High-grade gliomas are believed to derive from astrocytic precursor cells (anaplastic astrocytomas) or from ependymal cells lining the ventricular system (anaplastic ependymomas). Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively few data are available in childhood gliomas. In the current study 26 frozen and 100 paraffin-embedded high-grade astrocytomas were screened for microsatellite instability (MSI). We were not able to detect high level of instability (MSI-H) in any tumors examined. Low frequency of instability (MSI-L) was observed in 4 of 126 (3.2%) pediatric high-grade astrocytic tumors. To further analyze genetic and epigenetic changes in selected 34 high malignant gliomas of childhood we performed matrix-CGH and microarray-based methylation (DMH) analysis. On chromosome 1q, we found frequent gains of chromosomal material in 3 regions: 1q21, 1q22 and 1q25. In 5 out of 9 high-grade astrocytomas analyzed by DMH assay, we detected frequent hypermethylation of the promoter region of two putative genes: LHX9 (LIM homeobox 9) and BCLAF1 (BCL-2 associated transcription factor 1). The results were verified by bisulfite genomic sequencing and quantify by COBRA assay. Together our findings identify frequently aberrant chromosomal regions and putative candidate genes, whose epigenetic alterations may be involved in the tumorigenesis of pediatric high-grade astrocytic tumors.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA