TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups

International Working Group for MDS Molecular Prognostic Committee, Detlef Haase, Kristen E. Stevenson, Donna Neuberg, Jaroslaw P. Maciejewski, Aziz Nazha, Mikkael A. Sekeres, Benjamin L. Ebert, Guillermo Garcia-Manero, Claudia Haferlach, Torsten Haferlach, Wolfgang Kern, Seishi Ogawa, Yasunobu Nagata, Kenichi Yoshida, Timothy A. Graubert, Matthew J. Walter, Alan F. List, Rami S. Komrokji, Eric PadronDavid Sallman, Elli Papaemmanuil, Peter J. Campbell, Michael R. Savona, Adam Seegmiller, Lionel Adès, Pierre Fenaux, Lee Yung Shih, David Bowen, Michael J. Groves, Sudhir Tauro, Michaela Fontenay, Olivier Kosmider, Michal Bar-Natan, David Steensma, Richard Stone, Michael Heuser, Felicitas Thol, Mario Cazzola, Luca Malcovati, Aly Karsan, Christina Ganster, Eva Hellström-Lindberg, Jacqueline Boultwood, Andrea Pellagatti, Valeria Santini, Lynn Quek, Paresh Vyas, Heinz Tüchler, Peter L. Greenberg, Rafael Bejar

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Abstract

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (p < 0.005), monosomal karyotype (p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

Original languageEnglish
Pages (from-to)1747-1758
Number of pages12
JournalLeukemia
Volume33
Issue number7
Early online date11 Jan 2019
DOIs
Publication statusPublished - Jul 2019

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International Working Group for MDS Molecular Prognostic Committee, Haase, D., Stevenson, K. E., Neuberg, D., Maciejewski, J. P., Nazha, A., Sekeres, M. A., Ebert, B. L., Garcia-Manero, G., Haferlach, C., Haferlach, T., Kern, W., Ogawa, S., Nagata, Y., Yoshida, K., Graubert, T. A., Walter, M. J., List, A. F., Komrokji, R. S., ... Bejar, R. (2019). TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia, 33(7), 1747-1758. https://doi.org/10.1038/s41375-018-0351-2