Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes
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M. Teresa Cedena1,2,*, Inmaculada Rapado1,2,*, Alejandro Santos-Lozano2,3, Rosa Ayala1,2, Esther Onecha1,2 María Abaigar4, Esperanza Such5, Fernando Ramos6, José Cervera5,7, María Díez-Campelo4,8, Guillermo Sanz5, Jesús Hernández Rivas4,8, Alejandro Lucía2,9, Joaquin Martínez-López1,2
1Hematology Department, Hospital Universitario 12 Octubre, CNIO, Universidad Complutense, Madrid, Spain
2Research Institute of Hospital 12 de Octubre (‘i+12’), Madrid, Spain
3GIDFYS, European University Miguel de Cervantes, Valladolid, Spain
4IBSAL, Cancer Research Center (USAL-CSIC), Salamanca, Spain
5Hematology Department, Hospital Universitario La Fe, Valencia, Spain
6Hematology Department, Hospital Universitario de León, and IBIOMED, Universidad León, León, Spain
7Genetics Unit, Hospital Universitario La Fe, Valencia, Spain
8Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain
9Universidad Europea de Madrid, Madrid, Spain
*These authors have contributed equally to this work
M. Teresa Cedena, email: [email protected]
Keywords: myelodysplastic syndromes; mutational profile; next generation sequencing; hypomethylating agents
Received: July 22, 2017 Accepted: October 03, 2017 Published: October 27, 2017
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.
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