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

• Published in: Oncotarget Vol. 8; no. 63; pp. 106948 - 106961
• Main Authors: Cedena, M Teresa, Rapado, Inmaculada, Santos-Lozano, Alejandro, Ayala, Rosa, Onecha, Esther, Abaigar, María, Such, Esperanza, Ramos, Fernando, Cervera, José, Díez-Campelo, María, Sanz, Guillermo, Rivas, Jesús Hernández, Lucía, Alejandro, Martínez-López, Joaquin
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 05.12.2017
• Subjects: Research Paper; hypomethylating agents; next generation sequencing; mutational profile; myelodysplastic syndromes
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.22157

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: (OR: 4.76, 95%CI: 1.31-17.27; p=0.017). Mutations in (hazard ratio [HR]: 3.88; 95%CI: 1.94-7.75) and (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: and 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 mutations, and low number of total mutations are associated with a better response to azacitidine.