1. ¹Division of Molecular Genetics (B060), Deutsches Krebsforschungszentrum, Heidelberg, Germany
2. ²Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany
3. ³Department of Neuropathology, Charité University Medicine, Berlin, Germany
4. ⁴Department of Neurosurgery, Heinrich-Heine-University, Düsseldorf, Germany
5. ⁵Central Unit Biostatistics (C060), Deutsches Krebsforschungszentrum, Heidelberg, Germany

Correspondence: Professor G Reifenberger, Department of Neuropathology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail: reifenberger@med.uni-duesseldorf.de

⁶These authors contributed equally to this work.

Received 5 April 2006; Revised 14 December 2006; Accepted 3 January 2007; Published online 19 February 2007.

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.