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.

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and relation to 1p/19q loss in low grade gliomas: A GICNO study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20064-20064 ◽  
Author(s):  
L. Nicolardi ◽  
R. Bertorelle ◽  
L. Bonaldi ◽  
A. Compostella ◽  
A. Roma ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Tumor Localization ◽  
Response To Chemotherapy ◽  
Mgmt Promoter ◽  
The Impact

20064 Background: 1p and 19q deletions have been associated with a favorable response to chemotherapy and a good prognosis in patients (pts) with oligodendroglioma. MGMT promoter methylation has been associated with a longer survival in pts with glioblastoma who receive alkylating agents. As yet, there are no data on the expression of MGMT, and on the relationship between 1p/19q deletions and MGMT promoter methylation in low grade glioma (LGG). Methods: Pts that received a first line chemotherapy regimen with temozolomide for progressive LGG were enrolled in the study, designed to investigate the correlation between MGMT methylation status and 1p/19q deletions in this setting. 1p/19q deletions were analysed by FISH, and MGMT promoter methylation by methylation specific PCR (MSP). Results: Seventy-five pts (26 females, 49 males; median age 42 years: range 22–68 years) were accrued. Of these, 48 (64%) had oligodendrogliomas (O), 19 (25.3%) astrocytomas (A), and 8 (10.6%) oligoastrocytomas (OA); 44 (58.7%) had a history of epilepsy, 41 (54.7%) had a frontal tumor localization, 27 (36%) had MRI contrast enhancing lesions, and 35 (46.7%) had been pre-treated with radiotherapy. 1p/19q deletions, evaluable in 58 pts (77.3%), were both present in 36 pts (62%), (3 being A and 2 OA); 18 pts (31%) had no loss; 1 pt (1.7%) had 1p loss; 3 pts (5.2%) 19q loss. Combined 1p and 19q loss was not correlated with a frontal localization (p = 0.12), median age (0.47) and/or gender (0.62). MGMT promoter methylation, present in 17 (56.6%) of 30 assessable cases, was significantly associated with combined 1p/19q deletions (p = 0.03). MGMT promoter methylation was not significantly associated with age (p = 0.46), gender (p = 0.2), tumor localization (p = 0.12) and/or histology (0.37). Conclusions: 1p/19q deletions are strictly correlated to histology and to MGMT promoter methylation; further prospective trials are required to clarify the impact of these molecular signatures on clinical outcome. No significant financial relationships to disclose.

5-day dosing schedule of temozolomide in relapsed sensitive or refractory small cell lung cancer (SCLC) and methyl-guanine-DNA methyltransferase (MGMT) analysis in a phase II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
Alexander Edward Dela Cruz Drilon ◽  
Kadota Kyuichi ◽  
Kety H Huberman ◽  
Camelia S. Sima ◽  
John Joseph Fiore ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Response Rate ◽  
Alkylating Agents ◽  
Parp Inhibitor ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Dosing Schedule ◽  
Mgmt Expression ◽  
Mgmt Promoter

7052 Background: MGMT promoter methylation and loss of MGMT activity are associated with improved sensitivity to alkylating agents. We recently reported that the oral alkylating agent temozolomide is active in 2nd- and 3rd-line treatment of relapsed SCLC at 75mg/m2/day for 21 out of 28 days (Pietanza et al, Clin Can Res 2012). Here we evaluate the 5-day dosing schedule of temozolomide in a second cohort of patients and analyze MGMT activity in both cohorts of patients on the same study. Methods: Patients with disease progression after 1 or 2 prior chemotherapy regimens received temozolomide at 200mg/m2/day for 5 out of 28 days (n=25). Those with sensitive (S-SCLC, n=16) and refractory (R-SCLC, n=9) disease were enrolled to assess safety. Available tumor tissue from patients treated according to either schedule was assessed for MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry (IHC). Results: An overall response rate of 12% was noted (3 partial responses: 1 S-SCLC, 2 R-SCLC). 4 patients had stable disease for at least 3 cycles. Median progression-free survival and overall survival for all patients were 1.3 months and 7.9 months, respectively. Grade ≥3 thrombocytopenia and neutropenia was observed in 20% with a shorter mean duration of myelosuppression compared to the 21-day schedule. Results from MGMT evaluation of tumor samples from both dosing schedules were combined. Promoter methylation of MGMT was not significantly associated with response (p=0.23). However, patients that lacked MGMT expression by IHC had a higher response rate compared to those with MGMT-positive tumors (43% vs. 13%, p = 0.052; see table). Conclusions: The 5-day dosing schedule of temozolomide is both active and safe in patients with relapsed SCLC. A strong trend toward increased response was demonstrated in patients with MGMT-negative tumors compared to patients with MGMT-positive tumors by IHC. A trial combining temozolomide with the PARP inhibitor, ABT888, is planned. [Table: see text]

scholarly journals P14.108 Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii93-iii94
Author(s):  
K Seystahl ◽  
B Hentschel ◽  
S Loew ◽  
D Gramatzki ◽  
J Felsberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agent ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Recurrent Glioblastoma ◽  
Mgmt Promoter Methylation ◽  
University Hospital ◽  
Mgmt Promoter ◽  
First Recurrence

