scholarly journals Glioblastoma recurrence and the role of MGMT promoter methylation

2018 ◽  
Author(s):  
Katie Storey ◽  
Kevin Leder ◽  
Andrea Hawkins-Daarud ◽  
Kristin Swanson ◽  
Atique U. Ahmed ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Inhibitory Effect ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Repair Gene ◽  
Downward Shift ◽  
Dna Repair Gene ◽  
Mgmt Promoter

AbstractTumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT has been associated with sensitivity to TMZ, while increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors. However, the evolutionary processes driving this shift, and more generally the emergence and growth of TMZ-resistant tumor subpopulations, are still poorly understood. Here we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM (surgery, chemotherapy and radiation). We first find that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for GBM patients with high and low levels of MGMT methylation at diagnosis.

scholarly journals Glioblastoma Recurrence and the Role of O6-Methylguanine–DNA Methyltransferase Promoter Methylation

2019 ◽  
pp. 1-12 ◽  
Author(s):  
Katie Storey ◽  
Kevin Leder ◽  
Andrea Hawkins-Daarud ◽  
Kristin Swanson ◽  
Atique U. Ahmed ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Inhibitory Effect ◽  
Mgmt Methylation ◽  
Repair Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Downward Shift ◽  
Dna Repair Gene

Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O6-methylguanine–DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM—surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis.

scholarly journals Favorable role of IDH1/2 mutations aided with MGMT promoter gene methylation in the outcome of patients with malignant glioma

2020 ◽  
pp. FSO663
Author(s):  
Arshad A Pandith ◽  
Iqbal Qasim ◽  
Shahid M Baba ◽  
Aabid Koul ◽  
Wani Zahoor ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Gene Promoter ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Specific Pcr ◽  
Mgmt Promoter ◽  
Promoter Gene ◽  
Prognostic Outcome

Aim: The implications of molecular biomarkers IDH1/2 mutations and MGMT gene promoter methylation were evaluated for prognostic outcome of glioma patients. Materials & methods: Glioma cases were analyzed for IDH1/2 mutations and MGMT promoter methylation by DNA sequencing and methylation-specific PCR, respectively. Results: Mutations found in IDH1/2 genes totaled 63.4% (N = 40) wherein IDH1 mutations were significantly associated with oligidendrioglioma (p = 0.005) and astrocytoma (p = 0.0002). IDH1 mutants presented more, 60.5% in MGMT promoter-methylated cases (p = 0.03). IDH1 mutant cases had better survival for glioblastoma and oligodendrioglioma (log-rank p = 0.01). Multivariate analysis confirmed better survival in MGMT methylation carriers (hazard ratio [HR]: 0.59; p = 0.031). Combination of both biomarkers showed better prognosis on temozolomide (p < 0.05). Conclusion: IDH1/2 mutations proved independent prognostic factors in glioma and associated with MGMT methylation for better survival.

scholarly journals Tim-3 protein expression with MGMT methylation status in glioblastoma and association with survival

2020 ◽  
Author(s):  
ji zhang ◽  
Xiaoli Wang ◽  
Shengquan Ye ◽  
Lijiao Liang ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Protein Expression ◽  
Promoter Methylation ◽  
Immune Checkpoint ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Prognostic Significance ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Methylguanine Dna Methyltransferase ◽  
Mgmt Promoter

Abstract Background Understanding the molecular landscape of glioblastoma (GBM) is increasingly crucial for its therapy. Immune checkpoint molecules motivated the emergence of immune checkpoint-targeting therapeutic strategies. However, the prognostic significance of the immune checkpoint molecule T cell immunoglobulin mucin-3 (Tim-3) on tumor-infiltrating immune cells (TIICs) and O-6-Methylguanine-DNA methyltransferase (MGMT) methylation status remains to be fully elucidated. We aimed to develop an MGMT methylation status-associated immune prognostic signature for predicting prognosis in GBMs.Patients and Methods: A total of 84 patients with newly diagnosed GBM were involved. MGMT methylation status was retrospectively analyzed and the expression level of Tim-3 protein was investigated using immunohistochemistry (IHC). The correlation between Tim-3 protein expression and MGMT methylation status, and the prognosis was explored.Results The obtained data showed that Tim-3 protein was expressed at different levels in GBMs. Mesenchymal expression of Tim-3 protein in these tissues was 73.81% (62/84), including low 15.48% (13/84), moderate 7.14% (6/84) and strong expression 51.19% (43/84), respectively. Of the 48 patients whose tumors tested positive for MGMT methylation, the remaining 36 patients was negative.Conclusions We profiled the immune status in GBM with MGMT promoter methylation and established a local immune signature for GBM, which could independently identify patients with a favorable prognosis, indicating the relationship between prognosis and immune. MGMT promoter methylation with lower Tim-3 protein expression was statistically significantly associated with better survival.

scholarly journals XGBoost Improves Classification of MGMT Promoter Methylation Status in IDH1 Wildtype Glioblastoma

