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

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.20064 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 20064-20064 ◽

Cited By ~ 1

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.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7052 ◽

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]

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Multiple Assays to Determine Methylguanine-Methyltransferase Status in Lung Carcinoids and Correlation with Clinical and Pathological Features

Neuroendocrinology ◽

10.1159/000500158 ◽

2019 ◽

Vol 110 (1-2) ◽

pp. 1-9

Author(s):

Simona Vatrano ◽

Jessica Giorcelli ◽

Arianna Votta ◽

Guendalina Capone ◽

Stefania Izzo ◽

...

Keyword(s):

Gene Expression ◽

Promoter Methylation ◽

Alkylating Agents ◽

Mgmt Promoter Methylation ◽

High Grade ◽

Pathological Features ◽

Mgmt Gene ◽

Mgmt Promoter ◽

Methylguanine Methyltransferase ◽

Clinical And Pathological Features

Background: O6-methylguanine-methyltransferase (MGMT) is a key enzyme for the DNA repair machinery strongly associated with response to alkylating agents in different tumors. Data on its expression and related clinical impact in neuroendocrine tumors are limited to the gastro-entero-pancreatic system, with controversial results in terms of prognostic or predictive value. In lung carcinoids, although clinical efficacy of alkylating agents has been shown in small studies, very few data to date are available on MGMT status. Objective: To assess MGMT status in lung carcinoids using multiple assays and to compare data with major clinical and pathological features. Methods: A retrospective series of 95 lung carcinoids and 51 control cases of high-grade neuroendocrine lung carcinomas was analyzed for MGMT promoter methylation, MGMT gene expression, and MGMT protein expression using pyrosequencing, quantitative real-time PCR, and immunohistochemistry, respectively. Results: MGMT protein expression was inversely correlated with MGMT promoter methylation and positively with MGMT gene expression. MGMT promoter methylation progressively increased from carcinoids to high-grade carcinomas. In the carcinoid group, decreased MGMT gene expression was significantly associated with aggressive features (atypical histotype, grade G2, larger tumor size, higher T stage, and positive nodal status) but not with survival. MGMT promoter methylation was associated with lower stage and negative nodal status. Conclusions: Our study investigated MGMT status in a large series of lung carcinoids in the attempt to move forward a rational use of alkylating agents in these tumors. Interestingly, low MGMT gene expression defines a subgroup of lung carcinoids with aggressive features.

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P14.108 Bevacizumab versus alkylating chemotherapy in recurrent glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz126.343 ◽

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.

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Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients

European Journal of Cancer ◽

10.1016/j.ejca.2016.10.032 ◽

2017 ◽

Vol 71 ◽

pp. 43-50 ◽

Cited By ~ 18

Author(s):

Andrea Sartore-Bianchi ◽

Filippo Pietrantonio ◽

Alessio Amatu ◽

Massimo Milione ◽

Andrea Cassingena ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Promoter Methylation ◽

Alkylating Agents ◽

Digital Pcr ◽

Mgmt Promoter Methylation ◽

Prediction Of Response ◽

Mgmt Promoter ◽

Colorectal Cancer Patients

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Prognostic Significance of MGMT Promoter Methylation in Egyptian GBM Patients: A Single-institution Experience

Asian Pacific Journal of Cancer Biology ◽

10.31557/apjcb.2018.3.1.1-4 ◽

2018 ◽

Vol 3 (1) ◽

pp. 1-4

Author(s):

Rabab Abdel Moneim ◽

Mohamed Abdel-Rafei ◽

Hesham Hassan ◽

Ibrahim El-Zawahry ◽

Wedad Bassam Hashem

Keyword(s):

Promoter Methylation ◽

Alkylating Agents ◽

Prognostic Significance ◽

Mgmt Promoter Methylation ◽

Epigenetic Silencing ◽

P Value ◽

Female Ratio ◽

Mgmt Gene ◽

Mgmt Promoter ◽

Formalin Fixed Paraffin Embedded

Background: Glioblastoma Multiforme (GBM) is the highest-mortality tumor of the central nervous system. Epigenetic silencing of the MGMT gene by promoter methylation is associated with loss of MGMT expression and deficiency in MGMT-mediated DNA repair, which is affiliated with improved survival in patients treated with alkylating agents such as TMZ.Purpose: This is a retrospective work, studying the MGMT promoter status in a group of GBM patients; correlating this status to time to progression (TTP) and overall survival (OS).Methods: Thirty-nine patients with GBM, treated in Kasr El-Ainy Center of Clinical Oncology and Nuclear Medicine (NEMROCK) between January 2014 and January 2015, were included in our study. The QIAamp DNA FFPE Tissue Kit (Qiagen, USA) was used for genomic DNA extraction from Formalin-fixed paraffin-embedded tumor tissues of the 39 patients. Bisulfite modification of DNA was performed for detecting methylation in MGMT promoter using EpiTect Bisulfite Kit (Qiagen, USA). Specific primers were used to match methylated & un-methylated DNA that was visualized by loading its PCR products in gel electrophoresis system. All statistical analyses were carried out using SPSS version 20.0.Results: The mean age for our patients was 48 years; with a male to female ratio of 1.3:1. MGMT promoter methylation was found in 27 patients (69.2%) compared to 12 (30.8%) with un-methylation. TMZ was received in 71.8 % (28) of our patients throughout their treatment. The median OS for all patients was 20.03 months; while the median TTP 15.03 was months. Although the OS was statistically significantly higher for patients with the methylated promoter (p-value = 0.004) compared to the un-methylated group; yet the TTP difference did not reach a statistically significant value (p-value = 0.048). Conclusions: The epigenetic silencing of the MGMT gene by promoter methylation has been associated with longer OS & TTP in patients with GBM.

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.11.5964 ◽

2008 ◽

Vol 26 (25) ◽

pp. 4189-4199 ◽

Cited By ~ 499

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.

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