MGMT activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and glioblastoma

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

BMC Cancer ◽

10.1186/1471-2407-9-101 ◽

2009 ◽

Vol 9 (1) ◽

Cited By ~ 24

Author(s):

Alessandra Fabi ◽

Giulio Metro ◽

Michelangelo Russillo ◽

Antonello Vidiri ◽

Carmine Maria Carapella ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Erratum to: Prognostic significance of stem cell marker CD133 determined by promoter methylation but not by immunohistochemical expression in malignant gliomas

Journal of Neuro-Oncology ◽

10.1007/s11060-016-2089-x ◽

2016 ◽

Vol 127 (2) ◽

pp. 233-233

Author(s):

Xing Wu ◽

Fenlang Wu ◽

Dongwen Xu ◽

Tao Zhang

Keyword(s):

Stem Cell ◽

Promoter Methylation ◽

Malignant Gliomas ◽

Prognostic Significance ◽

Stem Cell Marker ◽

Cell Marker ◽

Immunohistochemical Expression

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Detection of MGMT promoter methylation in malignant gliomas.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e23131 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e23131-e23131

Author(s):

Michelle Afkhami ◽

Vandana Sharma ◽

Maria Cuellar ◽

Massimo D'Apuzzo ◽

Behnam Badie ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2013 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2013-2013

Author(s):

Wolfgang Wick ◽

Tobias Kessler ◽

Michael Platten ◽

Christoph Meisner ◽

Michael Bamberg ◽

...

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Predictive Biomarker ◽

Copy Number Variations ◽

Mgmt Promoter Methylation ◽

Published Data ◽

Global Methylation ◽

Methyl Transferase ◽

Mgmt Promoter

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.

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MGMT promoter methylation in malignant gliomas

Targeted Oncology ◽

10.1007/s11523-010-0153-6 ◽

2010 ◽

Vol 5 (3) ◽

pp. 161-165 ◽

Cited By ~ 43

Author(s):

Markus J. Riemenschneider ◽

Monika E. Hegi ◽

Guido Reifenberger

Keyword(s):

Promoter Methylation ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

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Immunotherapeutic early-phase clinical trials and malignant gliomas: a single-center experience and comprehensive immunophenotyping of circulating leukocytes

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab160 ◽

2021 ◽

Author(s):

Matteo Simonelli ◽

Pasquale Persico ◽

Arianna Capucetti ◽

Claudia Carenza ◽

Sara Franzese ◽

...

Keyword(s):

Clinical Trials ◽

Promoter Methylation ◽

Early Phase ◽

Univariate Analysis ◽

Malignant Gliomas ◽

Mgmt Promoter Methylation ◽

Control Group ◽

Large Expansion ◽

Mgmt Promoter ◽

Early Phase Clinical Trials

Abstract Background Immunotherapeutic early-phase clinical trials (ieCTs) increasingly adopt large expansion cohorts exploring novel agents across different tumor types. High-grade glioma (HGG) patients are usually excluded from these trials. Methods Data of patients with recurrent HGGs treated within multicohort ieCTs between February 2014 and August 2019 (experimental group, EG) at our Phase I Unit were retrospectively reviewed and compared to a matched control group (CG) of patients treated with standard therapies. We retrospectively evaluated clinical, laboratory, and molecular parameters through univariate and multivariate analysis. A prospective characterization of circulating leukocyte subpopulations was performed in the latest twenty patients enrolled in the EG, with a statistical significance cutoff of p <0.1. Results Thirty HGG patients were treated into six ieCTs. Fifteen patients received monotherapies (anti PD-1, anti CSF-1R, anti TGFβ, anti cereblon), fifteen patients combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSF-1R). In the EG, median progression-free survival and overall survival (OS) from treatment initiation were 1.8 and 8.6 months; twelve patients survived more than 12 months, and two of them more than six years. Univariate analysis identified O 6-methylguanine DNA methyltransferase (MGMT) promoter methylation and total protein value at six weeks as significantly correlated with a better outcome. Decreased circulating neutrophils and increased conventional dendritic cells levels lead to significantly better OS. Conclusions A subgroup of EG patients achieved remarkably durable disease control. MGMT promoter methylation identifies patients who benefit more from immunotherapy. Monitoring dynamic changes of innate immune cell populations may help to predict clinical outcomes.

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ECOA-2. Immuno-sensitization of Glioblastoma to NY-ESO-1 Targeting via Promoter Demethylation

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.002 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii1-ii1

Author(s):

Thomas Lai ◽

Janet Treger ◽

Jingyou Rao ◽

Tie Li ◽

Albert Lai ◽

...

Keyword(s):

T Cells ◽

Single Cell ◽

Rna Sequencing ◽

Promoter Methylation ◽

Bisulfite Sequencing ◽

Malignant Gliomas ◽

Cancer Testis Antigens ◽

Single Cell Rna Sequencing ◽

Cancer Testis

Abstract Introduction The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Mechanisms governing the expression of CTA have been explored in other cancers; however, neither the prevalence of NY-ESO-1 downregulation in GBM patient tumors nor the presumed mechanism of downregulation by promoter methylation in GBM has been formally established. Methods We characterized baseline CpG methylation of NY-ESO-1 in 30 bulk patient GBM samples, 10 patient-derived gliomaspheres, and three established tumor cell lines using bisulfite sequencing. We induced NY-ESO-1 expression in vitro in U251 human GBM cells using the hypomethylating agent decitabine (DAC). We investigated the epigenetic response of DAC-treated U251 with bisulfite sequencing and NY-ESO-1 expression with quantitative real-time PCR. Lastly, we performed single-cell RNA sequencing on DAC-treated GBM U251 to evaluate tumor subpopulations that upregulate NY-ESO-1 and other co-expressed CTA after DAC treatment. Results Baseline NY-ESO-1 expression is associated with promoter methylation in the majority of GBM. Treatment of cells with 1 µM DAC every day for 4 days explicitly demethylated the promoter region of NY-ESO-1 and resulted in a 1000-fold increase in mRNA expression. DAC treatment upregulates NY-ESO-1 coordinately with other cancer/testis antigens CTAG2 and MAGEA4 as demonstrated by single-cell RNA sequencing. Conclusion Exposure of U251 to DAC results in promoter demethylation in NY-ESO-1 and increased expression of CTA. DAC treatment may therefore render GBM susceptible to targeting of these antigens by T-cells, revealing a feasible strategy of NY-ESO-1 and co-expressed CTA promoter demethylation to sensitize GBM to immunotherapy.

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