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

// M. Teresa Cedena 1, 2, * , Inmaculada Rapado 1, 2, * , Alejandro Santos-Lozano 2, 3 , Rosa Ayala 1, 2 , Esther Onecha 1, 2 Maria Abaigar 4 , Esperanza Such 5 , Fernando Ramos 6 , Jose Cervera 5, 7 , Maria Diez-Campelo 4, 8 , Guillermo Sanz 5 , Jesus Hernandez Rivas 4, 8 , Alejandro Lucia 2, 9 , Joaquin Martinez-Lopez 1, 2 1 Hematology Department, Hospital Universitario 12 Octubre, CNIO, Universidad Complutense, Madrid, Spain 2 Research Institute of Hospital 12 de Octubre (‘i+12’), Madrid, Spain 3 GIDFYS, European University Miguel de Cervantes, Valladolid, Spain 4 IBSAL, Cancer Research Center (USAL-CSIC), Salamanca, Spain 5 Hematology Department, Hospital Universitario La Fe, Valencia, Spain 6 Hematology Department, Hospital Universitario de Leon, and IBIOMED, Universidad Leon, Leon, Spain 7 Genetics Unit, Hospital Universitario La Fe, Valencia, Spain 8 Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain 9 Universidad Europea de Madrid, Madrid, Spain * These authors have contributed equally to this work Correspondence to: M. Teresa Cedena, email: mariateresa.cedena@salud.madrid.org Keywords: myelodysplastic syndromes; mutational profile; next generation sequencing; hypomethylating agents Received: July 22, 2017      Accepted: October 03, 2017      Published: October 27, 2017 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.