Combinational analysis of IDH1/IDH2 mutations, 1p/19q deletions and MGMT promoter methylation for molecular testing of glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13152-e13152
Author(s):  
Xiaoni Zhang ◽  
Hongyue Qu ◽  
Qing Yang ◽  
Ziyang Zhu ◽  
Tanxiao Huang ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Genetic Alterations ◽  
Mgmt Promoter Methylation ◽  
Molecular Testing ◽  
Sequencing Data ◽  
Diagnosis And Prognosis ◽  
Mgmt Promoter ◽  
Ffpe Samples ◽  
Combinational Analysis ◽  
Idh2 Mutation

e13152 Background: Mutations in IDH1 and IDH2, co-deletion of 1p and 19q, and the hyper methylation of the MGMT promoter are the most reported genetic alterations in glioma tumors. Therefore, we designed a study to analyze the prevalence of these biomarkers in glioma, and the correlation of these biomarkers with diagnosis and prognosis. Methods: From September 2018 to January 2019, eighteen patients with primary glioma were prospectively enrolled. For each patient, freshly frozen tissue or FFPE samples were collected. DNA was extracted from these samples and sequenced to at least 5,000× coverage. IDH1/IDH2 mutations and 1p/19q deletions were detected from the sequencing data, whereas MGMT promoter methylation was evaluated by real-time fluorescence qPCR. Results: Of the eighteen patients, 44.4%(8/18) and 33.3%(6/18) harbored IDH1 /IDH2 mutations and 1p/19q deletions, respectively, and 72.2%(13/18) contained MGMT promoter hyper methylation. Within these patients, we found a correlation between IDH1/IDH2 mutation and 1p/19q deletion. Namely, among the 8 patients with a IDH1/IDH2 mutation, 75%(6/8) also contained a 1p/19q deletion, whereas none of the 10 patients with wide-type IDH1/IDH2 displayed the 1p/19q deletion. There was also a correlation between mutations at the loci and MGMT promoter hyper-methylation, specifically, 87.5%(7/8) of the patients with IDH1/IDH2 mutations also exhibited hyper-methylation in MGMT, whereas only hyper-methylation was observed in only 40% (4/10) of IDH1/IDH2 negative patients. Conclusions: From our preliminary result, IDH1/IDH2 mutations may be associated with 1p/19q deletion. To further verify this result, a larger, longitudinal study is ongoing at our institution.

scholarly journals Molecular Predictors of Progression-Free and Overall Survival in Patients With Newly Diagnosed Glioblastoma: A Prospective Translational Study of the German Glioma Network

2009 ◽  
Vol 27 (34) ◽  
pp. 5743-5750 ◽  
Author(s):  
Michael Weller ◽  
Jörg Felsberg ◽  
Christian Hartmann ◽  
Hilmar Berger ◽  
Joachim P. Steinbach ◽  
...  
Keyword(s):  
Overall Survival ◽  
Promoter Methylation ◽  
Genetic Alterations ◽  
Mgmt Promoter Methylation ◽  
Response To Therapy ◽  
Standards Of Care ◽  
Isocitrate Dehydrogenase 1 ◽  
Mutational Status ◽  
Mgmt Promoter ◽  
Idh1 Mutations

Purpose The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear. Patients and Methods Three hundred one patients with glioblastoma were prospectively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network. Two hundred fifty-eight patients had radiotherapy, 199 patients had temozolomide, 189 had both, and seven had another chemotherapy as the initial treatment. The tumors were investigated for TP53 mutation, p53 immunoreactivity, epidermal growth factor receptor, cyclin-dependent kinase CDK 4 or murine double minute 2 amplification, CDKN2A homozygous deletion, allelic losses on chromosome arms 1p, 9p, 10q, and 19q, O6-methylguanine methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutations. Results Median progression-free (PFS) and overall survival (OS) were 6.8 and 12.5 months. Multivariate analysis revealed younger age, higher performance score, MGMT promoter methylation, and temozolomide radiochemotherapy as independent factors associated with longer OS. MGMT promoter methylation was associated with longer PFS (relative risk [RR], 0.5; 95% CI, 0.38 to 0.68; P < .001) and OS (RR, 0.39; 95% CI, 0.28 to 0.54; P < .001) in patients receiving temozolomide. IDH1 mutations were associated with prolonged PFS (RR, 0.42; 95% CI, 0.19 to 0.91; P = .028) and a trend for prolonged OS (RR, 0.43; 95% CI, 0.15 to 1.19; P = .10). No other molecular factor was associated with outcome. Conclusion Molecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current standards of care. MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups.

