University NHS Foundation Trust · NIHR Manchester Biomedical Research Centre
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Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
Genomic Medicine, St Mary's Hospital, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK
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University of California, Los Angeles · Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen · Comprehensive Cancer Center Erlangen
Affiliation as printed
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
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National Institutes of Health · Edinburgh Cancer Research · National Cancer Institute · Division of Cancer Epidemiology and Genetics · University of Edinburgh
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Cancer Research UK Edinburgh Centre, Edinburgh, UK
Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK
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Herlev Hospital · Copenhagen University Hospital · Gentofte Hospital
Affiliation as printed
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
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University of California San Diego · Complejo Hospitalario Universitario de Santiago · Fundación Pública Galega de Medicina Xenómica · Instituto de Investigación Sanitaria de Santiago · Servicio Gallego de Salud · Moores Cancer Center
Affiliation as printed
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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Affiliation as printed
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
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National Institutes of Health · Institute of Cancer Research · National Cancer Institute · Division of Cancer Epidemiology and Genetics
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Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
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Hospital Clínico San Carlos · Instituto de Investigación Sanitaria del Hospital Clínico San Carlos · Centro de Investigación Biomédica en Red de Cáncer
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Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Affiliation as printed
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
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Affiliation as printed
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
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The University of Melbourne · Cancer Council Victoria · Monash University
Affiliation as printed
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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University of Utah · Huntsman Cancer Institute
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Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
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Spanish National Cancer Research Centre
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Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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Oulu University Hospital · University of Oulu
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Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
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Inserm · Centre de recherche en Epidémiologie et Santé des Populations
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Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), University Paris-Saclay, INSERM, University Paris-Sud, Villejuif, France
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Affiliation as printed
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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University of Southern California
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Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Affiliation as printed
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Affiliation as printed
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
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Affiliation as printed
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK
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Affiliation as printed
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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Affiliation as printed
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
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Affiliation as printed
Division of Cancer Sciences, University of Manchester, Manchester, UK
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National Taiwan University · National Taiwan University Hospital
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Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Affiliation as printed
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Harvard University · University of Oxford
Affiliation as printed
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Nuffield Department of Population Health, University of Oxford, Oxford, UK
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Affiliation as printed
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
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Stanford Medicine · Stanford Cancer Institute · Stanford University
Affiliation as printed
Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
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Affiliation as printed
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · Heidelberg University
Affiliation as printed
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
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National Cancer Institute · Division of Cancer Epidemiology and Genetics
Affiliation as printed
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
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Affiliation as printed
Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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Affiliation as printed
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Oslo University Hospital · University of Oslo
Affiliation as printed
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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VIB-KU Leuven Center for Cancer Biology · KU Leuven
Affiliation as printed
Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium
VIB, VIB Center for Cancer Biology, Leuven, Belgium
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University of Hawaii Cancer Center
Affiliation as printed
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
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Technion – Israel Institute of Technology · Carmel Medical Center
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Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
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Affiliation as printed
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Fondazione IRCCS Istituto Nazionale dei Tumori
Affiliation as printed
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT), Milan, Italy
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Karolinska Institutet · Stockholm South General Hospital
Affiliation as printed
Department of Clinical Science and Education, Sšdersjukhuset, Karolinska Institutet, Stockholm, Sweden
Department of Oncology, Sšdersjukhuset, Stockholm, Sweden
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University of California San Diego · Moores Cancer Center
Affiliation as printed
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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University Medical Center Hamburg-Eppendorf · University Cancer Center Hamburg
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Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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University Hospital of Heraklion
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Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece
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Ludwig-Maximilians-Universität München
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Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany
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The University of Melbourne · Cancer Council Victoria · Monash Health · Monash University
Affiliation as printed
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
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University Health Network · University of Toronto
Affiliation as printed
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
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City of Hope · Beckman Research Institute
Affiliation as printed
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
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University of Helsinki · Helsinki University Hospital
Affiliation as printed
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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Manchester Academic Health Science Centre · University of Manchester · St Mary's Hospital
Affiliation as printed
Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
Genomic Medicine, St Mary's Hospital, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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University of North Carolina at Chapel Hill · UNC Lineberger Comprehensive Cancer Center
Affiliation as printed
Department of Epidemiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Affiliation as printed
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
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Affiliation as printed
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
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