MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. N Engl J Med 352(10): 997-1003

Universität Regensburg, Ratisbon, Bavaria, Germany
New England Journal of Medicine (Impact Factor: 55.87). 03/2005; 352(10):997-1003. DOI: 10.1056/NEJMoa043331
Source: PubMed


Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.
We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis.
The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups.
Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

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    • "Better understanding of the specific molecular features underlying this LTS phenotype may lead to improved diagnosis, prognosis, treatment and, ultimately, survival of GBM patients[4]. At present, several molecular markers have been correlated to GBM prognosis, but they need further validation before they can be used in the clinical setting[28]. However, despite great effort over the last years, the cellular and molecular features of LTS have not been properly elucidated. "
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    • "Conditional knockout of DNMTs in neural precursor cells of mice affected viability, whereas ablation of DNMT1, 3A, or both in postmitotic neurons altered cell survival , morphology, synaptic plasticity, learning, and memory (Fan et al. 2001; Feng et al. 2010). DNA methylation is therefore a requirement for normal CNS function and altered DNMT expression and enzymatic activity have been identified in many neurological disorders including autism spectrum disorders (James et al. 2004; Feinberg 2007), schizophrenia (Grayson et al. 2005), Alzheimer's disease (Scarpa et al. 2003; Graff et al. 2012), brain tumors (Hegi et al. 2005), spinal muscular atrophy (Hauke et al. 2009), and epilepsy. "
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    ABSTRACT: Epigenetic processes in the brain involve the transfer of information arising from short-lived cellular signals and changes in neuronal activity into lasting effects on gene expression. Key molecular mediators of epigenetics include methylation of DNA, histone modifications, and noncoding RNAs. Emerging findings in animal models and human brain tissue reveal that epilepsy and epileptogenesis are associated with changes to each of these contributors to the epigenome. Understanding and influencing the molecular mechanisms controlling epigenetic change could open new avenues for treatment. DNA methylation, particularly hypermethylation, has been found to increase within gene body regions and interference with DNA methylation in epilepsy can change gene expression profiles and influence epileptogenesis. Posttranscriptional modification of histones, including transient as well as sustained changes to phosphorylation and acetylation, have been reported, which appear to influence gene expression. Finally, roles have emerged for noncoding RNAs in brain excitability and seizure thresholds, including microRNA and long noncoding RNA. Together, research supports strong effects of epigenetics influencing gene expression in epilepsy, suggesting future therapeutic approaches to manipulate epigenetic processes to treat or prevent epilepsy.
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    • "TMZ-induced hypermutation and resulting large mutational diversity can contribute to drug resistance (Bozic et al., 2013); our data suggest that such an adverse effect of TMZ is minimal for IDH1-wild-type primary GBM patients when used in accordance with the standard regimen. On the other hand, for patients with IDH1-mutated tumors, who often show MGMT promoter methylation, TMZ has been considered a preferred treatment option and is often administered with more cycles than for other patients; this was based on the proven efficacy of TMZ for MGMT-methylated tumors (Hegi et al., 2005). However , on the basis of our study and the prior study on paired gliomas with IDH1 mutations (Johnson et al., 2014), the benefits of TMZ should now be considered more carefully against its potentially adverse effects of hypermutation. "
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