Quantitative analysis of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2069-2069
Author(s):  
A. F. Ochsenbein ◽  
A. D. Schubert ◽  
E. Vassella ◽  
L. Mariani
Keyword(s):  
Promoter Methylation ◽  
Tumor Response ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
Response To Chemotherapy ◽  
Mgmt Promoter ◽  
Grade Ii

2069 Background: Loss of heterozygosity (LOH) on the chromosomes 1p and 19q is associated with sensitivity to alkylating agents like temozolomide (TMZ) in patients with low-grade gliomas; whether methylation of the MGMT-promoter, a predictive factor in glioblastoma patients, also correlates with tumor response to TMZ in low-grade gliomas is unclear. Methods: We performed a retrospective analysis of patients with histologically verified low-grade gliomas (WHO Grade II) who were treated with TMZ for tumor progression at our hospital between November 1999 and November 2007. Objective tumor response was assessed by MRI at 6-month intervals. LOH of microsatellite markers on chromosomes 1p and 19q was determined by polymerase chain reaction (PCR) amplification of the matched pairs of blood and tumor DNA. A methylation-specific, primer extension based PCR method was developed to quanitatively assess the MGMT methylation status in the tumour tissue. Results: Twenty-two patients with a median age of 53 years (range 27–72) were included in the study; 59% were male. Seven patients had prior surgical resection of the tumor. Histological classification revealed 10 oligodendrogliomas, 7 oligoastrocytomas, and 5 astrocytomas. All patients were treated with TMZ 200mg/m2 day1–5 in a 4 wk cycle. Grade 3–4 hematological toxicity occurred in 32% of the patients (9% leucopenia, 23% thrombocytopenia). The progression free survival was 32 months. Combined LOH 1p and 19q was found in 14 pts; 1 patient had LOH 1p alone and 1 patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. MGMT promoter methylation was detectable in 20 pts by conventional PCR and quantitative analysis revealed a methylation status between 12%-100%. The volumetric response to chemotherapy analyzed after 6 months by MRI correlated with the level of MGMT promoter methylation (p = 0.012). Conclusions: Quantitative methylation-specific PCR of the MGMT promoter correlates with radiological response to chemotherapy with temozolomide in WHO grade II gliomas. No significant financial relationships to disclose.

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.

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.

scholarly journals RARE-39. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) WITH LOMUSTINE (CCNU) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS - A BI-CENTRIC ANALYSIS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi229-vi230
Author(s):  
Lazaros Lazaridis ◽  
Niklas Schäfer ◽  
Teresa Schmidt ◽  
Johannes Weller ◽  
Theophilos-Dimitrios Tzaridis ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Case Series ◽  
Mgmt Promoter Methylation ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Skin Reactions ◽  
Term Survival ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND TTFields combined with TMZ chemotherapy demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial; independent of MGMT-promoter methylation-status, age, grade of resection, and performance status. Recently, improved efficacy of lomustine/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial. As TTFields demonstrated a favorable safety profile as well as a high potential for being combined with other modalities and the encouraging results for methylated MGMT-promoter GBM patients in the CeTeG trial, there is a strong rationale for combining these treatment regimens. Here, we present a case series of patients receiving a combination of TTFields and lomustine/TMZ. METHODS Patients with ndGBM and MGMT-promoter methylation underwent combined therapy of TTFields plus lomustine/TMZ after surgery and radiochemotherapy. MGMT-promoter status was measured by pyrosequencing. Safety, feasibility, and first efficacy results are reported at data cut-off (April 26, 2019). RESULTS Sixteen patients with MGMT-promoter methylated ndGBM (median, range: age 50, 27–70; KPS 90, 60–100) have been treated with a combination of TTFields plus lomustine/TMZ. The analysis included patients with complete resection (n=7), partial resection (n=8), as well as biopsy (n=1). CTCAE grade 3 hematotoxicity was observed in seven patients (44%) but was unlikely related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in six patients (38%). At data cut-off, the analyzed patient population demonstrated a median PFS of 20 months; the median OS was not yet reached. CONCLUSION The results of this analysis indicate that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and increased sample size are required and planned for further safety and efficacy assessment of this treatment regimen.