2020 ◽  
Vol 10 (3) ◽  
pp. 128 ◽  
Author(s):  
Nguyen Quoc Khanh Le ◽  
Duyen Thi Do ◽  
Fang-Ying Chiu ◽  
Edward Kien Yee Yapp ◽  
Hui-Yuan Yeh ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Gradient Boosting ◽  
Mgmt Methylation ◽  
Promoter Methylation Status ◽  
Extreme Gradient Boosting ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Approximately 96% of patients with glioblastomas (GBM) have IDH1 wildtype GBMs, characterized by extremely poor prognosis, partly due to resistance to standard temozolomide treatment. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a crucial prognostic biomarker for alkylating chemotherapy resistance in patients with GBM. However, MGMT methylation status identification methods, where the tumor tissue is often undersampled, are time consuming and expensive. Currently, presurgical noninvasive imaging methods are used to identify biomarkers to predict MGMT methylation status. We evaluated a novel radiomics-based eXtreme Gradient Boosting (XGBoost) model to identify MGMT promoter methylation status in patients with IDH1 wildtype GBM. This retrospective study enrolled 53 patients with pathologically proven GBM and tested MGMT methylation and IDH1 status. Radiomics features were extracted from multimodality MRI and tested by F-score analysis to identify important features to improve our model. We identified nine radiomics features that reached an area under the curve of 0.896, which outperformed other classifiers reported previously. These features could be important biomarkers for identifying MGMT methylation status in IDH1 wildtype GBM. The combination of radiomics feature extraction and F-core feature selection significantly improved the performance of the XGBoost model, which may have implications for patient stratification and therapeutic strategy in GBM.

scholarly journals BIOM-02. IDENTIFYING MGMT ALTERATIONS AS BIOMARKERS OF SURVIVAL IN LUNG ADENOCARCINOMA WITH BRAIN METASTASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
Yasin Mamatjan ◽  
Jeffrey Zuccato ◽  
Fabio Moraes ◽  
Michael Cabanero ◽  
Wumairehan Shali ◽  
...  
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Promoter Methylation ◽  
Patient Survival ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Mgmt Promoter ◽  
Egfr Mutant ◽  
Mgmt Promoter Methylation Status

Abstract EGFR-mutant lung adenocarcinomas (EGFRm-LUAD) have a higher risk of developing brain metastases (BM) compared to non-EGFR-mutant tumors. BM development has significant prognostic impact and leads to poorer patient survival. MGMT promoter methylation is known to determine response to therapy in other cancer types including intracranial gliomas but has not been investigated in EGFRm-LUAD BM. This work aims to assess whether MGMT promoter methylation predicts patient survival or BM development in EGFRm-LUAD patients. A large cohort of 90 primary EGFRm-LUAD tumors, of which 33 (37%) developed BM, were profiled using the Illumina Infinium MethylationEPIC Bead chip. Using the previously reported MGMT-STP27 approach that uses two CpG sites to predict MGMT methylation status, Cox modeling was performed to assess whether MGMT methylation status correlates with overall survival independent of other clinical factors. MGMT methylation significantly predicted poorer survival in EGFRm-LUAD patients that developed BM (p=0.0003) and did not develop BM (p=0.003). A multivariate cox analysis, adjusting for cancer stage and smoking status as potential confounders, showed that MGMT methylation (HR=6.2, 95%CI:2.2–17.4, p=0.0005) and BM development (HR=2.6, 95%CI:1.3–5.3, p=0.007) were both independently predictive of worse overall survival in EGFRm-LUAD patients. This finding of poorer survival in MGMT methylated EGFRm-LUAD is validated in an independent LUAD patient cohort. Total mutation burden, calculated by the number of mutations per megabase of DNA, was substantially higher in MGMT methylated tumours with an interquartile range (IQR) of 58 (30–71) compared to MGMT unmethylated tumours with the IQR of 5.5 (4.3–6.1) resulting p-value of 0.01 for this comparison. Overall, this work shows that MGMT promoter methylation status is an important prognostic biomarker in LUAD patients. MGMT promoter methylation status in EGFRm–LUAD patients with BM may be used to guide patient treatment with potentially a greater extent of treatment for high-risk patients.

scholarly journals BIOM-31. PROGNOSTIC VALUE OF MGMT METHYLATION IN IDH MUTANT GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Keng Lam ◽  
Blaine Eldred ◽  
Bryan Kevan ◽  
Matthew Ji ◽  
Jerry Lou ◽  
...  
Keyword(s):  
Los Angeles ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Cox Regression ◽  
Methylation Status ◽  
Hazard Ratio ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Cox Regression Analysis ◽  
Mgmt Promoter

