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

Dunn, Julie R.; Baborie, Atik; Alam, F.; Joyce, Kathy A.; Moxham, M; Sibson, Ross; Crooks, Daniel; Husband, David; Shenoy, Aditya; Brodbelt, Andrew; Wong, Helen; Liloglou, T.; Haylock, Brian; Walker, Carol

doi:10.1038/sj.bjc.6605127

Cited by 277 publications

(285 citation statements)

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“…Fifty-three percent of patients were considered methylated and had a median OS of 16.8 months. 12 Studying each CpG separately is of interest, as in some tumors methylation is very heterogeneous (Fig 5). We found that methylation at CpG4 was the most significantly correlated with OS, and PYRmean was the most significantly correlated with PFS.…”

Section: Discussionmentioning

confidence: 99%

“…Pyrosequencing is a sequence-by-synthesis method that is the only method analyzing methylation levels at each CpG separately (for review and comparison of techniques, see Weller et al 2 and Preusser 3 ). Currently, among these alternative techniques, only pyrosequencing 11,12 and MethyLight 13 have been shown to have predictive value for GBM patients. Furthermore, a realtime quantitative MS-PCR approach, proposed by MDxHealth (formerly Oncomethylome Sciences), is being used in several international clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Quillien

Lavenu

Karayan‐Tapon

et al. 2012

Cancer

183

165

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BACKGROUND: There is a strong need to determine the best technique for O 6 -methylguanine-DNA-methyltranferase (MGMT) analysis, because MGMT status is currently used in clinical trials and occasionally in routine clinical practice for glioblastoma patients. METHODS:The authors compared analytical performances and predictive values of 5 techniques in a series of 100 glioblastoma patients who received standard of care treatment (Stupp protocol). RESULTS: MGMT promoter was considered methylated in 33%, 33%, 42%, and 60% of patients by methylation-sensitive high-resolution melting, MethyLight, pyrosequencing (with an optimal risk cutoff at 8% for the average percentage of the 5 CpGs tested), and methylation-specific polymerase chain reaction (MS-PCR), respectively. Fifty-nine percent of the samples had <23% (the optimal risk cutoff) of MGMT-positive tumor cells. The best predictive values for overall survival (OS), after adjustment for age and performance status, were obtained by pyrosequencing (hazard ratio [HR], 0.32; P < .0001), MS-PCR (HR, 0.37; P < .0001), and immunohistochemistry (HR, 0.43; P ¼ .0005) as compared with methylation-sensitive high-resolution melting (HR, 0.52 P ¼ .02) and MethyLight (HR, 0.6; P ¼ .05). For progression-free survival (PFS), the best predictive values were obtained with pyrosequencing (HR, 0.35; P < .0001), methylation-sensitive high-resolution melting (HR, 0.46; P ¼ .002), and MS-PCR (HR, 0.49; P ¼ .002). Combining pyrosequencing and immunohistochemistry slightly improved predictive power for OS, but not for PFS. Poor reproducibility and interobserver variability were, however, observed for immunohistochemistry. CONCLUSIONS: Good prediction of survival in addition to high reproducibility and sensitivity made pyrosequencing the best among the 5 techniques tested in this study. Cancer 2012;118:4201-11.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Quillien

Lavenu

Karayan‐Tapon

et al. 2012

Cancer

183

165

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“…44,45 A study published this year proposed that the extent of MGMT methylation, as measured by pyrosequencing, is a prognostic factor in glioblastoma patients treated with temozolomide and radiotherapy. 46 Patients with >29% MGMT methylation over the 12 CpG sites measured had a significantly better outcome than patients with >9% but ≤ 29% methylation, a clinically interesting finding that will need prospective validation. The In contrast to newly diagnosed glioblastoma, the predictive value of MGMT promoter methylation has remained controversial in recurrent glioblastoma.…”

Section: The Role Of Mgmt In Glioma Subtypes Glioblastomamentioning

confidence: 94%

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

et al. 2009

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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.

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“…Sources of intratumoral heterogeneity may include phenotypic plasticity of tumor cells (such as cancer stem cells vs. non-stem cells) and tumor purity (caused by sampling bias or immune infiltration). Importantly, a prognostic value is suggested not only for a dichotomous MGMT promoter methylation status but also for the extent of methylation (1). It is therefore critical to standardize tumor purity of the input material for reproducible results (2).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Heuling

Knab

Radke

et al. 2017

Molecular Cancer Research

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Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific realtime PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n ¼ 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532-40. Ó2017 AACR.

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

Cited by 277 publications

References 34 publications

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

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

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

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