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

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


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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alleles
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Cytogenetic Analysis
  • Female
  • Follow-Up Studies
  • Gene Expression
  • Gene Frequency*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leukemia, Myeloid, Acute / diagnosis*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Mutation*
  • Myelodysplastic Syndromes / diagnosis*
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / mortality
  • Myelodysplastic Syndromes / pathology
  • Nuclear Proteins / genetics
  • Phenotype*
  • Phosphoproteins / genetics
  • Prognosis
  • RNA Splicing Factors
  • Ribonucleoprotein, U2 Small Nuclear / genetics
  • Ribonucleoproteins / genetics
  • Serine-Arginine Splicing Factors
  • Survival Analysis
  • Tumor Suppressor Protein p53 / genetics*


  • Core Binding Factor Alpha 2 Subunit
  • Nuclear Proteins
  • Phosphoproteins
  • RNA Splicing Factors
  • RUNX1 protein, human
  • Ribonucleoprotein, U2 Small Nuclear
  • Ribonucleoproteins
  • SF3B1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors