Abstract
Brain tumors are the most common solid tumors in childhood. There is the need for biomarkers of residual disease, therapy response and recurrence. Cerebrospinal fluid (CSF) is a source of brain tumor biomarkers. We analyzed the proteome of waste CSF from extraventricular drainage (EVD) from 29 children bearing different brain tumors and 17 controls needing EVD insertion for unrelated causes. 1598 and 1526 proteins were identified by liquid chromatography-coupled tandem mass spectrometry proteomics in CSF control and brain tumor patients, respectively, 263 and 191 proteins being exclusive of either condition. Bioinformatic analysis revealed promising protein biomarkers for the discrimination between control and tumor (TATA-binding protein-associated factor 15 and S100 protein B). Moreover, Thymosin beta-4 (TMSB4X) and CD109, and 14.3.3 and HSP90 alpha could discriminate among other brain tumors and low-grade gliomas plus glyoneuronal tumors/pilocytic astrocytoma, or embryonal tumors/medulloblastoma. Biomarkers were validated by ELISA assay. Our method was able to distinguish among brain tumor vs non-tumor/hemorrhagic conditions (controls) and to differentiate two large classes of brain tumors. Further prospective studies may assess whether the biomarkers proposed by our discovery approach can be identified in other bodily fluids, therefore less invasively, and are useful to guide therapy and predict recurrences.
Highlights
Pediatric brain tumors are a leading cause of tumor-related mortality in children[1,2]
We conducted a proteomic and bioinformatic analysis of cerebrospinal fluid (CSF) samples collected from the extra ventricular drainage (EVD) of 29 consecutive patients treated for common brain tumor types including both malignant and benign histopathologies, and compared these to CSF samples sourced from the EVD of 17 non-tumor patients and identified some putative protein biomarkers
Stratifying brain tumor samples according to three clinical groups (i.e. low-grade gliomas (LGG) plus glioneuronal tumors (GT), embryonal tumors (EMB), Other Brain Tumors), it was observed that 870 proteins (48.6%) were overall overlapping, while 30 (1.7%), 115 (6.4%) and 12 (0.7%) were exclusive for LGG plus GT, EMB, and Other Brain Tumors, respectively
Summary
Pediatric brain tumors are a leading cause of tumor-related mortality in children[1,2]. Pediatric primitive neuroectodermal tumors and ependymomas were studied by a proteome-wide approach, and three proteins (stathmin, annexin A1, and calcyphosine) were identified as tumor-specific[20]. Spreafico et al.[18] characterized the CSF proteome of children bearing CNS tumors, to identify biomarkers predictive of metastatic spread. We conducted a proteomic and bioinformatic analysis of CSF samples collected from the extra ventricular drainage (EVD) of 29 consecutive patients treated for common brain tumor types including both malignant and benign histopathologies, and compared these to CSF samples sourced from the EVD of 17 non-tumor patients and identified some putative protein biomarkers. Aim of our study was to utilize the considerable volume of CSF from EVD routinely treated as a waste, to seek for predictive protein biomarkers for estimating probability of a tumoral condition from any other needing an EVD, characterized by pathological CSF production (controls). We aimed to assess whether any of the putative biomarkers could discern specific brain tumor types
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