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Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in

M Teresa Cedena1,2, Inmaculada Rapado1,2, Alejandro Santos-Lozano2,3

  • 1Hematology Department, Hospital Universitario 12 Octubre, CNIO, Universidad Complutense, Madrid, Spain.

Oncotarget
|January 2, 2018
PubMed

Insights

Patients with myelodysplastic syndromes (MDS) and fewer mutations, particularly in DNA methylation genes like TET2, showed better response to azacitidine treatment. This finding aids in predicting treatment outcomes for MDS patients.

Area of Science:

  • Hematology
  • Oncology
  • Genetics

Background:

  • Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders.
  • Azacitidine is a hypomethylating agent used in MDS treatment.
  • Genetic mutations play a crucial role in MDS pathogenesis and treatment response.

Purpose of the Study:

  • To investigate the association between mutations in 34 candidate genes and response to azacitidine in MDS patients.
  • To identify specific genetic markers that predict azacitidine efficacy and patient survival.

Main Methods:

  • Somatic mutations in 84 MDS patients were identified using next-generation sequencing.
  • The overall response rate to azacitidine was assessed.
  • Statistical analyses, including odds ratios and hazard ratios, were used to evaluate associations between mutations, clinical characteristics, and outcomes. A meta-analysis of 6 studies plus the current data was performed.

Main Results:

  • The overall response rate to azacitidine was 42%; no clinical characteristic predicted response.
  • A higher total number of mutations per patient was negatively associated with response (OR: 0.56).
  • Mutations in DNA methylation-related genes (TET2, DNMT3A, IDH1/2) were positively associated with response (OR: 4.76). Mutations in TP53 and EZH2 were linked to shorter overall survival.
  • Meta-analysis confirmed TET2 mutations predict a more favorable drug response (pooled OR: 1.67).

Conclusions:

  • Mutations in DNA methylation pathway genes, particularly TET2, are associated with a better response to azacitidine in MDS.
  • A lower total mutation burden may also indicate a more favorable response to azacitidine.
  • These genetic findings can help personalize MDS treatment strategies.
Keywords:
hypomethylating agentsmutational profilemyelodysplastic syndromesnext generation sequencing

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