Abstract BACKGROUND Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those with IDH wildtype. Previous studies have also shown the predictive value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma. However, little is known in the prognostic value of MGMT methylation status for IDH mutant gliomas. METHODS We retrospectively identified IDH mutant gliomas patients from University of California Los Angeles and Kaiser Permanente Los Angeles that had been tested for MGMT methylation status. We performed Kaplan-Meier and Cox regression analyses of overall survival (OS) to compare the MGMT methylated versus MGMT unmethylated patients. RESULTS We identified a total of 375 IDH mutant gliomas with MGMT testing. Subgroups include 52 glioblastoma, 191 astrocytoma, and 132 oligodendroglioma. The median OS for all MGMT methylated patients was 20.0 years and for unmethylated patients 14.3 years (log-rank P=0.008). Cox regression analysis also confirmed patients with MGMT methylated to have better survival than those with MGMT unmethylated (hazard ratio of 0.47, P= 0.005). During subgroup analysis, MGMT methylated glioblastoma patients have a median OS of 13.7 years compared to MGMT unmethylated patients 3.2 years (log-rank P=0.004) with a hazard ratio of 0.14 (P=0.005). However, we see no difference yet for astrocytoma (hazard ratio of 1.09, P= 0.81) and oligodendrogliomas (hazard ratio of 0.36, P= 0.193), possibly as a result of immature survival data. CONCLUSIONS MGMT promoter methylation is associated with better outcomes in IDH mutant glioblastoma patients. Progression free survival will be analyzed to determine predictive benefit of MGMT methylation for other glioma subtypes.

scholarly journals PATH-05. RAPID SIMULTANEOUS IDH MUTATION AND MGMT METHYLATION STATUS ASSESSMENT IN GLIOMA PATIENTS USING CRISPR-Cas9-TARGETED NANOPORE SEQUENCING

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi143-vi144
Author(s):  
Thidathip Wongsurawat ◽  
Piroon Jejaroenpun ◽  
Annick DeLoose ◽  
David Ussery ◽  
Duah Alkam ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Diffuse Glioma ◽  
Nanopore Sequencing ◽  
Idh Mutation ◽  
Mgmt Methylation ◽  
Mgmt Promoter ◽  
Generation Sequencing ◽  
Mgmt Promoter Methylation Status

Abstract Molecular classification of diffuse glioma enables more-precise diagnosis, prognosis, and treatment decisions. Currently, combination of two molecular markers, isocitrate dehydrogenase 1 and 2 (IDH1/ IDH2) gene mutation information and O6-Methylguanine-DNA-methyltranferase (MGMT) methylation status, are the main prognostic biomarkers of newly diagnosed diffuse gliomas. Furthermore, an accurate interpretation of MGMT-promoter methylation status is essential to determining which patients benefit from temozolomide (TMZ) therapy. The presence of an IDH mutation can be easily tested by PCR or next generation sequencing. However, there remains controversy with the identification of MGMT-promoter methylation status since there exists variable degrees of methylation and no clear consensus on cutoff values for “methylated” or “unmethylated” have been defined. To be best suited for routine clinical setting and research use, the optimal test should be reproducible, readily available, and timely. Therefore, we explored the feasibility of single-molecule nanopore third generation sequencing technology to comprehensively assess both mutation and methylation status simultaneously. This technology allows methylation detection directly from the native DNA sequence without requiring bisulfite treatment which reduces processing time. To specifically study IDH1, IDH2, and MGMT-promoter loci, we combined the CRISPR-Cas9 system to cut desired DNA fragments in a non–amplification dependent fashion. In addition, a data analysis pipeline was developed to quantitatively detect methylation. We applied our approach on human DNA controls, glioma cell lines and 4 patient brain tumor samples and were enabled to assess mutation and methylation status of targeted loci within 1.5 days. The promise of CRISPR-Cas9-targeted nanopore sequencing in accelerating and improving the molecular diagnostics of diffuse glioma will be illustrated in this meeting. These efforts are in line with improving precision medicine and can be applied to all cancer types.

scholarly journals Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Larraitz Egaña ◽  
Jaione Auzmendi-Iriarte ◽  
Joaquin Andermatten ◽  
Jorge Villanua ◽  
Irune Ruiz ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Free Survival ◽  
Methylguanine Dna Methyltransferase ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

scholarly journals The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma

Medicina ◽  
2019 ◽  
Vol 55 (2) ◽  
pp. 34
Author(s):  
Nikola Jovanović ◽  
Tatjana Mitrović ◽  
Vladimir J. Cvetković ◽  
Svetlana Tošić ◽  
Jelena Vitorović ◽  
...  
Keyword(s):  
Overall Survival ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Primary Glioblastoma ◽  
Mgmt Promoter ◽  
The Impact

Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter as a key prognostic factor in primary glioblastoma. The aim of our study was to screen Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Materials and methods: A cohort of 30 Serbian primary glioblastoma patients treated with radiation therapy and chemotherapy were analyzed for MGMT promoter methylation and correlated with clinical data. Results: MGMT methylation status was determined in 25 out of 30 primary glioblastomas by methylation-specific PCR (MSP). MGMT promoter hypermethylation was detected in 12 out of 25 patients (48%). The level of MGMT promoter methylation did not correlate with patients’ gender (p = 0.409), age (p = 0.536), and OS (p = 0.394). Treatment with TMZ significantly prolonged the median survival of a patient (from 5 to 15 months; p < 0.001). Conclusions: Due to a small cohort of primary GBM patients, our study is not sufficient for definitive conclusions regarding the prognostic value of MGMT methylation for the Serbian population. Our preliminary data suggest a lack of association between MGMT promoter methylation and overall survival and a significant correlation of TMZ treatment with overall survival. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma.

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