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Background  Conventional cytogenetic and comparative genomic hybridization (CGH) studies in brain malignancies have shown that glioblastoma multiforme (GBM) is characterized by complex structural and numerical alterations. However, the limited resolution of these techniques has precluded the precise identification of detailed specific gene copy number alterations.    Results  We performed a genome-wide survey of gene copy number changes in 20 primary GBMs by CGH on cDNA microarrays. A novel amplicon at 4p15, and previously uncharacterized amplicons at 13q32-34 and 1q32 were detected and are analyzed here. These amplicons contained amplified genes not previously reported. Other amplified regions containg well-known oncogenes in GBMs were also detected at 7p12 ( EGFR ), 7q21 ( CDK6 ), 4q12 ( PDGFRA ), and 12q13-15 ( MDM2  and  CDK4 ). In order to identify the putative target genes of the amplifications, and to determine the changes in gene expression levels associated with copy number change events, we carried out parallel gene expression profiling analyses using the same cDNA microarrays. We detected overexpression of the novel amplified genes  SLA/LP  and  STIM2  (4p15), and  TNFSF13B  and  COL4A2  (13q32-34). Some of the candidate target genes of amplification ( EGFR, CDK6, MDM2 ,  CDK4 , and  TNFSF13B ) were tested in an independent set of 111 primary GBMs by using FISH and immunohistological assays. The novel candidate 13q-amplification target  TNFSF13B  was amplified in 8% of the tumors, and showed protein expression in 20% of the GBMs.    Conclusion  This high-resolution analysis allowed us to propose novel candidate target genes such as  STIM2  at 4p15, and  TNFSF13B  or  COL4A2  at 13q32-34 that could potentially contribute to the pathogenesis of these tumors and which would require futher investigations. We showed that overexpression of the amplified genes could be attributable to gene dosage and speculate that deregulation of those genes could be important in the development and progression of GBM. Our findings highlight the important influence in GBM of signaling pathways such as the PI3K/AKT, consistent with the invasive features of this tumor.

Identification of novel candidate target genes in amplicons of Glioblastoma multiforme tumors detected by expression and CGH microarray profiling