MGMT as a potential stratification marker in relapsed high‐grade glioma of children: The HIT‐GBM experience

Schlosser, Sabrina; Wagner, Sabine; Mühlisch, Jörg; Hasselblatt, Martin; Gerß, Joachim; Wolff, Johannes; Frühwald, Michael C.

doi:10.1002/pbc.22323

Cited by 20 publications

(6 citation statements)

References 37 publications

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“…Similar to the findings in adult glioma patients, MGMT promoter methylation [110], and reduced MGMT protein expression [100] have been reported to be associated with longer survival of pediatric malignant glioma patients. In ependymal tumors, MGMT promoter methylation is less common when compared with diffuse astrocytic and oligodendroglial tumors [13, 74].…”

Section: Mgmt Hypermethylation As a Prognostic Or Predictive Marker Isupporting

confidence: 74%

Molecular diagnostics of gliomas: state of the art

et al. 2010

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Modern neuropathology serves a key function in the multidisciplinary management of brain tumor patients. Owing to the recent advancements in molecular neurooncology, the neuropathological assessment of brain tumors is no longer restricted to provide information on a tumor’s histological type and malignancy grade, but may be complemented by a growing number of molecular tests for clinically relevant tissue-based biomarkers. This article provides an overview and critical appraisal of the types of genetic and epigenetic aberrations that have gained significance in the molecular diagnostics of gliomas, namely deletions of chromosome arms 1p and 19q, promoter hypermethylation of the O6-methylguanine-methyl-transferase (MGMT) gene, and the mutation status of the IDH1 and IDH2 genes. In addition, the frequent oncogenic aberration of BRAF in pilocytic astrocytomas may serve as a novel diagnostic marker and therapeutic target. Finally, this review will summarize recent mechanistic insights into the molecular alterations underlying treatment resistance in malignant gliomas and outline the potential of genome-wide profiling approaches for increasing our repertoire of clinically useful glioma markers.

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Section: Mgmt Hypermethylation As a Prognostic Or Predictive Marker Isupporting

confidence: 74%

Molecular diagnostics of gliomas: state of the art

et al. 2010

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“…The effectiveness of temozolomide, alone or combination with radiation and/or other agents, in pediatric gliomas remains uncertain (24) (27). However, none of these studies compared the MGMT status between pediatric and adult gliomas.…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics of pediatric non-ependymal, non‑pilocytic gliomas associated with resistance to temozolomide

et al. 2011

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Abstract. Temozolomide constitutes current standard of care for adult patients with high-grade gliomas. However, results for pediatric gliomas are rather disappointing. In order to investigate the molecular differences between pediatric and adult gliomas that could affect sensitivity to temozolomide, we studied 23 pediatric non-ependymal, non-pilocytic gliomas in comparison to 59 consecutive adult gliomas for the expression of O 6 -methylguanine methyltransferase (MGMT) and the DNA mismatch repair protein, mutS homolog 6 (MSH6) by immunohistochemistry, as well as for the presence or absence of promoter methylation of the MGMT gene by methylationspecific PCR. The expression of MGMT in pediatric gliomas was significantly higher than in adult gliomas, as shown by immunohistochemistry (p=0.00004). This association was conserved if statistical analysis was carried out only in astrocytic tumors (diffuse astrocytoma, anaplastic astrocytoma and glioblastoma, p=0.00007), or in oligodendroglial tumors (oligodendroglioma and anaplastic oligodendroglioma, p=0.020). Although methylation-specific PCR was successfully performed only in 15 pediatric gliomas, it also showed a trend toward less frequent methylation in pediatric as opposed to adult gliomas (p=0.242). MSH6 was almost equally expressed in pediatric and adult gliomas. Pediatric gliomas appear to have a distinct molecular profile associated with resistance to temozolomide. Higher expression of MGMT and a trend toward less frequent methylation of the promoter region of MGMT gene may partly account for relative resistance to temozolomide in pediatric gliomas as compared to adult gliomas. IntroductionTemozolomide, an oral methylating agent, has better activity and less toxicity than conventional agents, including nitrosoureas in the treatment of gliomas (1,2). Indeed, concomitant and adjuvant temozolomide has improved progression-free survival and overall survival compared to radiotherapy alone in adult patients with newly diagnosed supratentorial glioblastoma, and constitutes current standard of care for those patients (3,4). Nowadays, the majority of clinical trials for gliomas comprises protocols, including temozolomide. However, the efficacy of temozolomide is virtually based on reports on adult gliomas, and results for pediatric gliomas are rather disappointing. Verschuur et al treated 20 children with recurrent high-grade gliomas, including 11 grade III and 8 grade IV gliomas. Progression-free survival at 6 months was 18 and 12.5% for each grade (5). Those figures are less favorably compared to those reported in adult studies (1,2). Ruggiero et al and Lashford et al also reported lower response rate to temozolomide in recurrent pediatric, high-grade gliomas as compared to adult gliomas (6,7). Moreover, in a previous phase II trial (ACNS0126) for newly diagnosed pediatric high-grade gliomas, chemoradiotherapy with temozolomide only provided comparable results to the historical control with BCNU (8).Temozolomide rapidly hydrolyzed into 5-amino-1H-imidazole-4-carboxam...

