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Molecular taxonomy of myelodysplastic syndromes and its clinical implications

E. Bernard, RP. Hasserjian, PL. Greenberg, JE. Arango Ossa, M. Creignou, H. Tuechler, J. Gutierrez-Abril, D. Domenico, JS. Medina-Martinez, M. Levine, K. Liosis, N. Farnoud, M. Sirenko, M. Jädersten, U. Germing, G. Sanz, AA. van de Loosdrecht, Y....

. 2024 ; 144 (15) : 1617-1632. [pub] 20241010

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003907

Grantová podpora
P30 CA008748 NCI NIH HHS - United States
P50 CA254838 NCI NIH HHS - United States

Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.

Centro de Investigación Biomédica en Red Cáncer Instituto de Salud Carlos 3 Madrid Spain

Clinics of Hematology and Medical Oncology University Medical Center Göttingen Germany

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Biomedical Sciences Humanitas Clinical and Research Center and Humanitas University Milan Italy

Department of Computational Oncology UMR 981 Gustave Roussy Villejuif France

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY

Department of Genomics Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Hematology Amsterdam University Medical Center Vrije University Medical Center Amsterdam The Netherlands

Department of Hematology and Genetics Unit University Hospital La Fe Valencia Spain

Department of Hematology Assistance Publique Hôpitaux de Paris Hôpital Cochin and Université de Paris Université Paris Descartes Paris France

Department of Hematology Hemostasis Oncology and Stem Cell Transplantation Hannover Medical School Hannover Germany

Department of Hematology Hôpital St Louis and Paris University Paris France

Department of Hematology Hospital Universitario y Politécnico La Fe Valencia Spain

Department of Hematology Oncology and Clinical Immunology Heinrich Heine University Düsseldorf Germany

Department of Hematology Oncology Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Pavia Italy

Department of Hematology University Hospital of Alexandroupolis Democritus University of Thrace Alexandroupolis Greece

Department of Internal Medicine 1 Ludwig Boltzmann Institute for Hematology and Hemostaseology Medical University of Vienna Vienna Austria

Department of Medical Oncology and Howard Hughes Medical Institute Dana Farber Cancer Center Boston MA

Department of Medicine Huddinge Center for Hematology and Regenerative Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville TN

Department of Molecular Medicine University of Pavia Pavia Italy

Department of Pathology and Tumor Biology Kyoto University Kyoto Japan

Department of Pathology Massachusetts General Hospital Boston MA

Division of Hematology and Hemostaseology Department of Internal Medicine 1 Medical University of Vienna Vienna Austria

Division of Hematology Chang Gung Memorial Hospital at Linkou Chang Gung University Taoyuan City Taiwan

Division of Hematology Stanford University Cancer Institute Stanford CA

Drug Research and Development Center Federal University of Ceara Ceara Brazil

Hematology Department Catalan Institute of Oncology Hospital Germans Trias i Pujol Barcelona Spain

Independent Researcher Vienna Austria

Institute for the Advanced Study of Human Biology Kyoto University Kyoto Japan

Institute of Hematology Seràgnoli Istituti di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Laboratory of Hematology Department of Laboratory Medicine Radboud University Medical Centre Nijmegen The Netherlands

Medical Clinic and Policlinic 1 Hematology and Cellular Therapy University of Leipzig Leipzig Germany

Myelodysplastic Syndromes Cooperative Group Gruppo Laziale Mielo displasie Department of Biomedicine and Prevention Tor Vergata University Rome Italy

Myelodysplastic Syndromes Group Josep Carreras Leukemia Research Institute Barcelona Spain

Myelodysplastic Syndromes Unit Department of Experimental and Clinical Medicine Hematology Azienda Ospedaliero Universitaria Careggi University of Florence Florence Italy

Oncology Hematology Center Hospital Israelita Albert Einstein São Paulo Brazil

Radcliffe Department of Medicine Nuffield Division of Clinical Laboratory Sciences University of Oxford Oxford United KIngdom

University of California San Diego Moores Cancer Center La Jolla CA

Citace poskytuje Crossref.org

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$a Molecular taxonomy of myelodysplastic syndromes and its clinical implications / $c E. Bernard, RP. Hasserjian, PL. Greenberg, JE. Arango Ossa, M. Creignou, H. Tuechler, J. Gutierrez-Abril, D. Domenico, JS. Medina-Martinez, M. Levine, K. Liosis, N. Farnoud, M. Sirenko, M. Jädersten, U. Germing, G. Sanz, AA. van de Loosdrecht, Y. Nannya, O. Kosmider, MY. Follo, F. Thol, L. Zamora, RF. Pinheiro, A. Pellagatti, HK. Elias, D. Haase, C. Ganster, L. Ades, M. Tobiasson, L. Palomo, MG. Della Porta, P. Fenaux, M. Belickova, MR. Savona, VM. Klimek, FPS. Santos, J. Boultwood, I. Kotsianidis, V. Santini, F. Solé, U. Platzbecker, M. Heuser, P. Valent, C. Finelli, MT. Voso, LY. Shih, M. Fontenay, JH. Jansen, J. Cervera, N. Gattermann, BL. Ebert, R. Bejar, L. Malcovati, S. Ogawa, M. Cazzola, E. Hellström-Lindberg, E. Papaemmanuil
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$a Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.
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