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

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Cedena, MT
  • Rapado, I
  • Santos-Lozano, A
  • Ayala, R
  • Onecha, E
  • Abaigar, M
  • Diez-Campelo, M
  • Rivas, JH
  • Lucia, A
  • Martinez-Lopez, J

Grupos

Abstract

We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had >= 1 mutation (mean= 2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.33-0.94; p= 0.028), and a positive association was found for having = 1 mutation in a DNA methylation-related gene: TET2, DNMT3A, IDH1 and/or IDH2 (OR: 4.76, 95% CI: 1.31-17.27; p= 0.017). Mutations in TP53 (hazard ratio [HR]: 3.88; 95% CI: 1.94-7.75) and EZH2 (HR: 2.50; 95% CI: 1.23-5.09) were associated with shorter overall survival. Meta-analysis of 6 studies plus present data (n= 815 patients) allowed assessment of the association of drug response with mutations in 9 candidate genes: ASXL1, CBL, EZH2, SF3B1, SRSF2, TET2, DNMT3A, IDH1/2 and TP53. TET2 mutations predicted a more favorable drug response compared with 'wild-type' peers (pooled OR: 1.67, 95% CI: 1.14-2.44; p= 0.01). In conclusion, mutations in the DNA methylation pathway, especially TET2 mutations, and low number of total mutations are associated with a better response to azacitidine.

Datos de la publicación

ISSN/ISSNe:
1949-2553, 1949-2553

Oncotarget  IMPACT JOURNALS LLC

Tipo:
Article
Páginas:
106948-106961
PubMed:
29291002
Factor de Impacto:
1,942 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 38

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Keywords

  • myelodysplastic syndromes; mutational profile; next generation sequencing; hypomethylating agents

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