Abnormal gene expression can be linked to chromosomal gains and losses in paediatric astrocytoma

Abstract

Brain tumors are the most frequently found solid tumor in children, 40% of which are astrocytomas. These are graded according to the WHO classification into the more common low-grade (I and II) and high-grade (III and IV) tumors. Little is known about the genetic basis underlying the development of pediatric astrocytomas. In this study, we have studied the correlation between abnormal gene expression in pediatric astrocytoma with genomic copy number changes. We used the Affymetrix HGU133A array to identify differentially expressed genes in a group of pediatric astrocytoma short-term cell cultures comprising 9 grade I, 11 grade II and 12 grade IV tumors. Data analysis was carried out using Genespring version 6.0 software. In addition, we used the Spectral Chip 2600 to generate array-comparative genomic hybridization (aCGH) profiles of each short-term cell culture. Chromosome regions of gain and loss were then compared with differential gene expression using Formatter software. Hierarchical clustering of the short-term cultures according to expression profile similarity showed that the tumors clustered into 3 clear groups that were independent of grade. Two groups were predominantly low-grade tumors, comprised of a mixture of grade I and II tumors with 3 grade IV tumors, and the third group contained predominantly high-grade tumors with 2 low-grade tumors. Genes involved in the phosphatidylinositol signaling system, the cell cycle pathway, and the regulation of the actin cytoskeleton, were significantly differentially expressed between the 3 groups. Differential disruption of these cell pathways may be associated with subtypes of pediatric astrocytoma. Most tumors in the third group (including the low-grade tumors) showed copy number changes that can be correlated with changes in gene expression. In specific tumors, the downregulation of TSB1 (thrombospondin-1) correlated with loss at 15q15. This gene has previously been found to be downregulated in astrocytoma and is involved in cell adhesion. This finding suggests that gene expression in a subset of pediatric astrocytomas is influenced by gene dosage.