Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer
The Breast, vol. 85, pp. 104619
Abstract
The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.
Authors 99
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Centre National de la Recherche Scientifique · Inserm · Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers · Institut de Cancérologie de l'Ouest · IFOM · Université d'Angers · Nantes Université
Affiliation as printed
Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy; Unité de Génomique Fonctionnelle, Institut de Cancérologie de l'Ouest Nantes-Angers, Angers, France; Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, Angers, France
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Humanitas University · IFOM · IRCCS Humanitas Research Hospital
Affiliation as printed
Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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University of Copenhagen · University of Bologna
Affiliation as printed
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy
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Affiliation as printed
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
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IFOM · Italian Association for Cancer Research
Affiliation as printed
Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy
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Fondazione IRCCS Istituto Nazionale dei Tumori
Affiliation as printed
Unit of Predictive Medicine, Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
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Fondazione IRCCS Istituto Nazionale dei Tumori
Affiliation as printed
Unit of Predictive Medicine, Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
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National Institutes of Health · National Cancer Institute · Division of Cancer Epidemiology and Genetics
Affiliation as printed
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda MD, USA
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Mount Sinai Hospital · University of Toronto · Lunenfeld-Tanenbaum Research Institute
Affiliation as printed
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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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 Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany
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Affiliation as printed
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Institute of Biochemistry and Genetics of Ufa Scientific Centre
Affiliation as printed
Institute of Biochemistry and Genetics of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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European Institute of Oncology
Affiliation as printed
IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
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Institute for Prevention and Occupational Medicine
Affiliation as printed
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany
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University of Utah · Huntsman Cancer Institute
Affiliation as printed
Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Affiliation as printed
Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK
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Affiliation as printed
Oncólogy and Genétics Group, Instituto Investigación Sanitaria Galicia Sur-SERGAS, Vigo, Spain
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Affiliation as printed
Intermountain Healthcare, Salt Lake City, UT, USA
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German Cancer Research Center · University Medical Center Hamburg-Eppendorf · University Cancer Center Hamburg
Affiliation as printed
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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Peter Devilee Aachen
Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Gynecology and Obstetrics, Comprehensive Cancer Center Lower Saxony, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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University of Manchester · St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
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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 Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany
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National Institutes of Health · Edinburgh Cancer Research · National Cancer Institute · Division of Cancer Epidemiology and Genetics · University of Edinburgh
Affiliation as printed
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda MD, USA; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Complejo Hospitalario Universitario de Santiago · Fundación Pública Galega de Medicina Xenómica · Instituto de Investigación Sanitaria de Santiago · Servicio Gallego de Salud
Affiliation as printed
Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
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Instituto de Salud Carlos III · Spanish National Cancer Research Centre · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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Inserm · Université de Versailles Saint-Quentin-en-Yvelines · Université Paris-Saclay · Centre de recherche en Epidémiologie et Santé des Populations
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Team "Exposome and Heredity", CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France
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Cyprus Institute of Neurology and Genetics
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Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Affiliation as printed
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Department of Gynecology and Obstetrics, Comprehensive Cancer Center Lower Saxony, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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Affiliation as printed
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · University of Tübingen
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany
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University of Manchester · St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
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International Hereditary Cancer Center · Pomeranian Medical University
Affiliation as printed
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
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Oslo University Hospital · University of Oslo
Affiliation as printed
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
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International Hereditary Cancer Center · Pomeranian Medical University
Affiliation as printed
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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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, Italy
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University Hospital of Heraklion
Affiliation as printed
Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece
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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, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
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University Health Network · University of Toronto
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Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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University of Manchester · St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute for Occupational and Maritime Medicine (ZfAM), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Cyprus Institute of Neurology and Genetics · Mississippi State University
Affiliation as printed
Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus; Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, Mississippi, USA
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Spanish National Cancer Research Centre
Affiliation as printed
Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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German Cancer Research Center · Shaukat Khanum Memorial Cancer Hospital and Research Center
Affiliation as printed
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
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Affiliation as printed
Division of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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Affiliation as printed
School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK
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University of Cologne · University Hospital Cologne
Affiliation as printed
Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
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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, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia
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QIMR Berghofer Medical Research Institute
Affiliation as printed
Public Health Program, QIMR Berghofer, Brisbane, Queensland, Australia
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Affiliation as printed
Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford, UK
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Inserm · Université de Versailles Saint-Quentin-en-Yvelines · Université Paris-Saclay · Centre de recherche en Epidémiologie et Santé des Populations
Affiliation as printed
Team "Exposome and Heredity", CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France
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Affiliation as printed
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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Karolinska Institutet · Stockholm South General Hospital
Affiliation as printed
Department of Oncology, Södersjukhuset, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
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Medical College of Wisconsin · Medical College of Wisconsin Cancer Center
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Division of Biostatistics, Data Science Institute, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
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Affiliation as printed
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA
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Affiliation as printed
Department of Population Science, American Cancer Society, Atlanta, USA
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University of Wisconsin–Madison · University of Wisconsin Health
Affiliation as printed
Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, USA
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University of Southern California
Affiliation as printed
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, USA
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Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA
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Affiliation as printed
Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Brigham and Women's Hospital · Harvard University
Affiliation as printed
Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
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University of Southern California
Affiliation as printed
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, USA
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Affiliation as printed
Department of Population Science, American Cancer Society, Atlanta, USA
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Affiliation as printed
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA
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Affiliation as printed
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA
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Affiliation as printed
University of Washington, Seattle, USA
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University of California San Diego
Affiliation as printed
University of California, San Diego, La Jolla California, USA
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Affiliation as printed
Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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City Of Hope National Medical Center · City of Hope · Beckman Research Institute
Affiliation as printed
Beckman Research Institute of City of Hope, Duarte, USA
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National Institutes of Health · National Institute of Environmental Health Sciences
Affiliation as printed
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham NC, USA
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Affiliation as printed
Mayo Clinic, Rochester, USA
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Affiliation as printed
Slone Epidemiology Center, Boston University Chobanian & Avedisian School of Medicine, Boston, USA
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Affiliation as printed
Department of Population Science, American Cancer Society, Atlanta, USA
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Affiliation as printed
Mayo Clinic, Rochester, USA
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National Institutes of Health · National Institute of Environmental Health Sciences
Affiliation as printed
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham NC, USA
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Affiliation as printed
Department of Population Science, American Cancer Society, Atlanta, USA
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National Institutes of Health · National Institute of Environmental Health Sciences
Affiliation as printed
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Durham NC, USA
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The University of Kansas Cancer Center
Affiliation as printed
The University of Kansas Cancer Center, Kansas City, KS USA
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Affiliation as printed
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA
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Affiliation as printed
Department of Medical Oncology, Mayo Clinic, Rochester, USA
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Roswell Park Comprehensive Cancer Center
Affiliation as printed
Roswell Park Cancer Center, Buffalo, USA
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Affiliation as printed
Slone Epidemiology Center, Boston University Chobanian & Avedisian School of Medicine, Boston, USA
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Charles University · General University Hospital in Prague
Affiliation as printed
Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Charles University · General University Hospital in Prague
Affiliation as printed
Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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Charles University · General University Hospital in Prague
Affiliation as printed
Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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