Prognostic value of MGMT promoter status in non-resectable glioblastoma after adjuvant therapy

Iaccarino, Corrado; Orlandi, Elena; F, Ruggeri; Nicoli, Davide; Torricelli, Federica; Maggi, Massimo; Cerasti, Davide; Pisanello, Anna; Pedrazzi, Giuseppe; Froio, Elisabetta; Crafa, Pellegrino; D'Abbiero, N.; Michiara, Maria; Ghadirpour, Reza; Servadei, Franco

doi:10.1016/j.clineuro.2015.01.029

Cited by 17 publications

(7 citation statements)

References 19 publications

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“…The effect of MGMT promoter methylation on OS unadjusted for using univariate analysis was evaluated in 32 studies (four in Asia, six in North America, one in Australia and 21 in Europe). 12 , 22 – 25 , 29 , 31 , 34 , 36 , 39 , 43 , 44 , 46 , 47 , 49 – 60 , 73 , 74 , 77 – 80 , 93 As shown in Figure 3 , the HR of the American group is 0.49, the HR of the European group is 0.47, HR of the Asian group is 0.73 and the HR of the Australian group is 0.51; MGMT promoter methylation was significantly correlated with better OS according to univariate analysis, with a combined HR of 0.50 (95% CI 0.40, 0.59). The random-effects model (the DerSimonian and Laird method) was used as significant heterogeneity was detected among these studies ( p = 0.000, I 2 = 50.3%).…”

Section: Resultsmentioning

confidence: 99%

Is the prognostic significance of O6-methylguanine-DNA methyltransferase promoter methylation equally important in glioblastomas of patients from different continents? A systematic review with meta-analysis

Wang

Jiang

2017

CMAR

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BackgroundO6-methylguanine-DNA methyltransferase (MGMT) is an independent predictor of therapeutic response and potential prognosis in patients with glioblastoma multiforme (GBM). However, its significance of clinical prognosis in different continents still needs to be explored.Patients and methodsTo explore the effects of MGMT promoter methylation on both progression-free survival (PFS) and overall survival (OS) among GBM patients from different continents, a systematic review of published studies was conducted.ResultsA total of 5103 patients from 53 studies were involved in the systematic review and the total percentage of MGMT promoter methylation was 45.53%. Of these studies, 16 studies performed univariate analyses and 17 performed multivariate analyses of MGMT promoter methylation on PFS. The pooled hazard ratio (HR) estimated for PFS was 0.55 (95% CI 0.50, 0.60) by univariate analysis and 0.43 (95% CI 0.38, 0.48) by multivariate analysis. The effect of MGMT promoter methylation on OS was explored in 30 studies by univariate analysis and in 30 studies by multivariate analysis. The combined HR was 0.48 (95% CI 0.44, 0.52) and 0.42 (95% CI 0.38, 0.45), respectively.ConclusionIn each subgroup divided by areas, the prognostic significance still remained highly significant. The proportion of methylation in each group was in inverse proportion to the corresponding HR in the univariate and multivariate analyses of PFS. However, from the perspective of OS, compared with data from Europe and the US, higher methylation rates in Asia did not bring better returns.

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Section: Resultsmentioning

confidence: 99%

Is the prognostic significance of O6-methylguanine-DNA methyltransferase promoter methylation equally important in glioblastomas of patients from different continents? A systematic review with meta-analysis

Wang

Jiang

2017

CMAR

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“…Median OS for wtIDH LGGs (1.7 years) is between OS for wtIDH GBMs (1.1 years) and mutated IDH GBMs (2.1 years) [9]. MGMT promoter methylation was associated with longer PFS and OS in GBM patients without therapy, and with better OS in GBM patients treated by DNA-alkylating agents such as temozolomide [13,14]. In turn, methylated MGMT promoter is also a favorable predictor of PFS in LGG treated with neoadjuvant temozolomide [11].…”

Section: Introductionmentioning

confidence: 99%

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

Zolotovskaia

Tkachev

Sorokin

et al. 2021

Cancers

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Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (p < 1.63 × 10−13, AUC > 0.74). High FREM2 pathway activation level was associated with poor OS in LGG (p < 0.001), and low PFS in LGG (p < 0.001) and GBM (p < 0.05). FREM2 pathway activation level was poor prognosis biomarker for OS (p < 0.05) and PFS (p < 0.05) in LGG with IDH mutation, for PFS in LGG with wild type IDH (p < 0.001) and mutant IDH with 1p/19q codeletion(p < 0.05), in GBM with unmethylated MGMT (p < 0.05), and in GBM with wild type IDH (p < 0.05). Thus, we conclude that the activation level of the FREM2 pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.

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“…Accumulation of 2-hydroxyglutarate impairs DNA demethylation, leading to methylome and transcriptome remodeling (17, 18), thereby triggering the glioma-CpG island methylator phenotype (G-CIMP) (19, 20) . Among methylated genes, the O6-methylguanine DNA methyltransferase ( MGMT ) promoter frequently undergoes methylation in the presence of IDH mutations, suggesting a possible molecular link between the two events (21, 22). MGMT acts as a tumor suppressor gene that functions in DNA repair (23) and plays a fundamental role in maintaining genome integrity by removing O6-alkylguanine DNA adducts induced by radiotherapy or alkylating agents (i.e.…”

Section: Introductionmentioning

confidence: 99%

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

Fontana¹,

Tabano²,

Bonaparte³

et al. 2016

J Neuropathol Exp Neurol

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Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these 2 events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.

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Prognostic value of MGMT promoter status in non-resectable glioblastoma after adjuvant therapy

Cited by 17 publications

References 19 publications

Is the prognostic significance of O6-methylguanine-DNA methyltransferase promoter methylation equally important in glioblastomas of patients from different continents? A systematic review with meta-analysis

Is the prognostic significance of O6-methylguanine-DNA methyltransferase promoter methylation equally important in glioblastomas of patients from different continents? A systematic review with meta-analysis

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

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