Molecular Taxonomy of Myelodysplastic Syndromes and its Clinical Implications
Elsa Bernard, Robert P. Hasserjian, Peter L. Greenberg, Juan Esteban Arango Ossa, Maria Creignou, Heinz Tuechler, Jesús Gutiérrez-Abril, Dylan Domenico, Juan Santiago Medina-Martinez, Max Fine Levine, Konstantinos Liosis, Noushin Farnoud, Maria Sirenko, Martin Jädersten, Ulrich Germing, Guillermo F. Sanz, Arjan A Van de Loosdrecht, Yasuhito Nannya, Olivier Kosmider, Matilde Y Follo, Felicitas R. Thol, Lurdes Zamora, Ronald Feitosa Pinheiro, Andrea Pellagatti, Harold Kunal Elias, Detlef Thomas Haase, Christina Ganster, Lionel Ades, Magnus Tobiasson, Laura Palomo, Matteo Giovanni Della Porta, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia Klimek, Fabio P S Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Sole, Uwe Platzbecker, Michael Heuser, Peter Valent, Carlo Finelli, Maria Teresa Voso, Lee Yung Shih, Michaela Fontenay, Joop H Jansen, José Cervera, Norbert Gattermann, Benjamin L Ebert, Rafael Bejar, Luca Malcovati, Seishi Ogawa, Mario Cazzola, Eva S Hellstrom-Lindberg, Elli PapaemmanuilMyelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) 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 LOH 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 blast percentage across groups ranged from 1.5 to 10%, and the median overall survival 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 bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.