Cerebrospinal fluid top‐down proteomics evidenced the potential biomarker role of LVV‐ and VV‐hemorphin‐7 in posterior cranial fossa pediatric brain tumors

Abstract

Posterior cranial fossa is the most frequent location of pediatric brain tumors. Its diagnosis is currently performed by postsurgery histopathology and the identification of biomarkers in cerebrospinal fluid (CSF) could provide a less invasive tool. Patient CSF was collected during surgery before the tumor removal (PRE-CSF) and 6 days after the resection (POST-CSF) and analyzed by top down LC-MS proteomics for comparison. The PRE-CSFs generally exhibited a less complex LC-MS profile than the relative POST-CSFs suggesting a suppressive role of the tumor toward proteins and peptides production or release. Particularly, a panel of peptides, identified as alpha- and beta-hemoglobin chains fragments, were generally absent in the PRE-CSF and present in the POST ones independently from contaminant blood hemoglobin. Among them, the LVV- and VV-hemorphin-7 showed the most repeatable trend and with a few remarkable exceptions: their unusual absence in POST surgery CSF was in fact interestingly correlated to the presence of tumor in the patient despite surgery due to metastases or to subtotal resection. These results ascribed a relevant biological role to LVV- and VV-h7 peptides in the disease and a strong potential as biomarkers. Their analysis in POST surgery CSF could be used to predict patient prognosis.

Ependymoma Pediatric Brain Tumor Protein Fingerprinting by Integrated Mass Spectrometry Platforms: A Pilot Investigation

“…Specifically, in relation to the latter, the expression of both opioid receptors and their ligands in tumor cells suggested their role in tumor progression [40]. Additionally, non-classical opioid peptides, the hemorphins, were reported in our previous paper as potential biomarkers of prognosis in posterior fossa pediatric brain tumor cerebrospinal fluid [41].…”

Progress in Top-Down Proteomics and the Analysis of Proteoforms

“…Phosphorylated proteoforms of cardiac troponin I have been identified as candidate biomarkers for chronic heart failure by FTICR-MS (109). Orbitrap-based instrumentation has been applied to intact biomarker studies that have identified candidate proteoform biomarkers in cerebrospinal fluid for pediatric brain tumor prognosis (110) as well as multiple salivary proteoforms potentially associated with complications of Down syndrome, including early onset Alzheimer’s disease (111). Additionally, TDP has been applied to biomarker studies concerning cirrhosis at risk of malignancy (ubiquitin PTMs) (112), schizophrenia and bipolar disorder (113), neurodevelopmental disorders (in combination with MALDI MS imaging) (114), Parkinson’s disease (alpha-synuclein proteoforms) (115), and medulloblastoma and pilocytic astrocytoma (116), all in just the past two years.…”

Transition from identity to bioactivity‐guided proteomics for biomarker discovery with focus on the PF2D platform

“…More recently, capillary electrophoresis has allowed separation of intact proteins and peptides in small capillaries under high voltage, using low sample and reagent consumption, and with high efficiency [131]. Some of these approaches, called top-down proteomics, although less employed than bottom-up proteomics, have shown their usefulness in investigating disease biomarkers [132][133][134][135][136][137][138][139]. They have been described as a complementary cost-effective approach in clinical research [140], and recently promoted by a new consortium for the comprehensive analysis of intact proteins [www.topdownproteomics.org.…”