Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread
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Filippo Spreafico1, Italia Bongarzone2, Sara Pizzamiglio3, Ruben Magni4, Elena Taverna2, Maida De Bortoli2, Chiara M. Ciniselli3, Elena Barzanò1, Veronica Biassoni1, Alessandra Luchini4, Lance A. Liotta4, Weidong Zhou4, Michele Signore5, Paolo Verderio3 and Maura Massimino1
1Pediatric Oncology Unit, Department of Hematology and Pediatric Hematology-Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Proteomics Laboratory, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3Unit of Medical Statistics, Biometry and Bioinformatics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
5Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
Sara Pizzamiglio, email: email@example.com
Italia Bongarzone, email: firstname.lastname@example.org
Keywords: proteomic analysis, cerebrospinal fluid, pediatric central nervous system tumors, liquid chromatography/electrospray tandem mass spectrometry, protein-based biomarker
Received: August 04, 2016 Accepted: April 11, 2017 Published: May 03, 2017
Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher’s exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status.
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