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. 2019 Jul;33(7):1747-1758.
doi: 10.1038/s41375-018-0351-2. Epub 2019 Jan 11.

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

Detlef Haase  1 , Kristen E Stevenson  2 , Donna Neuberg  2 , Jaroslaw P Maciejewski  3 , Aziz Nazha  3 , Mikkael A Sekeres  3 , Benjamin L Ebert  2 , Guillermo Garcia-Manero  4 , Claudia Haferlach  5 , Torsten Haferlach  5 , Wolfgang Kern  5 , Seishi Ogawa  6 , Yasunobu Nagata  3 , Kenichi Yoshida  6 , Timothy A Graubert  7 , Matthew J Walter  8 , Alan F List  9 , Rami S Komrokji  9 , Eric Padron  9 , David Sallman  9 , Elli Papaemmanuil  10 , Peter J Campbell  11 , Michael R Savona  12 , Adam Seegmiller  12 , Lionel Adès  13 , Pierre Fenaux  13 , Lee-Yung Shih  14 , David Bowen  15 , Michael J Groves  16 , Sudhir Tauro  16 , Michaela Fontenay  17 , Olivier Kosmider  17 , Michal Bar-Natan  18 , David Steensma  2 , Richard Stone  2 , Michael Heuser  19 , Felicitas Thol  19 , Mario Cazzola  20 , Luca Malcovati  20 , Aly Karsan  21 , Christina Ganster  1 , Eva Hellström-Lindberg  22 , Jacqueline Boultwood  23 , Andrea Pellagatti  23 , Valeria Santini  24 , Lynn Quek  25   26 , Paresh Vyas  25   26 , Heinz Tüchler  27 , Peter L Greenberg  28 , Rafael Bejar  29 ; International Working Group for MDS Molecular Prognostic Committee
Affiliations

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

Detlef Haase et al. Leukemia. 2019 Jul.

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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Conflict of interest statement

RB has served as a consultant for Genoptix and Celgene and served on advisory boards for Otsuka/Astex, AbbVie/Genetech, and Celgene and has received research funding from Celgene and Takeda. DH has served as consultant and advisory board member for Celgene and Novartis from both of which he has received research funding. PV receives research funding from Celgene and has been on advisory boards for Celgene, Pfizer, Novartis, Jazz, Daiichi Sanko. LQ receives research funding from Celgene. MAS has served on an advisory board for Celgene. MRE reports consultancy and research funding from Astex, Incyte, Karyopharm, Sunesis, Takeda, and TG Therapeutics; equity in Karyopharm; and DSMB membership for Celgene and Gilead. TH, CH, and WK report partial ownership of MLL–Munich Leukemia Laboratory. All other authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Select somatically mutated genes and karyotype abnormalities. a Co-mutation plot for somatically mutated genes in complex karyotype MDS patients with and without mutated TP53 (left and right panels, respectively). Each column represents an individual patient. A colored bar indicates a mutation of the gene in that row with gray bars indicating missing data. The last column indicates the number of patients with a mutation of each gene. b Plot of recurrent karyotype abnormalities in patients with and without mutated TP53 (left and right panels, respectively) using the same schema as in (a). TP53 mutant patients had a higher rate of del(5q) abnormality (50% vs. 34%, p = 0.004), abnormal chromosome 13 (18% vs. 8%, p = 0.017), abnormal chromosome 17 (40% vs. 27%, p = 0.016), abnormal chromosome 18 (28% vs. 14%, p = 0.004), and del(7q) (14% vs. 7%, p = 0.033), but a lower rate of der(1;7)(q10;p10) ( < 1% vs. 5%, p = 0.025)
Fig. 2
Fig. 2
Interaction between TP53 mutation, monosomy, and number of karyotype abnormalities. a Each column represents an individual patient with orange and black bars indicating TP53 mutation and monosomal karyotype respectively. Colored bars in the last row indicate the number of karyotype abnormalities with green representing 3, blue representing 4, and red representing 5 or more. b Venn diagram showing number of cases with overlapping features
Fig. 3
Fig. 3
Overall survival by TP53 mutation, high complexity, and monosomal karyotype status. a Overall survival of the entire cohort. b Overall survival stratified by TP53 mutation status. c Overall survival stratified by the number of clonal karyotype abnormalities. d Overall survival stratified by monosomal karyotype status. e Stratification of overall survival by TP53 mutation status in patients with a monosomal karyotype. f Stratification of overall survival by TP53 mutation status in patients without a monosomal karyotype
Fig. 4
Fig. 4
Overall survival stratified by TP53 mutation and high complexity status
See this image and copyright information in PMC

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