Role of
            MGMT
            Methylation Status at Time of Diagnosis and Recurrence for Patients with Glioblastoma: Clinical Implications

2052 Background: MGMT methylation status has been found to be an important prognostic factor in glioblastoma patients (pts). However, further data on the epigenetic feature are needed before its role in rare diseases such as anaplastic astrocytomas (AA) can be established. Methods: A retrospective analysis was made on a database of 139 AA pts followed prospectively from January 1995 and August 2008. We evaluated only pts who met the following inclusion criteria: age >18 years; PS 0–2; histological diagnosis of AA; postoperative radiotherapy (RT) and chemotherapy (CT). MGMT status was determined with methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in AA. The log-rank test was employed to evaluate the significance of the prognostic variables. Results: 80 pts (m/f: 46/34, median age: 41 years, range: 18–71 years) were enrolled. MGMT was assessable in 71 of 80 pts (88.8%), being methylated in 30 (42.9%), and unmethylated in 41 (57.7%) pts. Median PFS was 48.6 months (95% CI: 33.7 - 63.5), being 96 months (95% CI: 29–163) and 38 months (95%CI: 18.9–57.2) in MGMT methylated and unmethylated pts, respectively (p = 0.09). At univariate analysis, complete resection (p = 0.02), age (p = 0.002), and KPS (p = 0.003) were significantly correlated with PFS. At multivariate analysis only age remains correlated with PFS (p = 0.01). Median survival (OS) was 93.7 months (95% CI: 63.5–123.8), being not reached and 77 months (95% CI: 20–134.2), in MGMT methylated and unmethylated pts, respectively (p = 0.03). MGMT methylation (p = 0.03), age (p = 0.0003), and KPS (p = 0.03) were significantly correlated with OS at univariate analysis. At multivariate analysis, age (p = 0.0002) and MGMT methylation (p = 0.01) were correlated with a better OS. Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA. This datum should provide the background to improve the therapeutic index with temozolomide concurrent with and adjuvant to RT in AA. No significant financial relationships to disclose.

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Management of Gliomas: Individualized Treatment Options

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.5008 ◽

2020 ◽

Vol 18 (7.5) ◽

pp. 985-988

Author(s):

Louis Burt Nabors

Keyword(s):

Performance Status ◽

Treatment Options ◽

Methylation Status ◽

Low Grade ◽

Prognostic Impact ◽

Mgmt Methylation ◽

Methyl Transferase ◽

Low Performance ◽

Hypofractionated Radiation

Optimizing treatment for patients with low-grade gliomas should focus on the role of radiation and chemotherapy, as well as the prognostic impact of molecular diagnostics (1p/19q and IDH status). For anaplastic oligodendroglioma, focus should be placed on molecular markers (particularly 1p/19q status) and combination treatment with chemotherapy (temozolomide or PCV [procarbazine, lomustine, and vincristine]) and radiation. For patients with malignant glioblastomas, the role of methylguanine methyl-transferase (MGMT) methylation status has become increasingly important to treatment decisions. MGMT methylation status should be considered in elderly patients and/or those with low performance status (methylated patients benefit from temozolomide) and a hypofractionated radiation schedule should be used.

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Glioblastoma recurrence and the role of MGMT promoter methylation

10.1101/317636 ◽

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.

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The prognostic role of gender and MGMT methylation status in glioblastoma patients: The female power

Annals of Oncology ◽

10.1093/annonc/mdx366.022 ◽

2017 ◽

Vol 28 ◽

pp. v116

Author(s):

A. Tosoni ◽

E. Franceschi ◽

R. Depenni ◽

B. Urbini ◽

M. Faedi ◽

...

Keyword(s):

Methylation Status ◽

Mgmt Methylation ◽

Prognostic Role ◽

Female Power

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MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas

European Radiology ◽

10.1007/s00330-020-07297-4 ◽

2020 ◽

Author(s):

Elies Fuster-Garcia ◽

David Lorente Estellés ◽

María del Mar Álvarez-Torres ◽

Javier Juan-Albarracín ◽

Eduard Chelebian ◽

...

Keyword(s):

Overall Survival ◽

Clinical Studies ◽

Regression Models ◽

Cerebral Blood Volume ◽

Methylation Status ◽

Mgmt Methylation ◽

Prognostic Information ◽

Tumor Vascularity ◽

Key Points

Abstract Objectives To assess the combined role of tumor vascularity, estimated from perfusion MRI, and MGMT methylation status on overall survival (OS) in patients with glioblastoma. Methods A multicentric international dataset including 96 patients from NCT03439332 clinical study were used to study the prognostic relationships between MGMT and perfusion markers. Relative cerebral blood volume (rCBV) in the most vascularized tumor regions was automatically obtained from preoperative MRIs using ONCOhabitats online analysis service. Cox survival regression models and stratification strategies were conducted to define a subpopulation that is particularly favored by MGMT methylation in terms of OS. Results rCBV distributions did not differ significantly (p > 0.05) in the methylated and the non-methylated subpopulations. In patients with moderately vascularized tumors (rCBV < 10.73), MGMT methylation was a positive predictive factor for OS (HR = 2.73, p = 0.003, AUC = 0.70). In patients with highly vascularized tumors (rCBV > 10.73), however, there was no significant effect of MGMT methylation (HR = 1.72, p = 0.10, AUC = 0.56). Conclusions Our results indicate the existence of complementary prognostic information provided by MGMT methylation and rCBV. Perfusion markers could identify a subpopulation of patients who will benefit the most from MGMT methylation. Not considering this information may lead to bias in the interpretation of clinical studies. Key Points • MRI perfusion provides complementary prognostic information to MGMT methylation. • MGMT methylation improves prognosis in glioblastoma patients with moderate vascular profile. • Failure to consider these relations may lead to bias in the interpretation of clinical studies.

