Abstract
Pediatric spinal ependymomas (SEPN) are important albeit uncommon malignant central nervous system tumors with limited treatment options. Our current knowledge about the underlying biology of these tumors is limited due to their rarity. To begin to elucidate molecular mechanisms that give rise to pediatric SEPN, we compared the transcriptomic landscape of SEPNs to that of intracranial ependymomas using genome-wide mRNA and microRNA (miRNA) expression profiling in primary tumour samples. We found that pediatric SEPNs are characterized by increased expression of genes involved in developmental processes, oxidative phosphorylation, cellular respiration, electron transport chain, and cofactor metabolic process. Next, we compared pediatric spinal and intracranial ependymomas with the same tumours in adults and found a relatively low number of genes in pediatric tumours that were shared with adult tumours (12.5%). In contrast to adult SEPN, down-regulated genes in pediatric SEPN were not enriched for position on chromosome 22. At the miRNA level, we found ten miRNAs that were perturbed in pediatric SEPN and we identified regulatory relationships between these miRNAs and their putative targets mRNAs using the integrative miRNA-mRNA network and predicted miRNA target analysis. These miRNAs include the oncomiR hsa-miR-10b and its family member hsa-miR-10a, both of which are upregulated and target chromatin modification genes that are down regulated in pediatric SEPN. The tumor suppressor, hsa-miR-124, was down regulated in pediatric SEPN and it normally represses genes involved in cell-cell communication and metabolic processes. Together, our findings suggest that pediatric SEPN is characterized by a distinct transcriptional landscape from that of pediatric intracranial EPNs or adult tumors (both SEPNs and intracranial EPNs). Although confirmatory studies are needed, our study reveals novel molecular pathways that may drive tumorigenesis and could serve as biomarkers or rational therapeutic targets.
Highlights
Ependymomas (EPNs) are primary tumours of the central nervous system (CNS) that affect both children and adults [1]
Based on gene expression signatures, including both proteincoding genes and miRNAs, we discovered significant upregulation in specific genes and their associated pathways in pSEPN when compared to pediatric intracranial ependymoma or adult EPN
The differential expression of a subset of genes expressed in pSEPN compared to pediatric intracranial EPN was validated in an independent cohort of pediatric EPNs
Summary
Ependymomas (EPNs) are primary tumours of the central nervous system (CNS) that affect both children and adults [1]. They account for 8-10% of CNS tumors in children and approximately 4% of adult CNS tumors [2, 3]. Current treatment strategies for malignant EPNs include maximal surgical resection, radiation therapy, and chemotherapy [4]. Current prognostic factors for EPNs are based on clinical and histological criteria, such as extent of tumor resection and histological grade [7]. Complete surgical resection is not always achieved and studies to investigate the prognostic value of the WHO grading system have yielded conflicting results. There is an important and unmet need to delineate the cellular and molecular pathogenesis of EPNs in order to develop more robust prognostic signatures and to identify new therapeutic targets to improve outcomes
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