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 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 MGMT methylation alterations in brain cancer following organochlorine pesticides exposure

2021 ◽  
Vol 8 (1) ◽  
pp. 47-53
Author(s):  
Fatemeh Yousefi ◽  
Gholamreza Asadikaram ◽  
Saeid Karamouzian ◽  
Moslem Abolhassani ◽  
Vahid Moazed ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Organochlorine Pesticides ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Gene Promoter ◽  
Primary Brain Tumor ◽  
Mgmt Methylation ◽  
Specific Pcr ◽  
Mgmt Promoter

Background: Alterations in the methylation levels of tumor suppressor genes are considered as one of the essential aspects of malignancies. The present study explored the association of O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, as a tumor suppressor, with some organochlorine pesticides (OCPs) in primary brain tumor (PBT) patients. Methods: The present study was conducted on a total of 73 PBT patients. The patients’ serum was analyzed using gas chromatography for seven OCP derivatives. The methylation-specific PCR (MSP) method was also used to determine the methylation status of the MGMT promoter. Results: The current findings demonstrated that the methylation of MGMT promoter occurred in 22 out of 34 glioma cases (64%), but in only one out of 35 meningioma cases. No MGMT promoter methylation was observed in other PBT, hemangioma, and anaplastic medulloblastoma stages. Besides, there were significant associations between MGMT methylation and γ-HCH (odds ratio [OR]: 1.50; 95% CI: 1.03- 2.40, P=0.04), 4,4DDE (OR: 1.44; 95% CI: 1.01- 2.05, P=0.02), 2,4 DDT (OR: 1.23; CI: 1.04- 1.45, P=0.03), and 4,4DDT (OR: 1.46; CI: 1.23- 2.15, P=0.02) in glioma patients. Conclusion: The results of the study suggested that the hypermethylation of the MGMT promoter in glioma patients is associated with increased OCPs in their serum, especially γ- HCH, 4,4DDE, 2,4DDT, and 4,4DDT. Moreover, it may lead to the hypermethylation of the MGMT promoter gene. Hence, it can be concluded that exposure to OCPs may potentially induce glioma.

scholarly journals NIMG-39. UTILITY OF PHYSIOLOGIC MR METRICS IN DISTINGUISHING TRUE-PROGRESSION FROM PSEUDOPROGRESSION IN GLIOBLASTOMAS STRATIFIED BY MGMT PROMOTER METHYLATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii156-ii156
Author(s):  
Sanjeev Chawla ◽  
Sumei Wang ◽  
Amir Nazem ◽  
Morgan Burke ◽  
Nasrallah MacLean ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Promoter Methylation ◽  
Cerebral Blood Volume ◽  
Mean Diffusivity ◽  
Gene Promoter ◽  
Threshold Value ◽  
Mgmt Promoter Methylation ◽  
P Value ◽  
Methyl Transferase ◽  
Mgmt Promoter

Abstract BACKGROUND Methylation of O6-methyl-guanine-methyl transferase MGMT gene promoter is associated with favorable prognosis in glioblastoma (GBM) patients treated with surgery and chemoradiation therapy (CRT). OBJECTIVE To investigate potential of diffusion and perfusion MR imaging in distinguishing TP from PsP in GBM patients stratified by MGMT status. METHODS A cohort of 92 patients demonstrating new/increasing enhancing lesions within six months of completion of CRT underwent 3T MR imaging. Median values of mean diffusivity (MD), fractional anisotropy (FA), anisotropy coefficients [linear(CL), planar (CP), and spherical (CS)] and maximum relative cerebral blood volume (rCBVmax) were computed from enhancing lesions. Patients were classified as TP (n=65) and PsP (n=27) based on histopathology or follow-up MRI scans. Mann-Whitney, independent-sample T-tests and receiver operating characteristic (ROC) curve analyses were performed to distinguish TP from PsP. Of 92 patients, MGMT status was available from 60 patients [MGMT-methylated (n=23) and MGMT-unmethylated (n=37)]. Statistical analyses were also performed in distinguishing TP (n=15) and PsP (n=8) from MGMT-methylated and MGMT-unmethylated subgroups (TP=28; PsP=9). A p-value of 0.05 was considered significant. RESULTS Significantly higher rCBVmax and FA and a trend towards higher CP were observed in TP compared to PsP. Among these parameters, rCBVmax had the best sensitivity=62%, specificity=68% and accuracy=67% in distinguishing TP from PsP. ROC analysis revealed sensitivity=54%, specificity=78% and accuracy=68% after combination of these parameters. In MGMT methylated patients, only rCBVmax was significantly higher in TP than in PsP with sensitivity=79%, specificity=67% and accuracy=74% at a threshold rCBVmax value of 2.23. In MGMT unmethylated group, a trend towards higher rCBVmax was observed in TP than in PsP with sensitivity=67%, specificity=77%, accuracy=69%, threshold value=2.89. CONCLUSION Physiologic imaging parameters demonstrate variable diagnostic values for detecting PsP in GBM patients stratified by MGMT status. The best parameter in distinguishing TP from PsP was rCBVmax in patients demonstrating MGMT promoter methylation.

Exploiting DNA repair alterations in metastatic pancreatic cancer (mPAC): Is MGMT methylation a new therapeutic target?

