Detection of Tumor Indicators of Diffuse Intrinsic Pontine Glioma in Cerebrospinal Fluid, Serum and Urine

Keywords: brain stem, cerebrospinal fluid, glioma, biomarker, brain tumor

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     Diffuse intrinsic pontine glioma (DIPG) is a leading cause of brain tumor death in children. Proteomic analysis of cerebrospinal fluid (CSF) can detect tumor-secreted proteins.
     We used the CSF protein profile of DIPG patients to identify two upregulated tumor proteins relevant to brainstem gliomagenesis, with clinical correlation.
     CSF was submitted for MS/MS proteomic analysis using LTQ-Orbitrap-XL. Isolated peptides identified using the Sequest algorithm in the Bioworks browser against the Uniprot database were submitted to quantitative and subgroup analysis using ProteoIQ and Partek Genomics Suite. Proteins of interest were validated with western blot of CSF, brain tissue, serum and urine from glioma patients and normal controls, and tissue immunohistochemistry. Clinical course and imaging was reviewed. Molecular pathways were explored using Ingenuity Pathway Analysis.
     CSF proteomic analysis revealed selective upregulation of Cyclophillin A (CypA) and dimethylarginase 1 (DDAH1) in DIPG (n=8) and focal BSG (n=2) compared to supratentorial glioma (n=1) and controls (n=4). Findings were validated using western blot of CSF (n=48), brain tissue (n=19), serum (n=5) and urine (n=6) from glioma patients and normal controls. Immunohistochemical staining showed selective upregulation of secreted but not cytosolic forms in BSG. Protein expression correlated with higher tumor grade and tumorigenic molecular pathways.
     This is a retrospective study.
     We use the first comprehensive protein profile of CSF specimens from patients with DIPG to demonstrate selective expression of tumor proteins potentially involved in brainstem gliomagenesis.
     Facile detection of secreted tumor indicator proteins in serum and urine has potential clinical application, with implications for DIPG prognosis and treatment.


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