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Molecular and clinicopathological characterization of a prognostic immune gene signature associated with MGMT methylation in glioblastoma

10.1101/2020.07.16.206318 ◽

2020 ◽

Author(s):

Liang Zhao ◽

Jiayue Zhang ◽

Shurui Xuan ◽

Zhiyuan Liu ◽

Yu Wang ◽

...

Keyword(s):

Risk Group ◽

Methylation Status ◽

Gene Signature ◽

Low Risk ◽

The Cancer Genome Atlas ◽

Immune Checkpoints ◽

Immune Gene ◽

Mgmt Methylation ◽

Genome Atlas

AbstractBackgroundO6-methylguanine-DNA methyltransferase (MGMT) methylation status affects tumor chemo-resistance and the prognosis of glioblastoma (GBM) patients. We aimed to investigate the role of MGMT methylation in the regulation of GBM immunophenotype and discover an effective biomarker to improve prognosis prediction of GBM patients.MethodsA total of 769 GBM patients with clinical information from five independent cohorts were enrolled in the present study. Samples from the Cancer Genome Atlas (TCGA) dataset were used as the training set, whereas transcriptome data from the Chinese Glioma Genome Atlas (CGGA) RNA-seq, CGGA microarray, GSE16011, and the Repository for Molecular Brain Neoplasia (REMBRANDT) cohort were used for validation. A series of bioinformatics approaches were carried out to construct a prognostic signature based on immune-related genes, which were tightly related with the MGMT methylation status. The influence of the signature on immunosuppression and remodeling of the tumor microenvironment were comprehensively investigated. Then, the utility of this immune gene signature was analyzed by the development and evaluation of a nomogram.ResultsWe found that MGMT unmethylation was closely associated with immune-related biological processes in GBM. Sixty-five immune genes were more highly expressed in the MGMT unmethylated than the MGMT methylated group. An immune gene-based risk model was further established to divide patients into high and low-risk groups, and the prognostic value of this signature was validated in several GBM cohorts. Functional analyses manifested a universal up-regulation of immune-related pathways in the high-risk group as compared to the low-risk group. Furthermore, the risk score was highly correlated to the immune cell infiltration, immunosuppression, inflammatory activities, as well as the expression levels of immune checkpoints. Finally, a nomogram was developed for clinical application.ConclusionsMGMT methylation is strongly related to the immune responses in GBM. The immune gene-based signature we identified may have potential implications in predicting the prognosis of GBM patients and mechanisms underlying the role of MGMT methylation.

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Change in MGMT methylation status between first and second surgery for recurrence: Clinical implications

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2027 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2027-2027

Author(s):

A. A. Brandes ◽

E. Franceschi ◽

A. Tosoni ◽

A. Fioravanti ◽

R. Agati ◽

...

Keyword(s):

Methylation Status ◽

Postoperative Treatment ◽

Rank Test ◽

Time Interval ◽

Mgmt Methylation ◽

Second Surgery ◽

Mgmt Promoter ◽

Prognostic Utility ◽

Newly Diagnosed Glioblastoma

2027 Background: MGMT promoter methylation status is known to be a potent prognostic factor in newly diagnosed glioblastoma (GBM) patients (pts). However, it is not yet clear whether and, if so, how MGMT methylation status may change; nor is it known whether the prognostic role of this epigenetic feature is retained during the disease course. Methods: A retrospective analysis was made using a database of 614 GBM pts treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age ≥18; PS 0–2; two distinct surgical procedures; histological diagnosis of GBM both at first and at second surgery for recurrence; postoperative treatment consisting of: a) radiotherapy (RT) followed by temozolomide (TMZ) until 2005, and b) TMZ concurrent with and adjuvant to RT after 2005; a time interval ≥3 month between first and second surgery. The study aim was to evaluate changes of MGMT status during the course of GBM. The log-rank test was employed to evaluate the significance of the prognostic variables. The percentages of MGMT methylated cases at first and second surgery were compared using the McNemar test. Results: MGMT status, evaluated at first and second surgery in all 44 pts (M:F 32:12, median age: 49 years, range: 27–67), was assessable in 38 (86.4%) cases: MGMT promoter was methylated in 13 (34.2%) pts at first surgery. MGMT methylation status, unchanged in 63.2% of second surgery samples, changed more frequently in methylated than in unmethylated pts (61.5% vs 24%, p = 0.03). The median survival was 24.3 months (95% CI: 20.8–27.7), being 35.2 months (95% CI: 10.1–60.2) and 21.9 months (95% CI: 17.3–26.5) for pts with methylated and unmethylated MGMT assessed at first surgery, respectively (p = 0.04). However, MGMT status at second surgery was no longer prognostic for survival (p = 0.1). Conclusions: Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. Moreover, while MGMT methylation status is prognostic at first surgery, it appears to be of no prognostic utility at the time of second surgery. No significant financial relationships to disclose.

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Glioblastoma Recurrence and the Role of O6-Methylguanine–DNA Methyltransferase Promoter Methylation

JCO Clinical Cancer Informatics ◽

10.1200/cci.18.00062 ◽

2019 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Katie Storey ◽

Kevin Leder ◽

Andrea Hawkins-Daarud ◽

Kristin Swanson ◽

Atique U. Ahmed ◽

...

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Inhibitory Effect ◽

Mgmt Methylation ◽

Repair Gene ◽

Methylguanine Dna Methyltransferase ◽

Downward Shift ◽

Dna Repair Gene

Tumor 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 (O6-methylguanine–DNA methyltransferase) has been associated with sensitivity to TMZ, whereas 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 that drive 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 found 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 patients with GBM with high and low levels of MGMT methylation at diagnosis.

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