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15770-e15770
Author(s):  
Monica Niger ◽  
Federica Morano ◽  
Sara Manglaviti ◽  
Alessandra Raimondi ◽  
Federica Perrone ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Repair ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Ffpe Tissue ◽  
Metastatic Pancreatic Cancer ◽  
Mgmt Methylation ◽  
Mgmt Promoter

e15770 Background: Metastatic pancreatic cancer (mPAC) has a poor prognosis, with few therapeutic options and an overall survival (OS) at 5 years < 5%. O6-methylguanine-DNA methyltransferase ( MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Its promoter methylation results in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). Of note, both reductions in MGMT expression and MGMT promoter methylation are described in a variety of gastrointestinal malignancies, including colorectal cancer (CRC). Here we present data on MGMT methylation tested in mPAC pts treated at our center. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI). Furthermore, the exploratory analysis of MGMT status was performed via methyl specific PCR (EZ DNA Methylation-Gold™ KIT) to assess promoter methylation, and immunohistochemistry (IHC) was done to assess protein expression. Results: Archived FFPE tissue sections obtained from 60 pts treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to December 2018 were analyzed. 47 samples (78%) had adequate tissue for extended analyses. As expected, 44 (93%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 pts (6%), respectively. MGMT promoter methylation was identified in 14 pts (29%), with low/negative MGMT protein expression in 7 (14%). Interestingly, amongst MGMT methylated pts, there were 3 (21%) BRCA1/2 somatic mutant and 1 (7%) MSI, suggesting possible genomic instability. Conclusions: MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 29% of patients with mPAC. This data warrant further prospective confirmation, but there is definitely a growing interest in the role of MGMT methylation as a predictive and prognostic biomarker in mPAC.

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.

MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2051-2051
Author(s):  
K. D. Aldape ◽  
G. Jones ◽  
M. Wang ◽  
M. Hegi ◽  
R. C. Janzer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Real Time ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Phase Iii ◽  
Major Advance ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Mgmt Promoter ◽  
Central Pathology

2051 Background: MGMT promoter methylation has been described as a prognostic marker in glioblastoma (GBM) and may be associated with chemosensitivity to alkylating agents. This study determined the feasibility of real-time determination of MGMT promoter methylation testing in a large international phase III clinical trial. Methods: Paraffin tumor blocks were obtained from patients registered onto RTOG 0525 then distributed to one of two central pathology labs: MD Anderson (Houston TX, K. Aldape) or CHUV (Lausanne, CH, R. Janzer). After histologic confirmation of GBM, unstained slides (40 microns of tumor tissue) were sent to the testing laboratories. Results were used for randomization into a treatment arm. MGMT methylation was assessed using methylation specific real-time PCR (MSP). The assay determined the number of copies of both methylated MGMT and of beta-actin (ACTB) in the sample. The ACTB copy number was used to assess the quality and quantity of the sample DNA. Results: Results were available for 995 samples. Following MSP samples were categorized into one of five possible results: failed (2, 0.2%), methylated (302, 30.2%), non-methylated (602, 60.2%), indeterminate (62, 6.2%), and invalid (27, 2.7%). Among cases that were evaluable as either methylated or unmethylated (n = 904) the MGMT promoter methylation rate in newly diagnosed GBM was approximately 1/3 (33.4%), a rate that is somewhat lower than prior reports. The average time from receipt of sample at the central pathology laboratory to reporting of results was 9.3 days. The time required decreased over the course of the clinical trial. This was due, in part, to training of the sites to deliver samples just before the start of runs. Conclusions: The results demonstrate the feasibility of performing real-time MGMT methylation testing, a tumor based assay, as a stratification factor in a multinational clinical trial. This study confirms that treatment decisions based on the molecular characteristics of the tumor are feasible, thereby providing opportunities to develop more molecularly-based tumor stratification or selection, a major advance in developing personalized treatment regimens. No significant financial relationships to disclose.

THE CORRELATION AND PROGNOSTIC SIGNIFICANCE OF MGMT PROMOTER METHYLATION AND MGMT PROTEIN IN GLIOBLASTOMAS

Neurosurgery ◽  
2009 ◽  
Vol 65 (5) ◽  
pp. 866-875 ◽  
Author(s):  
Van Thang Cao ◽  
Tae-Young Jung ◽  
Shin Jung ◽  
Shu-Guang Jin ◽  
Kyung-Sub Moon ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Protein Expression ◽  
Median Survival ◽  
Promoter Methylation ◽  
Immunohistochemical Staining ◽  
Prognostic Significance ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Mgmt Expression ◽  
Mgmt Promoter

Abstract OBJECTIVE The aim of this study was to evaluate the correlation and prognostic significance of MGMT promoter methylation and protein expression in patients with glioblastoma. METHODS Eighty-three patients with glioblastoma underwent surgery followed by radiotherapy and temozolomide chemotherapy between October 2000 and June 2008. To investigate the correlation between MGMT methylation and MGMT expression, methylation-specific polymerase chain reaction (MSP) and immunohistochemical staining was performed. To analyze the correlation between MGMT methylation and MGMT expression according to location, biopsies were obtained from 37 different sites within the tumors in 12 patients. Age, sex, Karnofsky Performance Scale status, extent of removal, chemotherapeutic methods, and MGMT promoter methylation and protein expression were analyzed as prognostic factors. RESULTS The total median survival was 15.8 months (range, 12.6–19.1 months). The results of MSP were the same at various sites in 12 patients. A correlation between MSP and immunohistochemical staining was observed in 50% of the patients. In 73 patients, negative MGMT expression was detected in 70.5% of 44 patients with MGMT promoter methylation, and positive expression was observed in 55.2% of the 29 patients with unmethylated promoters. Multivariate analysis revealed that the extent of removal (P = 0.001) and the combination of MGMT promoter methylation and negative MGMT expression (median survival, 20.06 months; P = 0.006) were significantly associated with longer survival. CONCLUSION We report the feasibility of using MSP combined with immunohistochemical staining as a prognostic factor. The results of the present study suggest that MGMT promoter methylation in combination with negative MGMT expression might be a good prognostic factor in patients with glioblastoma.

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.

Sign in / Sign up

Export Citation Format

Share Document