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Leukemia. 2019 Jan 11. doi: 10.1038/s41375-018-0351-2. [Epub ahead of print]

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

Author information

1
University Medical Center, Georg- August-University, Goettingen, Germany.
2
Dana-Farber Cancer Institute, Boston, MA, USA.
3
Cleveland Clinic Taussig Cancer Center, Cleveland, OH, USA.
4
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
MLL Munich Leukemia Laboratory, Munich, Germany.
6
Kyoto University, Kyoto, Japan.
7
Massachusetts General Hospital Cancer Center, Boston, MA, USA.
8
Washington University School of Medicine, St. Louis, MO, USA.
9
H. Lee Moffitt Cancer Center and Research Institute, Tampa Bay, FL, USA.
10
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
11
Wellcome Trust Sanger Institute, Cambridge, UK.
12
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
13
Hôpital St Louis, Assistance Publique-Hôpitaux de Paris and Paris Diderot University, Paris, France.
14
Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
15
St. James's Institute of Oncology, Leeds Teaching Hospitals, Leeds, UK.
16
University of Dundee, Ninewells Hospital, Dundee, UK.
17
Université Paris Descartes, Hopital Cochin Assistance Publique-Hopitaux de Paris, Paris, France.
18
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
19
Hannover Medical School, Hannover, Germany.
20
Fondazione IRCCS Policlinico San Matteo & University of Pavia, Pavia, Italy.
21
University of British Columbia, Vancouver, BC, Canada.
22
Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
23
Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
24
MDS Unit, AOU Careggi, University of Florence, Florence, Italy.
25
MRC Molecular Hematology Unit, WIMM University of Oxford, Oxford, UK.
26
Haematology Theme Oxford Biomedical Research Centre and Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
27
Ludwig-Boltzmann Institute for Leukemia Research, Vienna, Austria.
28
Stanford University Cancer Institute, Stanford, CA, USA.
29
UC San Diego Moores Cancer Center, La Jolla, CA, USA. rabejar@ucsd.edu.

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.

PMID:
30635634
DOI:
10.1038/s41375-018-0351-2

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