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

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

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