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Downregulation of RUNX3 and TES by hypermethylation in glioblastoma

Oncogene volume 26, pages 583–593 (2007)Cite this article

Abstract

Glioblastoma, the most aggressive and least treatable form of malignant glioma, is the most common human brain tumor. Although many regions of allelic loss occur in glioblastomas, relatively few tumor suppressor genes have been found mutated at such loci. To address the possibility that epigenetic alterations are an alternative means of glioblastoma gene inactivation, we coupled pharmacological manipulation of methylation with gene profiling to identify potential methylation-regulated, tumor-related genes. Duplicates of three short-term cultured glioblastomas were exposed to 5 μ M 5-aza-dC for 96 h followed by cRNA hybridization to an oligonucleotide microarray (Affymetrix U133A). We based candidate gene selection on bioinformatics, reverse transcription-polymerase chain reaction (RT–PCR), bisulfite sequencing, methylation-specific PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Two genes identified in this manner, RUNX3 and Testin (TES), were subsequently shown to harbor frequent tumor-specific epigenetic alterations in primary glioblastomas. This overall approach therefore provides a powerful means to identify candidate tumor-suppressor genes for subsequent evaluation and may lead to the identification of genes whose epigenetic dysregulation is integral to glioblastoma tumorigenesis.

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Acknowledgements

This work was supported by NIH CA57683 and Deutsche Forschungsgemeinschaft MU 1777 1-1. We thank Joe Costello, Therese Visted, Sean Lawler and Kazue Kasai for their technical advice and helpful discussions.

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Authors and Affiliations

  1. Department of Pathology, Cancer Center and Neurosurgical Service, Massachusetts General Hospital, Boston, MA, USA

    W Mueller, C L Nutt, M J Riemenschneider & D N Louis

  2. Harvard Medical School, Boston, MA, USA

    W Mueller, C L Nutt, M J Riemenschneider & D N Louis

  3. SEQUENOM Inc., John Hopkins Ct, San Diego, CA, USA

    M Ehrich & D van den Boom

  4. Department of Neuropathology, University Hospital Charité, Berlin, Germany

    A von Deimling

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  1. W Mueller
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  2. C L Nutt
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Mueller, W., Nutt, C., Ehrich, M. et al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 26, 583–593 (2007). https://doi.org/10.1038/sj.onc.1209805

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