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

ABSTRACT 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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    • "The inactivation of other genes mutated in low-grade gliomas, such as ATRX (Jiao et al., 2012) and SMARCA4 (Johnson et al., 2014), is known to induce specific DNA methylation changes as well (Banine et al., 2005; Gibbons et al., 2000). Of clinical importance is DNA hypermethylation of the MGMT promoter, which is associated with loss of SP1 binding, closed chromatin, and transcriptional silencing in GBM cells (Costello et al., 1994a, 1994b), and increased survival in GBM patients treated with TMZ (Hegi et al., 2005). Whether the DNA methylation status at this locus predicts the same survival benefit in patients with low-grade glioma is unclear (Everhard et al., 2006; Kesari et al., 2009; Taal et al., 2011; van Thuijl et al., 2015; Wick et al., 2013). "
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    • "This regimen, which has minimal additional toxicity, was demonstrated to increase the median OS to 14.6 months and the 2-year OS to 27.2%, compared to 12.1 months and 10.9%, respectively, in the radiotherapy alone group [35] [36]. Moreover, patients with epigenetic silencing of O 6 -methylguanine DNA methyltransferase (MGMT) benefitted more from TMZ treatment [37]. On the basis of these findings, TMZ has been incorporated into multimodal treatment strategies for malignant gliomas. "
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    • "Although aggressive treatment significantly reduced mortality in Classical (HR = 0.45; p = 0.02) and Mesenchymal (HR = 0.54; p = 0.02) subtypes, and efficacy was suggested in Neural (HR = 0.56; p = 0.1), it did not alter survival in the Proneural subtype (HR = 0.8; p = 0.4; Figure 5). Dichotomous methylation status of the DNA repair gene MGMT, which has been positively linked to response to therapy (Hegi et al., 2005), was not associated with subtype (Table 1). "
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