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Leukemia. 2016 Mar;30(3):666-73. doi: 10.1038/leu.2015.304. Epub 2015 Oct 30.

Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

Author information

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Genoptix, Inc., a Novartis company, Carlsbad, CA, USA.
Hematology Department, CHU of Nice, Nice, France.
Faculty of Medicine, University Nice Sophia Antipolis, Nice, France.
Mediterranean Center of Molecular Medicine, INSERM U1065, Nice, France.
French Group of Myelodysplasia, Paris, France.
Health Informatics Institute, University of South Florida, Tampa, FL, USA.
King's College London School of Medicine, Department of Haematological Medicine, Rayne Institute, King's College London School of Medicine, London, UK.


Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

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