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. 2021 Feb 15;18(1):272-282.
doi: 10.20892/j.issn.2095-3941.2020.0179.

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

Ruichao Chai  1 , Guanzhang Li  1 , Yuqing Liu  1 , Kenan Zhang  1 , Zheng Zhao  1 , Fan Wu  1 , Yuzhou Chang  2 , Bo Pang  1 , Jingjun Li  1 , Yangfang Li  1 , Tao Jiang  1   2 , Yongzhi Wang  1   2
Affiliations

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

Ruichao Chai et al. Cancer Biol Med. .

Abstract

Objective: O6methylguanine-DNA methyltransferase (MGMT) promoter methylation is a biomarker widely used to predict the sensitivity of IDH-wildtype glioblastoma to temozolomide therapy. Given that the IDH status has critical effects on the survival and epigenetic 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) MGMT promoter methylation. We demonstrated that MGMT promoter methylation status, as determined by a high cutoff value (≥30%) in pyrosequencing, 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-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases, and 18.37 and 41.61 months for methylated cases, and in cohort B were 6.97 and 9.10 months for unmethylated cases, and 23.40 and 26.40 months for methylated cases. In addition, we confirmed that the MGMT promoter methylation was significantly (P = 0.0001) correlated with longer OS in IDH-mutant patients with GBM, independently of age, gender distribution, tumor type (primary or recurrent/secondary), and the extent of resection.

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

Keywords: Glioblastoma; O6methylguanine-DNA methyltransferase; isocitrate dehydrogenase; pyrosequencing; temozolomide.

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Conflict of interest statement

Conflict of interest statement No potential conflicts of interest are disclosed.

Figures

Figure 1
Figure 1
The workflow and sample selection criteria of this study.
Figure 2
Figure 2
The effect of IDH mutation on MGMT promoter methylation in GBM. (A) Heatmap showing the methylation levels of CpG sites 75–78 in the MGMT promoter in GBM samples with different IDH mutant status. For the MGMT promoter, the average methylation level of CpG sites 75–78 is denoted unmethy (unmethylated), <10%; weak methy (methylated), ≥10% and <30%; or methy, ≥30%. (B) The distribution of average methylation levels of CpG sites 75–78 was compared between IDH-wildtype and IDH-mutant GBM. ****P < 0.0001 calculated by the chi-square test. (C) The age of IDH-wildtype and IDH-mutant patients with GBM was compared. ****P < 0.0001 calculated by the nonparametric test. (D) The gender distribution was compared between IDH-wildtype and IDH-mutant patients with GBM.
Figure 3
Figure 3
Survival analysis of IDH-mutant GBM with different MGMT promoter methylation levels. (A, B) Kaplan-Meier curves for PFS and OS of IDH-mutant patients with GBM in different methylation groups. (C, D) Kaplan-Meier curves for PFS and OS of IDH-mutant patients with GBM stratified by different cutoff values. (E, F) Kaplan-Meier curves for PFS and OS of IDH-wildtype patients with GBM in different methylation groups. (G, H) Kaplan-Meier curves for PFS and OS of IDH-wildtype patients with GBM stratified by different cutoff values. P-value calculated by the log-rank test. MGMT promoter methylation levels were calculated on the basis of the average methylation levels of CpG sites 75–78.
Figure 4
Figure 4
Validation of the predictive value of MGMT promoter methylation in another cohort of TMZ treated IDH-mutant GBM. (A) Kaplan-Meier curves for PFS of IDH-mutant patients with GBM in different methylation groups. (B) Kaplan-Meier curves for PFS of IDH-mutant patients with GBM, stratified by different cutoff values. (C) Kaplan-Meier curves for OS of IDH-mutant patients with GBM in different methylation groups. (D) Kaplan-Meier curves for OS of IDH-mutant patients with GBM, stratified by different cutoff values. P-value calculated by the log-rank test. MGMT promoter methylation levels were calculated on the basis of the average methylation levels of CpG sites 76–79.
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