Abstract BACKGROUND The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status PATIENTS AND METHODS We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n=260) or bevacizumab without or with irinotecan (n=84) for first recurrence of glioblastoma. Outcome was stratified for MGMT status and cross-over to bevacizumab or alkylators at further tumor progression. RESULTS Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agent chemotherapy at first recurrence was longer than for patients receiving bevacizumab (11.1 versus 7.4 months, p<0.001). The use of alkylating agents was associated with longer PRS-1 for patients with a methylated versus an unmethylated MGMT promoter (p=0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in the group receiving alkylating chemotherapy compared to bevacizumab for patients with a methylated (p<0.001) or unmethylated MGMT promoter (p=0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p=0.002). CONCLUSION This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of a methylated MGMT promoter.

scholarly journals ACTR-05. PROCARBAZINE AND CCNU CHEMOTHERAPY FOR RECURRENT GLIOBLASTOMA WITH MGMT PROMOTER METHYLATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi13-vi13
Author(s):  
Yong Kil Hong ◽  
Seung Ho Yang
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Target Therapy ◽  
Malignant Gliomas ◽  
Chemotherapeutic Agents ◽  
Recurrent Glioblastoma ◽  
Mgmt Promoter Methylation ◽  
Recurrent Glioblastoma Multiforme ◽  
Serious Adverse Events ◽  
Mgmt Promoter

Abstract BACKGROUND While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6). RESULTS One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM

scholarly journals Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

2008 ◽  
Vol 26 (25) ◽  
pp. 4189-4199 ◽  
Author(s):  
Monika E. Hegi ◽  
Lili Liu ◽  
James G. Herman ◽  
Roger Stupp ◽  
Wolfgang Wick ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Tumor Tissue ◽  
Alkylating Agents ◽  
Malignant Gliomas ◽  
Chemotherapy Resistance ◽  
Mgmt Promoter Methylation ◽  
Hematologic Toxicity ◽  
Major Mechanism ◽  
Mgmt Promoter ◽  
Methylguanine Methyltransferase

Resistance to alkylating agents via direct DNA repair by O6-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O6-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

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

MGMT Promoter Methylation as an Epigenetic Biomarker for the Estimation of Chemosensitivity towards the Alkylating Agents Based Chemotherapies

2017 ◽  
Vol 17 ◽  
pp. S391-S392
Author(s):  
Natalia Cucu ◽  
V. Constantinescu ◽  
Lilia Matei ◽  
Mihaela Dragomir ◽  
Silvia Aposteanu ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Alkylating Agents ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter ◽  
Epigenetic Biomarker

scholarly journals GENE-35. MGMT PROMOTER METHYLATION IN NEWLY DIAGNOSED LGG AS A POTENTIAL BIOMARKER FOR TMZ-ASSOCIATED HYPERMUTATION AT RECURRENCE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi105-vi105
Author(s):  
Radhika Mathur ◽  
Yalan Zhang ◽  
Matthew Grimmer ◽  
Chibo Hong ◽  
Mitchel Berger ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Level ◽  
Dna Methyltransferase ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Potential Biomarker ◽  
Mgmt Promoter ◽  
Grade Ii ◽  
Mechanistic Basis

Abstract Low-grade gliomas (LGGs), which include grade II astrocytoma and grade II oligodendroglioma, inevitably recur despite aggressive treatment with surgery, and sometimes, with radiation and the chemotherapeutic agent temozolomide (TMZ). The clinical benefit of TMZ in LGG is unclear, and a subset of TMZ-treated LGGs recur with hypermutation in association with malignant progression to high-grade tumors. It is currently unknown why some TMZ-treated LGGs recur with hypermutation while others do not. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that reverses mutagenic lesions induced by TMZ. The amount of MGMT protein in a cell is regulated at the epigenetic level by promoter methylation. Here, we hypothesize that epigenetic silencing of MGMT by promoter methylation facilitates TMZ-induced mutagenesis and contributes to the development of hypermutation. We demonstrate in a cohort of 37 TMZ-treated patients with an initial diagnosis of IDH-mutant LGG that methylation level of the MGMT promoter in initial untreated tumors is significantly associated with hypermutation at recurrence. We also confirm our previous finding that methylation level of the MGMT promoter in recurrent hypermutated tumors is higher than in recurrent tumors that are not hypermutated. These results provide a plausible mechanistic basis for observed differences in propensity of TMZ-treated LGG patients to develop hypermutation at recurrence. Furthermore, they establish the potential of MGMT promoter methylation level to inform treatment decisions in the clinic for patients with newly diagnosed LGG.

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