MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma

Apr 13, 2006Pediatric blood & cancer

MGMT gene changes linked to better survival and response to temozolomide in children with aggressive brain tumors

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Abstract

40% of pediatric GBM patients showed methylation of the MGMT gene promoter.

Methylation of the MGMT promoter is associated with improved survival in pediatric GBM patients.
Patients with methylated MGMT had an average survival time of 13.7 months compared to 2.5 months for those with unmethylated MGMT.
Among patients receiving temozolomide, those with methylated MGMT responded better to treatment.
A significant correlation exists between MGMT methylation and overall survival, regardless of treatment.
MGMT methylation may serve as a prognostic factor for survival and a marker for temozolomide sensitivity in pediatric GBM.

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BACKGROUND: Methylation of the DNA-repair gene O6-methylguanine-DNA methyltransferase (MGMT) causes gene silencing. This epigenetic modification has been associated with a favorable prognosis in adult patients with glioblastoma (GBM) who receive temozolomide and other alkylating agents. We explored MGMT promoter methylation in pediatric GBM and its relationship to survival and temozolomide sensitivity.

PROCEDURE: We performed a retrospective study of MGMT promoter methylation in 10 pediatric GBM. The methylation status of the MGMT was determined using a 2-stage methylation specific PCR analysis on DNA extracted from tumor specimens which had been snap frozen at surgery. The relationships between MGMT promoter methylation and patient outcome and response to temozolomide were evaluated.

RESULTS: Four of our 10 pediatric patients with GBM were found to have methylation of the MGMT gene promoter. Methylation of the MGMT promoter was shown to correlate (P = 0.0005) with survival. The average survival time for patients with methyltated MGMT was 13.7 months as compared to 2.5 months for the 6 patients with unmethylated MGMT promoter. Of the seven patients that received temozolomide, those patients that had the methylated MGMT gene promoter responded better to treatment (P = 0.007).

CONCLUSIONS: As in adults, pediatric GBM patients with methylated MGMT promoter benefited from temozolomide. However, a stronger correlation with overall survival, regardless of treatment, was observed in this group of patients. These data suggest that MGMT methylation may be a prognostic factor for survival in pediatric GBM, as well as a marker for temozolomide sensitivity.

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MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma

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