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The Changes in MGMT Promoter Methylation Status in Initial and Recurrent Glioblastomas.

ABSTRACT: To evaluate the mechanism of the development of therapeutic resistance after temozolomide treatment, we focused on changes in O(6)-methylguanine DNA methyltransferase (MGMT) and mismatch repair (MMR) between initial and recurrent glioblastomas. Tissue samples obtained from 24 paired histologically confirmed initial and recurrent adult glioblastoma patients who were initially treated with temozolomide were used for MGMT and MMR gene promoter methylation status and protein expression analysis using methylation-specific multiplex ligation probe amplification (MS-MLPA), methylation-specific polymerase chain reaction (MSP), and immunohistochemical staining. There was a significant decrease in the methylation ratio of the MGMT promoter determined by MS-MLPA, which was not detectable with MSP, and MGMT protein expression changes were not remarkable. However, there was no epigenetic variability in MMR genes, and a relatively homogeneous expression of MMR proteins was observed in initial and recurrent tumors. We conclude that the development of reduced methylation in the MGMT promoter is one of the mechanisms for acquiring therapeutic resistance after temozolomide treatment in glioblastomas.

SUBMITTER: Park CK

PROVIDER: S-EPMC3468928 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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The Changes in MGMT Promoter Methylation Status in Initial and Recurrent Glioblastomas.

Park Chul-Kee CK Kim Ja Eun JE Kim Ji Young JY Song Sang Woo SW Kim Jin Wook JW Choi Seung Hong SH Kim Tae Min TM Lee Se-Hoon SH Kim Il Han IH Park Sung-Hye SH

Translational oncology 20121001 5

To evaluate the mechanism of the development of therapeutic resistance after temozolomide treatment, we focused on changes in O(6)-methylguanine DNA methyltransferase (MGMT) and mismatch repair (MMR) between initial and recurrent glioblastomas. Tissue samples obtained from 24 paired histologically confirmed initial and recurrent adult glioblastoma patients who were initially treated with temozolomide were used for MGMT and MMR gene promoter methylation status and protein expression analysis usin ...[more]

PMID: 23066447

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Project description:Background and purposeO6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in primary and recurrent glioblastoma may change during treatment. The purpose of this study was to correlate MGMT promoter methylation status changes with DWI and DSC PWI features in patients with recurrent glioblastoma after standard treatment.Materials and methodsBetween January 2008 and November 2016, forty patients with histologically confirmed recurrent glioblastoma were enrolled. Patients were divided into 3 groups according to the MGMT promoter methylation status for the initial and recurrent tumors: 2 groups whose MGMT promoter methylation status remained, group methylated (n = 13) or group unmethylated (n = 18), and 1 group whose MGMT promoter methylation status changed from methylated to unmethylated (n = 9). Normalized ADC and normalized relative CBV values were obtained from both the enhancing and nonenhancing regions, from which histogram parameters were calculated. The ANOVA and the Kruskal-Wallis test followed by post hoc tests were performed to compare histogram parameters among the 3 groups. The t test and Mann-Whitney U test were used to compare parameters between group methylated and group methylated to unmethylated. Receiver operating characteristic curve analysis was used to measure the predictive performance of the normalized relative CBV values between the 2 groups.ResultsGroup methylated to unmethylated showed significantly higher means and 90th and 95th percentiles of the cumulative normalized relative CBV values of the nonenhancing region of the initial tumor than group methylated and group unmethylated (all P < .05). The mean normalized relative CBV value of the nonenhancing region of the initial tumor was the best predictor of methylation status change (P < .001), with a sensitivity of 77.78% and specificity of 92.31% at a cutoff value of 2.594.ConclusionsMGMT promoter methylation status might change in recurrent glioblastoma after standard treatment. The normalized relative CBV values of the nonenhancing region at the first preoperative MR imaging were higher in the MGMT promoter methylation change group from methylation to unmethylation in recurrent glioblastoma.

Project description:Glioblastoma (GBM) is the most malignant glioma, with a median overall survival (OS) of 14-16 months. Temozolomide (TMZ) is the first-line chemotherapy drug for glioma, but whether TMZ should be withheld from patients with GBMs that lack O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is still under debate. DNA methylation profiling holds great promise for further stratifying the responses of MGMT promoter unmethylated GBMs to TMZ. In this study, we studied 147 TMZ-treated MGMT promoter unmethylated GBM, whose methylation information was obtained from the HumanMethylation27 (HM-27K) BeadChips (n = 107) and the HumanMethylation450 (HM-450K) BeadChips (n = 40) for training and validation, respectively. In the training set, we performed univariate Cox regression and identified that 3,565 CpGs were significantly associated with the OS of the TMZ-treated MGMT promoter unmethylated GBMs. Functional analysis indicated that the genes corresponding to these CpGs were enriched in the biological processes or pathways of mitochondrial translation, cell cycle, and DNA repair. Based on these CpGs, we developed a 31-CpGs methylation signature utilizing the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm. In both training and validation datasets, the signature identified the TMZ-sensitive GBMs in the MGMT promoter unmethylated GBMs, and only the patients in the low-risk group appear to benefit from the TMZ treatment. Furthermore, these identified TMZ-sensitive MGMT promoter unmethylated GBMs have a similar OS when compared with the MGMT promoter methylated GBMs after TMZ treatment in both two datasets. Multivariate Cox regression demonstrated the independent prognostic value of the signature in TMZ-treated MGMT promoter unmethylated GBMs. Moreover, we also noticed that the hallmark of epithelial-mesenchymal transition, ECM related biological processes and pathways were highly enriched in the MGMT unmethylated GBMs with the high-risk score, indicating that enhanced ECM activities could be involved in the TMZ-resistance of GBM. In conclusion, our findings promote our understanding of the roles of DNA methylation in MGMT umethylated GBMs and offer a very promising TMZ-sensitivity predictive signature for these GBMs that could be tested prospectively.

Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

Dataset Information

The Changes in MGMT Promoter Methylation Status in Initial and Recurrent Glioblastomas.

Publications

The Changes in MGMT Promoter Methylation Status in Initial and Recurrent Glioblastomas.

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