Subependymal Giant Cell Astrocytoma: Gene Expression Profiling

Abstract

Subependymal giant cell astrocytomas (SEGAs) are rare brain tumors occurring in patients with tuberous sclerosis complex (TSC). TSC is characterized by formation of benign tumors in many organs and neurologic disorders (epilepsy, mental retardation, and autism). The disease is caused by mutations in TSC1 (hamartin) or TSC2 (tuberin) which encode tumor suppressors. Inactivation of TSC1/TSC2 leads to enhanced activity of mTOR kinase that regulates i.a. transcription, translation, and cell growth. Data from experiments on lower eukaryotes showed several hundred newly identified genes modulated by TOR at the transcriptional level. However, very little was known about such genes in the human brain. Therefore, we performed global gene expression profiling in SEGAs with use of Affymetrix microarrays, which revealed a considerable number of differentially expressed genes. Identified genes differentially expressed in SEGAs when compared to normal human brain were mainly involved in tumorigenesis (ANXA1, GPNMB, S100A11, LTF, RND3, and SFRP4; up-regulated in SEGA), and the nervous system development and differentiation. Moreover, down-regulation of genes associated with functioning of the nervous system (e.g. CADPS2, CNDP1, ERMIN, GABRA1, MBP, MOBP, NEUROD1, NPTX1, RELN, SHANK3, and TF) in SEGA may be a cause of neurologic dysfunctions in TSC patients. Furthermore, up-regulation of MBP, ERMIN (markers of oligodendrocytes), NEUROD1, and NPTX1 (markers of immature neurons) in SEGA cells compared with normal human astrocytes suggested their mixed, glio-neuronal nature and inability to undergo terminal differentiation. Since SEGAs in patients with TSC appear to be of a mixed glio-neuronal lineage, the current practice of classifying these tumors as astrocytomas merits revision. Finally, it was shown that expression of ANXA1, GPNMB, S100A11, LTF, RND3, SFRP4, and NPTX1 was regulated by mTOR in SEGA cells. The presented data demonstrate new insights into transcriptional regulation induced by mTOR signaling dysfunctions. We anticipate that these results may influence future preclinical and clinical trials for TSC.