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

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Blood. 2024 Oct 10;144(15):1552-1554. doi: 10.1182/blood.2024025676. PubMed

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Cazzola M. Myelodysplastic syndromes. N Engl J Med. 2020;383(14):1358–1374. PubMed

Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–3699. PubMed PMC

Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241–247. PubMed PMC

Nazha A, Komrokji R, Meggendorfer M, et al. Personalized prediction model to risk stratify patients with myelodysplastic syndromes. J Clin Oncol. 2021;39(33):3737–3746. PubMed PMC

Bersanelli M, Travaglino E, Meggendorfer M, et al. Classification and personalized prognostic assessment on the basis of clinical and genomic features in myelodysplastic syndromes. J Clin Oncol. 2021;39(11):1223–1233. PubMed PMC

Kewan T, Durmaz A, Bahaj W, et al. Molecular patterns identify distinct subclasses of myeloid neoplasia. Nat Commun. 2023;14(1):3136. PubMed PMC

Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1(7) PubMed

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405. PubMed

Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200–1228. PubMed PMC

Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703–1719. PubMed PMC

Yoshizato T, Nannya Y, Atsuta Y, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129(17):2347–2358. PubMed PMC

Bernard E, Nannya Y, Hasserjian RP, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26(10):1549–1556. PubMed PMC

Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–2221. PubMed PMC

Bernard E. R package for the IPSS-M. https://github.com/papaemmelab/ipssm

Smith AE, Kulasekararaj AG, Jiang J, et al. CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis. Lancet Haematol. 2015;2(5):e212–e221. PubMed

Beauchamp EM, Leventhal M, Bernard E, et al. is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. Blood Cancer Discov. 2021;2(5):500–517. PubMed PMC

Okuda R, Nannya Y, Ochi Y, et al. Der(1;7)(q10;p10) presents with a unique genetic profile and frequent ETNK1 mutations in myeloid neoplasms [abstract] Blood. 2021;138(suppl 1):1513.

Gao T, Ptashkin R, Bolton KL, et al. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis. Nat Commun. 2021;12(1):338. PubMed PMC

Saiki R, Momozawa Y, Nannya Y, et al. Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis. Nat Med. 2021;27(7):1239–1249. PubMed

Sanada M, Suzuki T, Shih L-Y, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460(7257):904–908. PubMed

Awada H, Nagata Y, Goyal A, et al. Invariant phenotype and molecular association of biallelic mutant myeloid neoplasia. Blood Adv. 2019;3(3):339–349. PubMed PMC

Ilagan JO, Ramakrishnan A, Hayes B, et al. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res. 2015;25(1):14–26. PubMed PMC

Shiozawa Y, Malcovati L, Gallì A, et al. Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia. Nat Commun. 2018;9(1):3649. PubMed PMC

Dalton WB, Helmenstine E, Pieterse L, et al. The K666N mutation in SF3B1 is associated with increased progression of MDS and distinct RNA splicing. Blood Adv. 2020;4(7):1192–1196. PubMed PMC

Adema V, Khouri J, Ni Y, et al. Analysis of distinct hotspot mutations in relation to clinical phenotypes and response to therapy in myeloid neoplasia. Leuk Lymphoma. 2021;62(3):735–738. PubMed PMC

Huber S, Haferlach T, Müller H, et al. MDS subclassification-do we still have to count blasts? Leukemia. 2023;37(4):942–945. PubMed PMC

Makishima H, Saiki R, Nannya Y, et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood. 2023;141(5):534–549. PubMed PMC

Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33(7):1747–1758. PubMed PMC

Acha P, Mallo M, Solé F. Myelodysplastic syndromes with Isolated del(5q): Value of molecular alterations for diagnostic and prognostic assessment. Cancers. 2022;14(22) PubMed PMC

Woll PS, Kjällquist U, Chowdhury O, et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 2014;25(6):794–808. PubMed

Malcovati L, Papaemmanuil E, Bowen DT, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011;118(24):6239–6246. PubMed PMC

Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233–241. PubMed PMC

Garcia-Gisbert N, Arenillas L, Roman-Bravo D, et al. Multi-hit TET2 mutations as a differential molecular signature of oligomonocytic and overt chronic myelomonocytic leukemia. Leukemia. 2022;36(12):2922–2926. PubMed

Sanada M, Uike N, Ohyashiki K, et al. Unbalanced translocation der(1;7)(q10;p10) defines a unique clinicopathological subgroup of myeloid neoplasms. Leukemia. 2007;21(5):992–997. PubMed

Ganster C, Müller-Thomas C, Haferlach C, et al. Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes. Genes Chromosomes Cancer. 2019;58(10):689–697. PubMed

Gallì A, Todisco G, Catamo E, et al. Relationship between clone metrics and clinical outcome in clonal cytopenia. Blood. 2021;138(11):965–976. PubMed

Meggendorfer M, Bacher U, Alpermann T, et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia. 2013;27(9):1852–1860. PubMed

Gurnari C, Pagliuca S, Prata PH, et al. Clinical and molecular determinants of clonal evolution in aplastic anemia and paroxysmal nocturnal hemoglobinuria. J Clin Oncol. 2023;41(1):132–142. PubMed PMC

Pastor V, Hirabayashi S, Karow A, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia. 2017;31(3):759–762. PubMed

Sahoo SS, Pastor VB, Goodings C, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med. 2021;27(10):1806–1817. PubMed PMC

Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125(9):1367–1376. PubMed PMC

Tazi Y, Arango-Ossa JE, Zhou Y, et al. Unified classification and risk-stratification in acute myeloid leukemia. Nat Commun. 2022;13(1):4622. PubMed PMC

Cazzola M, Sehn LH. Developing a classification of hematologic neoplasms in the era of precision medicine. Blood. 2022;140(11):1193–1199. PubMed

Duncavage EJ, Bagg A, Hasserjian RP, et al. Genomic profiling for clinical decision making in myeloid neoplasms and acute leukemia. Blood. 2022;140(21):2228–2247. PubMed PMC

Sirenko M, Bernard E, Creignou M, et al. UBA1 mutations identify a rare but distinct subtype of myelodysplastic syndromes [abstract] Blood. 2023;142(suppl 1):1862.

Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376(6):536–547. PubMed PMC

Weinberg OK, Siddon A, Madanat YF, et al. TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML. Blood Adv. 2022;6(9):2847–2853. PubMed PMC

Kuendgen A, Nomdedeu M, Tuechler H, et al. Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS. Leukemia. 2021;35(3):835–849. PubMed PMC

Aguirre LE, Al Ali N, Sallman DA, et al. Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes. Leukemia. 2023;37(7):1530–1539. PubMed

Palomo L, Meggendorfer M, Hutter S, et al. Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms. Blood. 2020;136(16):1851–1862. PubMed PMC

Geissler K, Jäger E, Barna A, et al. Correlation of RAS-pathway mutations and spontaneous myeloid colony growth with progression and transformation in chronic myelomonocytic leukemia-a retrospective analysis in 337 patients. Int J Mol Sci. 2020;21(8) PubMed PMC

Carr RM, Vorobyev D, Lasho T, et al. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis. Nat Commun. 2021;12(1):2901. PubMed PMC

Papaemmanuil E, Döhner H, Campbell PJ. Genomic classification in acute myeloid leukemia. N Engl J Med. 2016;375(9):900–901. PubMed

Bolton KL, Ptashkin RN, Gao T, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet. 2020;52(11):1219–1226. PubMed PMC