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Patho-Epigenetics of Disease pp 71–90Cite as

Epigenetic Alterations in Glioblastoma Multiforme

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Abstract

Glioblastoma (GBM) is a high-grade glioma that represents the most common malignant brain tumor in adults. GBM has been recognized to arise in two different settings: most commonly as a de novo tumor and a less common secondary form that progresses from a previously diagnosed lower grade glioma (secondary GBM, sGBM). The genetic pathways involved in de novo and sGBM and their associations with gene expression patterns have been well studied. Recently, the epigenetic alterations in GBM have been elucidated with emphasis on their relationship to previous genomic studies. Hyper-and hypomethylation of CpG sites within GBM have been observed. The most common de novo GBM is characterized by genome-wide DNA hypomethylation whereas sGBM are hypermethylated at many hundreds of gene loci. The discovery of isocitrate dehydrogenase (IDH) mutations in glioma has transformed our understanding of the pathogenesis of these principal GBM subtypes. IDH mutations are typical of sGBM and a small but significant fraction of de novo GBMs. A DNA hypermethylation phenotype and improved patient survival are associated with IDH mutation. The most recent mechanistic studies implicate the TET enzymes as being involved in an active DNA demethylation process, and these insights help to provide a possible link between IDH mutations and DNA hypermethylation in glioma. Clinical studies of therapies that target epigenetic targets are underway, although the nonspecific nature of such approaches is a major limitation. Many aspects of the GBM epigenome are uncharacterized, but advances in technology to assess epigenetic alterations hold great promise in making the epigenome a fruitful target for new therapeutic approaches for this devastating disease.

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Abbreviations

CNS:

Central nervous system

CpG:

Cytosine-phosphate-guanine dinucleotide

DNMT:

DNA methyltransferase

EGFR:

Epithelial growth factor receptor

GBM:

Glioblastoma multiforme WHO grade IV astrocytoma

sGBM:

Secondary glioblastoma multiforme

G-Cimp:

Glioma-CpG island methylator phenotype

GFAP:

Glial fibrillary acid protein

HDAC:

Histone deacetylase

PTEN:

Phosphatase tensin analogue deleted on chromosome 10

MSP:

Methylation-specific polymerase chain reaction

MGMT:

O6-Methylguanine DNA methyltransferase

qMSP:

Quantitative methylation-specific polymerase chain reaction

SAHA:

Suberoylanilide hydroxamic acid

STAT:

Signal transducer and activator of transcription

TET:

Enzymes of the ten-eleven-translocation family

TP53:

Tumor suppressor protein p53

WHO:

World Health Organization

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Acknowledgments

I acknowledge the important contributions of Shichun Zheng, Ashley Smith, Karl T. Kelsey, Brock Christensen, Carmen Marsit, E. Andres Houseman, Heather Nelson, Margaret Wrensch, Joe Wiemels, Jennette D. Sison, Terri Rice, Lucie McCoy, and Joe Patoka in the data presented from our publications. JKW was supported by NIEHS R01ES06717, R01CA126831, P50CA092725, and RO1CA52689.

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  1. Department of Neurological Surgery and Epidemiology, University of California San Francisco, Helen Diller Family Cancer Center, San Francisco, CA, USA

    John K. Wiencke PhD

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  1. John K. Wiencke PhD
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Correspondence to John K. Wiencke PhD .

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  1. Microbiological Research Group, National Center for Epidemiology, Piheno u. 1, Budapest, 1529, Hungary

    Janos Minarovits

  2. University of Regensburg, Regensburg, 93053, Germany

    Hans Helmut Niller

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Wiencke, J.K. (2012). Epigenetic Alterations in Glioblastoma Multiforme. In: Minarovits, J., Niller, H. (eds) Patho-Epigenetics of Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3345-3_4

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