Extent and prognostic value of MGMT promotor methylation in glioma WHO grade II

Karschnia, Philipp; Teske, Nico; Dorostkar, Mario M.; Siller, Sebastian; Weller, Jonathan; Baehring, Joachim M.; Dietrich, Jörg; Baumgarten, Louisa von; Herms, Jochen; Tonn, Joerg‐Christian; Thon, Niklas

doi:10.1038/s41598-020-76312-x

Cited by 11 publications

(11 citation statements)

References 26 publications

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“…Other cut-off points which have been validated in studies by others range from a mean MGMT promotor methylation of 7% to 30% [22,23] which is lower than our calculated cut-off points. Of interest, mean number of methylated CpG sites in glioblastoma as well as IDHwt astrocytoma with pTERTmut were comparable to mean number of methylated CpG sites in a cohort of glioma WHO grade II recently described by our group [8], suggesting extent of MGMT promotor methylation to be independent of histopathological WHO grade and may rather depend on molecular markers. Technical cut-off values for the distinction of methylated versus unmethylated cases usually would be set at the nadir of the distribution.…”

Section: A B C D Esupporting

confidence: 76%

“…In the prospective CATNON trial (which compares radiotherapy with or without chemotherapy), a subgroup analysis of IDHwt astrocytoma with molecular features of glioblastoma demonstrated improved survival for tumors with MGMT promotor methylation (but surprisingly did not find evidence for beneficial effects of alkylating chemotherapy among methylated tumors) [ 7 ]. We recently reported on a large cohort of gliomas WHO grade II, and found that a higher number of methylated CpG sites within the MGMT promotor region also represents a positive prognostic factor for outcome in gliomas of lower grades [ 8 ]. Of note, a subgroup analysis of our cohort showed that the prognostic value of MGMT promotor methylation was only retained in IDHwt astrocytomas, but not in IDH-mutant glioma with or without 1p19q co-deletion.…”

Section: Introductionmentioning

confidence: 99%

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Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

et al. 2021

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Introduction The cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. Methods We searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. Results We identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome. Conclusions Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted.

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Section: A B C D Esupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

et al. 2021

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“… 19 A larger number of methylated CpG sites has also shown to be associated with favorable outcome for low-grade gliomas. 15 Taken together, a possible proposal is that within lower-grade IDH mutant gliomas, comparing MGMT methylated vs. MGMT unmethylated tumors, the extent of methylation may be similar quantitatively, despite being qualitatively different in our testing methods. This hypothesis will require further confirmation.…”

Section: Discussionmentioning

confidence: 95%

“… 14 This is also consistent with a recent retrospective analysis of 155 patients with grade II glioma, showing that MGMT promoter methylation is only prognostic for IDH wildtype astrocytoma, but not for IDH mutant gliomas, regardless of the 1p19q co-deletion. 15 …”

Section: Discussionmentioning

confidence: 99%

Prognostic value of O6-methylguanine-DNA methyltransferase methylation in isocitrate dehydrogenase mutant gliomas

Lam

Eldred

Kevan

et al. 2022

Neuro-Oncology Advances

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Background Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those that are IDH wildtype. Previous studies have shown the prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma multiforme (GBM), which are predominantly IDH wildtype. Little is known of the prognostic value of MGMT methylation status for IDH mutant gliomas. Methods We retrospectively identified IDH mutant gliomas patients between 2011 and 2020 that were tested for MGMT promoter methylation. We generated Kaplan-Meier estimator curves and performed Cox proportional hazard models for overall survival (OS) and progression-free survival (PFS) to compare the outcomes of MGMT promoter methylated versus MGMT unmethylated patients. Results Of 419 IDH mutant gliomas with MGMT promoter methylation testing, we identified 54 GBM, 223 astrocytoma, and 142 oligodendroglioma. 62.3% patients had MGMT methylated tumors while 37.7% were MGMT unmethylated. On Kaplan-Meier analysis, median OS for all MGMT methylated patients was 17.7 years and for unmethylated patients 14.6 years. Median PFS for all MGMT methylated patients was 7.0 years and for unmethylated patients 5.2 years. During univariate subgroup analysis, MGMT methylation is only prognostic for GBM in OS and PFS and anaplastic oligodendroglioma for OS. In multivariate analysis, MGMT unmethylated GBM patients carry a higher risk of dying (HR 7.72, 95% CI 2.10-28.33) and recurrence (HR 3.85, 95% CI 1.35-10.96). Conclusions MGMT promoter methylation is associated with better OS and PFS for IDH mutant GBM. MGMT promoter methylation testing for other IDH mutant glioma subtypes may not provide additional information on prognostication.

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“…A subset of the included patients has partly been reported in a previous study on molecular markers in low-grade glioma 15 .…”

Section: Methodsmentioning

confidence: 99%

Subventricular zone involvement is associated with worse outcome in glioma WHO grade 2 depending on molecular markers

Karschnia

Weller

Blobner

et al. 2021

Sci Rep

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Neural stem cells within the subventricular zone were identified as cells of origin driving growth of high-grade gliomas, and anatomical involvement of the subventricular zone has been associated with an inferior clinical outcome. Whether the association between poor outcome and subventricular zone involvement also applies to glioma of lower grades is unclear. We therefore analysed a retrospective cohort of 182 patients with glioma grade 2 (according to the WHO 2016 classification) including 78 individuals (43%) with subventricular zone involvement. Patients with and without subventricular zone involvement did not differ in regard to demographics, histopathology, and molecular markers. Notably, subventricular zone involvement was a negative prognostic marker for malignant progression and overall survival on uni- and multivariate analysis. When patients were stratified according to the cIMPACT-NOW update 6, subventricular zone involvement was negatively associated with outcome in IDH-wildtype astrocytomas and 1p19q-codeleted oligodendrogliomas but not in IDH-mutant astrocytomas. Collectively, subventricular zone involvement may represent a risk factor for worse outcome in glioma WHO grade 2 depending on the molecular tumor signature. The present data confirm the relevance of molecular glioma classifications as proposed by the cIMPACT-NOW update 6. These findings warrant evaluation in prospective cohorts.

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Extent and prognostic value of MGMT promotor methylation in glioma WHO grade II

Cited by 11 publications

References 26 publications

Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

Extent, pattern, and prognostic value of MGMT promotor methylation: does it differ between glioblastoma and IDH-wildtype/TERT-mutated astrocytoma?

Prognostic value of O6-methylguanine-DNA methyltransferase methylation in isocitrate dehydrogenase mutant gliomas

Subventricular zone involvement is associated with worse outcome in glioma WHO grade 2 depending on molecular markers

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