Your browser doesn't support javascript.
loading
Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.
Acta Neuropathol ; 129(4): 597-607, 2015 Apr.
Article en En | MEDLINE | ID: mdl-25724300
Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Antineoplásicos Alquilantes / Dacarbazina / Trastornos por Deficiencias en la Reparación del ADN / Glioma Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Idioma: En Revista: Acta Neuropathol Año: 2015 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Antineoplásicos Alquilantes / Dacarbazina / Trastornos por Deficiencias en la Reparación del ADN / Glioma Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Idioma: En Revista: Acta Neuropathol Año: 2015 Tipo del documento: Article