Predictive value of MGMT promoter methylation on the survival of TMZ treated IDH-mutant glioblastoma

Abstract

Objective: O6methylguanine-DNA methyltransferase (MGMT) promoter methylation is a biomarker widely used to predict thesensitivity of IDH-wildtype glioblastoma to temozolomide therapy. Given that the IDH status has critical effects on the survival andepigenetic features of glioblastoma, we aimed to assess the role of MGMT promoter methylation in IDH-mutant glioblastoma.

Methods: This study included 187 IDH-mutant glioblastomas and used 173 IDH-wildtype glioblastomas for comparison. Kaplan-Meier curves and multivariate Cox regression were used to study the predictive effects.

Results: Compared with IDH-wildtype glioblastomas, IDH-mutant glioblastomas showed significantly higher (P < 0.0001) MGMTpromoter methylation. We demonstrated that MGMT promoter methylation status, as determined by a high cutoff value (≥30%) inpyrosequencing, could be used to significantly stratify the survival of 50 IDH-mutant glioblastomas receiving temozolomide therapy(cohort A); this result was validated in another cohort of 25 IDH-mutant glioblastomas (cohort B). The median progression-freesurvival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases, and 18.37 and 41.61 monthsfor methylated cases, and in cohort B were 6.97 and 9.10 months for unmethylated cases, and 23.40 and 26.40 months for methylatedcases. In addition, we confirmed that the MGMT promoter methylation was significantly (P = 0.0001) correlated with longer OS inIDH-mutant patients with GBM, independently of age, gender distribution, tumor type (primary or recurrent/secondary), and theextent of resection.

Conclusions: MGMT promoter methylation has predictive value in IDH-mutant glioblastoma, but its cutoff value should be higherthan that for IDH-wildtype glioblastoma.