Journal Article

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

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

2019

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Abnormalities / Anemia / Chromosome aberrations / Complexity / Cytogenetics / Disorders / Hemoglobin / Karyotypes / Medical prognosis / Monosomy / Mutation / Myelodysplastic syndrome / Myelodysplastic syndromes / p53 Protein / Risk / Subgroups / Survival