Unraveling the Glioma Epigenome—From Molecular Mechanisms to Novel Biomarkers and Therapeutic Targets

Malzkorn, Bastian; Wolter, Marietta; Riemenschneider, Markus J.; Reifenberger, Guido

doi:10.1111/j.1750-3639.2011.00536.x

Cited by 39 publications

(29 citation statements)

References 150 publications

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“…The EMP3 gene has been proposed to belong to the CpG island methylator phenotype, recently described in gliomas (G-CIMP) [25, 26]. This phenotype, characterized by aberrant promoter methylation at multiple genes, identifies a distinct molecular subclass of glial tumors.…”

Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation of theEMP3Gene in a Series of 229 Human Gliomas

Mellai

Piazzi

Caldera

et al. 2013

BioMed Research International

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The epithelial membrane protein 3 (EMP3) is a candidate tumor suppressor gene in the critical region 19q13.3 for several solid tumors, including tumors of the nervous systems. The aim of this study was to investigate the EMP3 promoter hypermethylation status in a series of 229 astrocytic and oligodendroglial tumors and in 16 GBM cell lines. The analysis was performed by methylation-specific PCR and capillary electrophoresis. Furthermore, the EMP3 expression at protein level was evaluated by immunohistochemistry and Western blotting analysis. Associations of EMP3 hypermethylation with total 1p/19q codeletion, MGMT promoter hypermethylation, IDH1/IDH2 and TP53 mutations, and EGFR amplification were studied, as well as its prognostic significance. The EMP3 promoter hypermethylation has been found in 39.5% of gliomas. It prevailed in low-grade tumors, especially in gliomas with an oligodendroglial component, and in sGBMs upon pGBMs. In oligodendroglial tumors, it was strongly associated with both IDH1/IDH2 mutations and total 1p/19q codeletion and inversely with EGFR gene amplification. No association was found with MGMT hypermethylation and TP53 mutations. In the whole series, the EMP3 hypermethylation status correlated with 19q13.3 loss and lack of EMP3 expression at protein level. A favorable prognostic significance on overall survival of the EMP3 promoter hypermethylation was found in patients with oligodendroglial tumors.

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Section: Discussionmentioning

confidence: 99%

Promoter Hypermethylation of theEMP3Gene in a Series of 229 Human Gliomas

Mellai

Piazzi

Caldera

et al. 2013

BioMed Research International

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“…In particular, epigenetic biomarkers such as DNA methylation and their effects on tumor biology have been analyzed in a number of GBM studies [5]. With the recent development of high-resolution microarray platforms, it is now possible to measure the level of methylation across an entire genome.…”

Section: Introductionmentioning

confidence: 99%

G-Cimp Status Prediction Of Glioblastoma Samples Using mRNA Expression Data

et al. 2012

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Glioblastoma Multiforme (GBM) is a tumor with high mortality and no known cure. The dramatic molecular and clinical heterogeneity seen in this tumor has led to attempts to define genetically similar subgroups of GBM with the hope of developing tumor specific therapies targeted to the unique biology within each of these subgroups. Recently, a subset of relatively favorable prognosis GBMs has been identified. These glioma CpG island methylator phenotype, or G-CIMP tumors, have distinct genomic copy number aberrations, DNA methylation patterns, and (mRNA) expression profiles compared to other GBMs. While the standard method for identifying G-CIMP tumors is based on genome-wide DNA methylation data, such data is often not available compared to the more widely available gene expression data. In this study, we have developed and evaluated a method to predict the G-CIMP status of GBM samples based solely on gene expression data.

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“…[124][125][126] Emerging roles of epigenetic alterations in glioma biology have been recently reported. 27,28,118,[127][128][129] DNA methylation occurs at the 5′ position of the cytosine ring within CpG dinucleotides, resulting in gene silencing. DNMT1 is the DNA methyltransferase that maintains existing methylation during DNA replication, whereas DNMT3A and DNMT3B are responsible for methylating previously unmethylated regions.…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

“…CpG islands in the promoters of tumor suppressor p53, PTEN, RB, CDKN2/p16, and P14ARF are frequently methylated in GBM, indicating that their tumor suppressive function is inhibited. 127,129 In addition, the DNA repair protein MGMT is frequently methylated in the promoter regions. MGMT removes TMZ-generated O6-methylguanine DNA adducts by transferring the methyl adducts to its own cysteine residues, indicating that MGMT activity is associated with the therapeutic response to TMZ.…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

Molecular biomarkers of glioblastoma: current targets and clinical implications

Yoshimoto¹,

Mizoguchi²,

Hata³

et al. 2012

CBF

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Recent genome-wide analysis of glioblastoma has revealed various molecular alterations that can be candidate targets of biomarker findings. Although glioblastomas are diagnosed on the basis of their histopathological morphological features, it has been demonstrated that molecular heterogeneity among glioblastomas is prominent, and pathological diagnosis cannot always predict the clinical behavior of the tumor. Thus, molecular biomarkers have been anticipated to provide prognostic and predictive significance. Given that recent medical treatment strategies have been progressing toward individualized therapy and many targeted drugs have been investigated, the identification of molecular biomarkers in glioblastoma will be of considerable therapeutic importance. Although the clinical implications of these biomarkers must be determined in prospective studies, a growing number of candidate biomarkers have been investigated. In this review, the recent molecular alterations in glioblastoma that may be significant biomarkers are summarized; particular focus is on loss of heterozygosity on chromosome 10, epidermal growth factor receptor (EGFR)/EGFR variant III expression, alterations in the receptor tyrosine kinase-phosphatidylinositol 3-kinase pathway, isocitrate dehydrogenase mutation, epigenetic alterations, gene expression profiling, and microRNA expression.

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Unraveling the Glioma Epigenome—From Molecular Mechanisms to Novel Biomarkers and Therapeutic Targets

Cited by 39 publications

References 150 publications

Promoter Hypermethylation of theEMP3Gene in a Series of 229 Human Gliomas

Promoter Hypermethylation of theEMP3Gene in a Series of 229 Human Gliomas

G-Cimp Status Prediction Of Glioblastoma Samples Using mRNA Expression Data

Molecular biomarkers of glioblastoma: current targets and clinical implications

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