Methylation of O6-Methylguanine DNA Methyltransferase and Loss of Heterozygosity on 19q and/or 17p Are Overlapping Features of Secondary Glioblastomas with Prolonged Survival

Abstract

Purpose: Recent data suggest that methylation of the DNA repair gene O 6 -methylguanine DNA methyltransferase (MGMT), by increasing the chemosensitivity of glioblastoma multiforme, is significantly associated with improved prognosis. Results in contradiction with these findings, however, are present in the literature and the clinical and genetic context framing MGMT methylation is poorly characterized. Experimental Design: To address these issues, we have investigated the MGMT methylation status, clinical and magnetic resonance imaging characteristics, and relevant genetic features (loss of heterozygosity on17p and19q, EGFR amplification, and p53 mutations) in a retrospective study on 86 patients affected by glioblastoma multiforme: 72 patients had a clinical history indicating de novo insurgence of the tumor and the remaining 14 were secondary glioblastoma multiforme. Results: MGMT methylation was detected by methylation-specific PCR in 41 of 86 cases (47.7%; Meth+). Progression-free survival and overall survival were significantly longer in Meth+ than in Meth-patients [10 versus 7 months (P = 0.003, log-rank test) and 18 versus 14 months (P = 0.0003, log-rank test), respectively]. Mixed-nodular enhancement at magnetic resonance imaging was significantly more frequent in Meth+ and secondary glioblastoma multiforme and ring enhancement in Meth-and primary glioblastoma multiforme (P < 0.005). MGMT methylation was more present in secondary glioblastoma multiforme (P = 0.006) and associated with loss of heterozygosity on 17p and/or 19q (P = 0.005). Conclusions: These observations suggest that MGMT methylation is part of a genetic signature of glioblastomas that developed from lower-grade gliomas.

The hypermethylation of the O6‐methylguanine‐DNA methyltransferase gene promoter in gliomas—correlation with array comparative genome hybridization results and IDH1 mutation

“…This finding is in agreement with published reports, showing that 45-68% of the glioblastomas have methylated MGMT promoters. (Hegi et al, 2004(Hegi et al, , 2005Eoli et al, 2007;Dunn et al, 2009;Jha et al, 2010). In our study, all oligoastrocytomas as well as nearly all oligodendrogliomas (93.3%) were methylated.…”

“…We found that gain of chromosome arm 7p, was more frequent in unmethylated than in methylated gliomas (75.0% vs. 40.4%, P < 0.05). Similarly, Eoli et al (2007) observed that EGFR amplification was more common in unmethylated than in methylated glioblastomas, even if the difference was not statistically significant. In contrast to this, Jha et al (2010) did not find a significant association of EGFR amplification with MGMT hypermethylation in glioblastomas.…”

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

“…The dependency of MGMT on the expression levels of mGlu3 receptors might help to explain the controversial data on the correlation between MGMT promoter methylation and patients' survival. [34][35][36][37][38][39][40] Our data may pave the way to a new strategy in the pharmacological treatment of malignant gliomas because mGlu3 receptor antagonists could be added to temozolomide or other DNA-alkylating agents for the optimization of adjuvant chemotherapy. The evidence that a combined treatment with temozolomide and LY341495 was still efficacious in restraining tumor growth when initiated 45 days after cell implantation in mice is particularly promising for translation into medical practice because of the long interval between onset and treatment of malignant gliomas.…”

Predicting MGMT Methylation Status of Glioblastomas from MRI Texture

“…Recently Eoli et al, in [4], found significant correlations between MGMT promoter methylation status and magnetic resonance (MR) imaging features. Motivated by these findings, this research presents an automated method for predicting the methylation status of the GBM based on texture analysis of T2, FLAIR and T1-postcontrast MRI scans.…”