Prognostic and Clinical Values of Chaperone Protein P4HB in Malignant Glioma

2021 ◽  
Author(s):  
Stella Sun ◽  
Karrie Mei-Yee Kiang ◽  
Gilberto Ka-Kit Leung
Keyword(s):  
Promoter Methylation ◽  
Clinical Decision Making ◽  
Methylation Status ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Mgmt Promoter Methylation ◽  
Clinicopathological Parameters ◽  
Who Grade ◽  
Free Survival ◽  
Mgmt Promoter

Abstract Introduction. Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified by our group to play important roles in association with glioma malignancy and temozolomide (TMZ) resistance through the unfolded protein response (UPR). The present study focused on the prognostic value of P4HB in glioma. Methods. P4HB expression was assessed by immunohistochemical staining and semi-quantified by pathologist visual scoring in 73 WHO grade I-IV gliomas. Results were correlated with clinicopathological data. Results. Our results show that P4HB expression was significantly associated several clinicopathological parameters including age (p=0.035), tumour grade (p=0.002), and the number of TMZ treatment cycles received (p=0.043). Using Kaplan-Meier analysis, P4HB expression was positively correlated with mortality (p=0.014) and disease progression (p=0.026). In patients treated with TMZ, high P4HB expression level was significantly associated with poorer overall survival (OS) (p=0.014) and progression free survival (PFS) (p=0.027). The association between MGMT promoter methylation and P4HB expression was also interrogated. Patients with MGMTMethP4HBLow tumours had the most favourable progression free survival (48 months) than patients with other combination of MGMT methylation status and P4HB expression (log rank p=0.001). Multivariate analysis revealed that P4HB was an independent prognostic indicator for OS (p=0.048). Conclusions. P4HB could constitute an independent prognostic marker, especially for high grade glioma with the potential for informing a nuanced pathological stratification during clinical decision-making with respect to MGMT promoter methylation status and TMZ treatment.

scholarly journals Genotyping low-grade gliomas among Hispanics

2016 ◽  
Vol 3 (3) ◽  
pp. 164-172 ◽  
Author(s):  
Andrés Felipe Cardona ◽  
Leonardo Rojas ◽  
Beatriz Wills ◽  
José Behaine ◽  
Enrique Jiménez ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Isocitrate Dehydrogenase ◽  
Mgmt Promoter Methylation ◽  
World Health ◽  
Low Grade ◽  
Mgmt Methylation ◽  
Low Grade Gliomas ◽  
Molecular Abnormalities ◽  
1P19q Codeletion ◽  
Mgmt Promoter

AbstractBackgroundLow-grade gliomas (LGGs) are classified by the World Health Organization as astrocytoma (DA), oligodendroglioma (OD), and mixed oligoastrocytoma (OA). TP53 mutation and 1p19q codeletion are the most-commonly documented molecular abnormalities. Isocitrate dehydrogenase (IDH) 1/2 mutations are frequent in LGGs; however, IDH-negative gliomas can also occur. Recent research suggests that ATRX plays a significant role in gliomagenesis.MethodsWe investigated p53 and Olig2 protein expression, and MGMT promoter methylation, 1p19q codeletion, IDH, and ATRX status in 63 Colombian patients with LGG. The overall survival (OS) rate was estimated and compared according to genotype.ResultsThe most common histology was DA, followed by OD and OA. IDH1/2 mutations were found in 57.1% and MGMT+ (positive status of MGMT promoter methylation methyl-guanyl-methyl-transferase gene) in 65.1% of patients, while overexpression of p53 and Olig2 was present in 30.2% and 44.4%, respectively, and 1p19q codeletion in 34.9% of the patients. Overexpression of ATRX was analyzed in 25 patients, 16% tested positive and were also mutations in isocitrate dehydrogenase and negative 1p19q-codelition. The median follow-up was 15.8 months (95% CI, 7.6–42.0) and OS was 39.2 months (95% CI, 1.3–114). OS was positively and significantly affected by MGMT+, 1p19q codeletion, surgical intervention extent, and number of lobes involved. Multivariate analysis confirmed that MGMT methylation status and 1p19q codeletion affected OS.ConclusionsThis is the first study evaluating the molecular profile of Hispanic LGG patients. Findings confirmed the prognostic relevance of MGMT methylation and 1p19q codeletion, but do not support IDH1/2 mutation as a relevant marker. The latter may be explained by sample size and selection bias. ATRX alterations were limited to patients with DA and were mutations in isocitrate dehydrogenase and negative 1p19q-codelition.

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