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Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

Oncogene volume 26, pages 5010–5016 (2007)Cite this article

Abstract

Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio- and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2′-deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

LOH:

loss of heterozygosity

OS:

overall survival

RFS:

recurrence-free survival

WHO:

World Health Organisation

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Acknowledgements

This study was supported by grants from the Deutsche Krebshilfe to GR and MS (70-3088-Sa1) as well as to GR and AvD (70-3163-Wi3), and from the German Bundesministerium für Bildung und Forschung (BMBF) within the National Genome Research Network 2 (NGFN-2) to PL, MH, GR, CH and AvD (01GS0460, 01GS0462 and 01GS0463). BT was a scholar of the Studienstiftung des Deutschen Volkes.

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Author notes

  1. B Tews, P Roerig and G Reifenberger: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Genetics (B060), Deutsches Krebsforschungszentrum, Heidelberg, Germany

    B Tews, M Hahn, G Toedt, K Neben & P Lichter

  2. Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany

    P Roerig, J Felsberg, B Blaschke & G Reifenberger

  3. Department of Neuropathology, Charité University Medicine, Berlin, Germany

    C Hartmann, A Kunitz & A von Deimling

  4. Department of Neurosurgery, Heinrich-Heine-University, Düsseldorf, Germany

    M Sabel

  5. Central Unit Biostatistics (C060), Deutsches Krebsforschungszentrum, Heidelberg, Germany

    A Benner

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  1. B Tews
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Corresponding author

Correspondence to G Reifenberger.

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Tews, B., Roerig, P., Hartmann, C. et al. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene 26, 5010–5016 (2007). https://doi.org/10.1038/sj.onc.1210297

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  • DOI: https://doi.org/10.1038/sj.onc.1210297

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