MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

Wiewrodt, Dorothee; Nagel, Georg; Dreimüller, Nadine; Hundsberger, Thomas; Perneczky, Axel; Kaina, Bernd

doi:10.1002/ijc.23219

Cited by 97 publications

(105 citation statements)

References 49 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nevertheless, we did not detect a significant cooperative effect of MGMT hypermethylation and lack of TP53 mutation in terms of longer TTP after initiation of chemotherapy and longer OS in our patient cohort. The finding of MGMT protein expression not being significantly different between TP53 mutant and wild-type glioblastomas is in line with a recent study that reported no relationship between MGMT protein expression and p53 immunostaining (22). Thus, our results do not support the hypothesis that low MGMT expression is associated with increased p53 immunopositivity in glioblastomas (23).…”

Section: Discussionsupporting

confidence: 64%

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Felsberg

Rapp

Loeser

et al. 2009

Clinical Cancer Research

186

133

View full text Add to dashboard Cite

Purpose: Despite multimodal aggressive treatment glioblastoma patients still face a rather poor prognosis. Recent data indicate that certain molecular markers, in particular MGMT promoter hypermethylation, are associated with response to alkylating chemotherapy and longer survival. The clinical significance of other glioblastoma-associated molecular aberrations and their relationship to MGMT promoter hypermethylation is still poorly understood. Experimental Design: We conducted a translational study involving 67 newly diagnosed glioblastoma patients treated at our institution from 1998 to 2004. All patients were treated by open resection, followed by radiotherapy and adjuvant temozolomide chemotherapy. The tumors were investigated for MGMT promoter methylation, mRNA and protein expression, as well as presence of MGMT sequence polymorphisms. In addition, we screened for genetic aberrations of the EGFR, TP53, CDK4, MDM2, and PDGFRA genes as well as allelic losses on chromosomal arms 1p, 10q, and 19q. Results: Correlation of molecular findings with clinical data revealed significantly longer time to progression after onset of chemotherapy and longer overall survival of patients with MGMT-hypermethylated tumors. In contrast, MGMT protein expression, MGMT polymorphisms, and aberrations in any of the other genes and chromosomes were not significantly linked to patient outcome. Multivariate analysis identified MGMT promoter hypermethylation and near-complete tumor resection as the most important parameters associated with better prognosis. Conclusion: Our study provides novel insights into the significance of molecular and clinical markers in predicting the prognosis of glioblastoma patients, which may improve stratification of patients into distinct prognostic subgroups. (Clin Cancer Res 2009;15(21):6683-93) Glioblastoma is the most common primary brain tumor in adults and belongs to the most malignant types of human cancers, as indicated by a median survival time of <1 year in a population-based study (1). The standard treatment for glioblastoma comprises surgical resection followed by local radiotherapy as well as systemic chemotherapy with the DNA alkylating agent temozolomide. According to the results of the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) prospective clinical trial 26981-22981/CE.3, the combination of surgery followed by radiotherapy with concomittant and adjuvant temozolomide increased the median survival of glioblastoma patients by 2.5 months in comparison with treatment with surgery followed by radiotherapy alone (2). Furthermore, the 2-year survival rate increased from 10.4% in the radiotherapy group to 26.5% in the radiotherapy plus temozolomide group (2). Based on molecular analysis of 206 patients from this trial, O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation was shown to play an important role as a molecular predictor for response to temozolomide and longer survival (3). The MGMT ge...

show abstract

Section: Discussionsupporting

confidence: 64%

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Felsberg

Rapp

Loeser

et al. 2009

Clinical Cancer Research

186

133

View full text Add to dashboard Cite

show abstract

“…Although consideration of the extent of methylation allows greater prognostic stratification, a single cut-off in methylation derived from a quantitative assay may be more useful in the clinic. Wiewrodt et al (Wiewrodt et al, 2008) showed that patients expressing p30 fmol mg À1 MGMT protein in the pre-treatment tumour volume had a significantly better response to alkylating therapy than those with MGMT protein above this level. Others have shown that patients with low MGMT protein expression had significantly improved survival compared with those with high expression (Brell et al, 2005;Chinot et al, 2007;Nagane et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

et al. 2009

View full text Add to dashboard Cite

BACKGROUND: Epigenetic silencing of O 6 -methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre. METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas. RESULTS: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation 4non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS. CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.

show abstract

“…By means of an assay that measured the transfer of 3 Hlabeled methyl groups from the O 6 position of guanine to protein in the cell extract, MGMT activity was shown to be increased in recurrent tumors specifically in patients who had received alkylating agent chemotherapy. 21,22 However, such data have not been generated in a controlled, prospective manner and with parallel assessment of MGMT promoter methylation.…”

Section: Enzyme Activitymentioning

confidence: 99%

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

et al. 2009

View full text Add to dashboard Cite

The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile.Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

show abstract

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

Cited by 97 publications

References 49 publications

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Contact Info

Product

Resources

About