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

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dc.contributor.author Cedena, María Teresa
dc.contributor.author Rapado, María Inmaculada
dc.contributor.author Santos-Lozano, Alejandro
dc.contributor.author Ayala, Rosa
dc.contributor.author Onecha, Esther
dc.contributor.author Abaigar, María
dc.contributor.author Such, Esperanza
dc.contributor.author Ramos Ortega, Fernando
dc.contributor.author Lucía Mulas, Alejandro
dc.contributor.author Martínez López, Joaquín
dc.date.accessioned 2018-06-21T14:57:43Z
dc.date.available 2018-06-21T14:57:43Z
dc.date.issued 2017
dc.identifier.citation Cedena, M. T., Rapado, I., Santos-Lozano, A., Ayala, R., Onecha, E., Lucía Mulas, A., ... & Martínez López, J. (2017). Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes. Oncotarget, 8(63), 106948-106961. spa
dc.identifier.issn 1949-2553
dc.identifier.uri http://hdl.handle.net/11268/7326
dc.description.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. spa
dc.description.sponsorship SIN FINANCIACIÓN spa
dc.language.iso eng spa
dc.rights Attribution-NonCommercial-NoDerivatives 4.0 Internacional *
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/ *
dc.subject.other Myelodysplastic syndromes spa
dc.title Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes spa
dc.type article spa
dc.description.impact 5.168 JCR (2017) Q1, 44/217 Oncology; Q2, 48/190 Cell Biology spa
dc.identifier.doi 10.18632/oncotarget.22157
dc.rights.accessRights openAccess spa
dc.subject.uem Genética spa
dc.subject.unesco Mutación spa
dc.subject.unesco Genética humana spa
dc.description.filiation UEM spa
dc.peerreviewed Si spa


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 Internacional