MGMT gene silencing and benefit from temozolomide in glioblastoma

Monika E. Hegi*, Annie Claire Diserens, Thierry Gorlia, Marie France Hamou, Nicolas De Tribolet, Michael Weller, Johan M. Kros, Johannes A. Hainfellner, Warren Mason, Luigi Mariani, Jacoline E C Bromberg, Peter Hau, René O. Mirimanoff, J. Gregory Cairncross, Robert C. Janzer, Roger Stupp

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4702 Scopus citations

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)997-1003
Number of pages7
JournalNew England Journal of Medicine
Volume352
Issue number10
DOIs
StatePublished - Mar 10 2005

ASJC Scopus subject areas

  • Medicine(all)

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