Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. There remains an unmet need for diagnostics to sensitively detect the disease, particularly recurrences. Cerebrospinal fluid (CSF) provides a window into the central nervous system, and liquid biopsy of CSF could provide a relatively non-invasive means for disease diagnosis. There has yet to be an integrated analysis of the transcriptomic, metabolomic, and lipidomic changes occurring in the CSF of children with MB. CSF samples from patients with (n = 40) or without (n = 11; no cancer) MB were subjected to RNA-sequencing and high-resolution mass spectrometry to identify RNA, metabolite, and lipid profiles. Differentially expressed transcripts, metabolites, and lipids were identified and their biological significance assessed by pathway analysis. The DIABLO multivariate analysis package (R package mixOmics) was used to integrate the molecular changes characterizing the CSF of MB patients. Differentially expressed transcripts, metabolites, and lipids in CSF were discriminatory for the presence of MB but not the exact molecular subtype. One hundred and ten genes and ten circular RNAs were differentially expressed in MB CSF compared with normal, representing TGF-β signaling, TNF-α signaling via NF-kB, and adipogenesis pathways. Tricarboxylic acid cycle and other metabolites (malate, fumarate, succinate, α-ketoglutarate, hydroxypyruvate, N-acetyl-aspartate) and total triacylglycerols were significantly upregulated in MB CSF compared with normal CSF. Although separating MBs into subgroups using transcriptomic, metabolomic, and lipid signatures in CSF was challenging, we were able to identify a group of omics signatures that could separate cancer from normal CSF. Metabolic and lipidomic profiles both contained indicators of tumor hypoxia. Our approach provides several candidate signatures that deserve further validation, including the novel circular RNA circ_463, and insights into the impact of MB on the CSF microenvironment.
Highlights
Medulloblastoma (MB) is the most common malignant tumor of the cerebellum in children, and it accounts for 10–15% of pediatric central nervous system (CNS) tumors [1]
The eleven normal samples were purchased from BioIVT (Westbury, NY USA), Discovery Life Sciences (Huntsville, AL USA), and Lee Biosolutions (Maryland Heights, MO USA); thirty samples were from the Children Brain Tumor Tissue Consortium (CBTTC); five samples were from Johns Hopkins University (JHU); and five samples from Johns Hopkins All Children’s Hospital (JHACH)
There was no clear separation into molecular subtypes, one hundred and ten genes were differentially expressed in cerebrospinal fluid (CSF) samples from patients with and without MB (Fig. 1c, Additional file 4: Table S2, and Additional file 4: Fig. S1; log2 fold-change (FC) < -2 or > 2; adjusted p-value < 0.05) that were enriched for several pathways by geneset enrichment analysis (GSEA) [35]: TGF-β signaling (SKI, FKBP1A, ID2, RHOA, BMPR1A; false discovery rate (FDR) 2.59E-04), TNF-α signaling via NF-kB (TSC22D1, DUSP1, ID2, KLF9, FOS, IL6ST, SAT1; FDR 1.19E-03), and adipogenesis (ALDH2, CMPK1, APOE, UQCR10, TOB1, YWHAG; FDR 4.51E-03)
Summary
Medulloblastoma (MB) is the most common malignant tumor of the cerebellum in children, and it accounts for 10–15% of pediatric central nervous system (CNS) tumors [1]. Recent advances in imaging have improved MB detection and monitoring, there remain unmet needs for diagnostics to sensitively detect the disease at both initial presentation and at recurrence. More recent studies with increased cohort sizes have identified intra-subtypes and described a total of twelve subgroups [7, 8] Despite this considerable progress in the molecular characterization of MB, the biology and impact of the disease on the CSF microenvironment is still poorly understood, despite the tumor microenvironment contributing to cancer progression, metastasis, and resistance and potentially providing a rich source of biomarkers that can be sampled relatively non-invasively to chart the course of disease
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