Molecular Portraits Of Ependymoma Recurrence By Paired Analysis Of Microarray Data

10048 Background: Relapse is a frequent phenomenon in intracranial childhood ependymomas. To gain new insights into this process and identify pathways associated with relapse, we compared the genomic and gene expression profiles of the relapses with the corresponding initial tumors. Methods: We studied 27 relapses in 17 patients by comparing their gene expression profile to the one obtained at diagnosis in the same child. Recurrences analyzed occurred after surgery alone in seven, surgery plus chemotherapy in 10 and any treatment plus radiotherapy in 11 cases. For each recurrence, gene expression levels were compared by dual color competitive hybridization on Agilent 44K gene expression microarrays. Statistical analysis was performed after initial filtering which retained only sequences differentially expressed (p<0.05) on at least 50% of experiments. Filtering criteria as well as the research of a common signature in recurrences and group comparisons were performed with Rosetta Resolver. Genomic profiling at diagnosis and at recurrence was performed using Agilent 44K oligo-CGH DNA microarrays and expression signatures were compared to gene copy number changes. Results: A subset of 48 sequences appeared to be significantly associated with recurrences (p<0.01) in at least 60% of cases. Among the genes upregulated at recurrence, some belonged to the Wnt and Notch pathways; 15 genes involved in proliferation and mitotic spindle were also upregulated. Metallothioneins were the genes most frequently (85%) downregulated at recurrence. RT-PCR and IHC data on selected genes confirmed the microarray results. Most frequent copy number changes were 3p and 6p losses and 9q and 1q gains. Copy number changes increased at recurrence compared with diagnosis in 9 patients and remained stable or decreased in 8. Comparison of microarray data with genomic imbalances revealed that most of the modifications in gene expression were not related to copy number changes. Conclusions: The most frequent molecular events associated with ependymoma relapse include increased proliferation associated with over-expression of kinetochore proteins and down-regulation of metallothioneins. Targeting of these pathways may offer novel therapeutic options in these refractory brain tumors. No significant financial relationships to disclose.