Impact on prognosis of the regional distribution of MGMT methylation with respect to the CpG island methylator phenotype and age in glioma patients

Abstract

Clinical and molecular prognostic factors in gliomas include age, IDH mutation, the glioma CpG island methylator phenotype (G-CIMP+) and promoter methylation of the O(6)-methylguanine DNA-methyltransferase (MGMT) gene. Among these markers, a predictive value was reported in glioblastomas (GBM) for MGMT promoter methylation, in particular in elderly GBM patients. In this study, methylation data from 46 glioma samples with the Illumina 450K platform were obtained and extended using external data to include a total of 247 glioma samples. Methylation analysis of the whole MGMT gene with this platform revealed two strongly survival-associated CpG regions within the promoter and the gene body, which were confirmed in a reported dataset of high grade-gliomas. Methylation at the promoter (CpG 25, cg12981137 and the prognostic model MGMT-STP27) and at the gene body CpG 165 (cg07933035), were significantly associated with better overall survival, and strongly correlated with G-CIMP+ status. In this series, the prognostic value of MGMT methylation at the promoter was not observed in G-CIMP- cases, although around 50 % of them were MGMT-methylated. These results were also obtained in an homogeneously-treated series of chemoradiated G-CIMP- GBMs analyzed by MSP and qMSP, and confirmed in a reported pyrosequencing-analyzed series of gliomas. Interestingly, in contrast to the MGMT promoter, gene body methylation was of prognostic value in G-CIMP-patients older than 65 years. Our study highlights the relevance of the prognostic value of the different regions of methylation throughout the MGMT gene that could be affected by specific G-CIMP profiles and age groups.

Glioma CpG Island Methylator Phenotype (G-CIMP): Biological and Clinical Implications

“…Interestingly, better OS associated with MGMT promoter methylation was reported in patients harboring G-CIMP+ but not G-CIMP-GBM 47 . In addition, the predictive value of MGMT promoter methylation was described only in the context of IDH1/2 wildtype in anaplastic gliomas 49 .…”

“…IDH mutations, codeletion of 1p/19q, MGMT promoter methylation, and G-CIMP+ are N-O-D-17-00175R2 12 independent, favorable prognostic biomarkers 47 . However, combining some of them has shown to improve their individual prognostic value 7,18,47 .…”

“…IDH mutations, codeletion of 1p/19q, MGMT promoter methylation, and G-CIMP+ are N-O-D-17-00175R2 12 independent, favorable prognostic biomarkers 47 . However, combining some of them has shown to improve their individual prognostic value 7,18,47 . For instance, patients harboring a triple combination of 1p19q codeletion, IDH mutation and MGMT methylation had significantly better OS than those carrying the MGMT methylation biomarker alone 48 .…”

Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis

“…IDH gene was amplified by PCR; IDH1 codon 132 was analyzed by direct sequencing, and if no mutation was found, exon 4 of IDH2 was sequenced. These protocols have been described and verified in previous publication [26,27].…”

The Roles of DNA Methylation in the Stages of Cancer

“…MGMT hypermethylation, as previously discussed is also an important predictive biomarker for treatment success; patients with hypermethylated MGMT are more likely to respond to temozolamide treatment in brain cancers (characteristically, glioma phenotypes with IDH1 mutation) 40,51 . IDH1 mutation, observed in some gliomas, acute-myeloid leukemia (AML), cholangiocarcinoma (CC), and some chondrosarcomas is also an important prognostic biomarker, with prolonged survival observed in glioma, AML, and CC and response to therapy 19,52–54 .…”