scholarly journals Prognostic Implications of Epidermal and Platelet-derived Growth Factor Receptor Alterations in Two Cohorts of IDHwt Glioblastoma

2021 ◽  
Author(s):  
Iyad Alnahhas ◽  
Appaji Rayi ◽  
Maria del Pilar Guillermo Prieto Eibl ◽  
Shirley Ong ◽  
Pierre Giglio ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Medical Center ◽  
Genetic Alterations ◽  
Mgmt Promoter Methylation ◽  
Response To Treatment ◽  
Cancer Center ◽  
Dismal Prognosis ◽  
Idh Mutations ◽  
Mgmt Promoter ◽  
The Impact

Abstract Background Glioblastoma remains a deadly brain cancer with dismal prognosis. Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT promoter methylation have been proven to be prognostic and predictive to response to treatment in gliomas. In this manuscript, we aimed to correlate other mutations and genetic alterations with various clinical endpoints in patients with IDH-wild-type (IDHwt) glioblastoma. Methods We compiled a comprehensive clinically annotated database of IDHwt GBM patients treated at the Ohio State University Wexner Medical Center for whom we had mutational data through a CLIA-certified genomic laboratory. We then added data that is publicly available from Memorial Sloan Kettering Cancer Center through cBioPortal. Each of the genetic alterations (mutations, deletions and amplifications) served as a variable in univariate and multivariate Cox proportional hazard models. Results A total of 175 IDHwt GBM patients with available MGMT promoter methylation data from both cohorts were included in the analysis. As expected, MGMT promoter methylation was significantly associated with improved overall survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was 26.5 and 18 months, respectively (HR 0.45; p=0.003). Moreover, EGFR/ERBB alterations were associated with favorable outcome (HR of 0.37 (p=0.003), but only in MGMT promoter unmethylated GBM. We further found that patients with EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly worse outcome (HR 7.89; p=0.025). Conclusions Our data provides further insight into the impact of genetic alterations on various clinical outcomes in IDHwt GBM in two cohorts of patients with detailed clinical information and inspire new therapeutic strategies for IDHwt GBM.

scholarly journals Prognostic significance of MGMT promoter methylation in diffuse glioma patients

2019 ◽  
Vol 33 (1) ◽  
pp. 639-644
Author(s):  
Nikola Jovanović ◽  
Tatjana Mitrović ◽  
Vladimir J. Cvetković ◽  
Svetlana Tošić ◽  
Jelena Vitorović ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Prognostic Significance ◽  
Mgmt Promoter Methylation ◽  
Diffuse Glioma ◽  
Mgmt Promoter

scholarly journals Fast Routine Assessment of MGMT Promoter Methylation

2020 ◽  
Author(s):  
Ivana Bratic Hench ◽  
Rosa Della Monica ◽  
Lorenzo Chiariotti ◽  
Michel Bihl ◽  
Markus Tolnay ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter ◽  
Routine Assessment

scholarly journals MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System

2021 ◽  
Vol 22 (8) ◽  
pp. 3845
Author(s):  
Sarah Teuber-Hanselmann ◽  
Karl Worm ◽  
Nicole Macha ◽  
Andreas Junker
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Demyelinating Diseases ◽  
Brain Diseases ◽  
Tumor Biomarker ◽  
Mgmt Promoter ◽  
First Time

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.

scholarly journals Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BMC Cancer ◽  
2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Alessandra Fabi ◽  
Giulio Metro ◽  
Michelangelo Russillo ◽  
Antonello Vidiri ◽  
Carmine Maria Carapella ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

OC-0322: 4-miRNA signature and MGMT promoter methylation improve risk stratification in glioblastoma.

2020 ◽  
Vol 152 ◽  
pp. S169-S170
Author(s):  
K. Unger ◽  
D.F. Fleischmann ◽  
V. Ruf ◽  
J. Felsberg ◽  
D. Piehlmaier ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Mirna Signature ◽  
Improve Risk Stratification ◽  
Mgmt Promoter

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.

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