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“…Another small retrospective study (N ¼ 24) reported that 50 % of pediatric glioblastoma patients had MGMT promoter methylation but did not provide correlation with clinical outcome (Srivastava et al 2010). One retrospective study of a small set of pediatric patients (N ¼ 24) who were more uniformly treated by enrollment in the German HIT-GBM trial showed that MGMT promoter methylation was seen in 77 % of patients and was associated with longer event-free survival compared with the unmethylated cohort whereas MGMT protein levels did not exhibit this correlation (Schlosser et al 2010). However, other retrospective studies have reported 0-30 % cases of high grade gliomas with MGMT promoter methylation (Buttarelli et al 2010;Fassan et al 2011;Lee et al 2011) emphasizing the need for analysis of a larger patient population to accurately establish the true proportion of pediatric gliomas with this finding.…”

Section: Epigenetics In Cancermentioning

confidence: 94%

Epigenetic Changes in Gliomas

Puduvalli

2014

Glioma Cell Biology

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Epigenetic alterations have been fundamentally implicated in the pathobiology of several malignancies including gliomas. Such changes involve tumor specific promoter methylation, histone modifications, and changes in microRNA. Several such recently reported alterations have also been seen to highly correlate with outcome highlighting their clinical significance, including the following: Promoter methylation of MGMT correlates with improved survival in glioblastoma patients who receive chemoradiation therapy and in anaplastic glioma patients treated with radiation alone as frontline therapy. A glioma CpG island methylator phenotype (G-CIMP) confers better survival to patients with the proneural subtype of glioblastoma. Mutations of IDH1 are commonly seen as early events in low grade and anaplastic gliomas and are also associated with a hypermethylator phenotype. Mutations of H3F3A which encodes the histone variant H3.3 have been reported in pediatric high grade gliomas which in turn have been linked to reduction in the histone H3 lysine trimethylation mark (H3K27me3) and possibly DNA hypomethylation as mechanisms for activated gene expression. Lastly, altered expression of several microRNA has been implicated in glioma biology. These findings point to a rapidly expanding recognition of the critical role of epigenetic changes in gliomagenesis and pathobiology. This in turn has given rise to clinical trials that either utilize epigenetic alterations as prognostic markers for patient stratification or in attempts at therapeutic targeting of epigenetic states of gliomas. However, much remains to be learned about the complex interplay between various epigenetic factors in glioma cells and their influence on genetic alterations; such insights will provide a foundation for therapeutic strategies aimed at modulating epigenetic factors to target high and low grade gliomas.

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MGMT as a potential stratification marker in relapsed high‐grade glioma of children: The HIT‐GBM experience

Abstract: DNA methylation, but not protein expression of MGMT was associated with an increased median EFS and OS of children with relapsed HGG. MGMT methylation status warrants prospective evaluation as a stratification marker for children with HGG.

Cited by 20 publications

References 37 publications

Molecular diagnostics of gliomas: state of the art

Molecular diagnostics of gliomas: state of the art

Molecular characteristics of pediatric non-ependymal, non‑pilocytic gliomas associated with resistance to temozolomide

Epigenetic Changes in Gliomas

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