Abstract
Abstract BACKGROUND Current management of pediatric brain tumor patients relies on imaging as the only non-invasive tool available for monitoring therapeutic response and tumor progression. Results are often inconclusive and unable to capture biologically relevant changes that presage progression on imaging. Circulating miRNA provides an attractive non-invasive biomarker because miRNA has an essential role in regulating gene expression, stability in bio-fluids, selective over-expression in tumors, and is actively released from tumors into the extracellular environment. We aimed to establish the diagnostic and monitoring value of miRNA biomarkers for pediatric brain tumors in cerebrospinal fluid (CSF). METHODS We performed HTG EdgeSeq miRNA panel profiling (2100 targets) of CSF (n=33) samples across pediatric brain tumors from 5 histologies (low grade glioma, ependymoma, germ cell tumor, medulloblastoma, high-grade glioma). We utilized unsupervised consensus clustering, differential expression analysis, and machine learning approaches to investigate miRNA biomarkers. Results were validated using qPCR and ddPCR methods. RESULTS CSF miRNA signatures revealed a correlation with leptomeningeal disease and higher disease burden (p<0.05). Differentially expressed miRNA revealed histology-specific signatures for low grade glioma, medulloblastoma, and germinoma (p<0.05). miR216 expression was significantly elevated in medulloblastoma patients with active disease, indicating a potential novel biomarker for tumor monitoring. The miR216b-5p expression in CSF was confirmed using qPCR and ddPCR. The analysis of independent tumor tissue-based dataset confirmed miR216b-5p and its coding gene MIR217HG expression upregulated in medulloblastoma. MiR-216b-5p expression was also confirmed in patient-derived medulloblastoma cell lines and detected in cell free-media composition indicating extracellular release of miR216b-5p. CONCLUSIONS These results support the use of circulating miRNA in CSF as a potential biomarker for diagnosis and clinical monitoring of medulloblastoma. Further utilization of this approach provides a unique platform to inform liquid biopsy-based management in the clinical setting.
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