Circulating tumour DNA, microRNA and metabolites in cerebrospinal fluid as biomarkers for central nervous system malignancies

Abstract

<jats:p>Central nervous system (CNS) malignancies can be difficult to diagnose and many do not respond satisfactorily to existing therapies. Monitoring patients with CNS malignancies for treatment response and tumour recurrence can be challenging because of the difficulty and risks of brain biopsies, and the low specificity and sensitivity of the less invasive methodologies that are currently available. Uncertainty about tumour diagnosis or whether a tumour has responded to treatment or has recurred can cause delays in therapeutic decisions that can impact patient outcome. Therefore, there is an urgent need to develop and validate reliable and minimally invasive biomarkers for CNS tumours that can be used alone or in combination with current clinical practices. Blood-based biomarkers can be informative in the diagnosis and monitoring of various types of cancer. However, blood-based biomarkers have proven suboptimal for analysis of CNS tumours. In contrast, circulating biomarkers in cerebrospinal fluid (CSF), including circulating tumour DNA, microRNAs and metabolites, hold promise for accurate and minimally invasive assessment of CNS tumours. This review summarises the current understanding of these three types of CSF biomarkers and their potential use in neuro-oncologic clinical practice.</jats:p>

The Clinical Significance of Soluble Programmed Cell Death-Ligand 1 (sPD-L1) in Patients With Gliomas

“…However, regarding tumor size and molecular markers, the differences remained statistically significant in the CSF but not in the serum. An explanation for the results may be that the CSF is in direct contact with the CNS (51), which indicates that CSF sPD-L1 may be more suitable for CNS malignancies than serum sPD-L1 in clinical practice.…”

Peripheral biomarkers for pediatric brain tumors: current advancements and future challenges

“…Immunohistochemical assays are also possible, making the cytologic analysis of CSF somewhat comparable to tissue biopsy in the range of qualitative information it can provide. However, CSF cytology has a low sensitivity (45%), unless performed repeatedly on the same patient, making it an inaccurate and impractical brain tumor screening modality by itself [16,17] .…”

“…In the case of the CNS, intravascular spaces, parenchymal interstitial spaces, and the intraventricular/subarachnoid spaces represent the major extracellular compartments where biomarkers can collect. With diffusion into the intravascular spaces being limited by the blood brain barrier (BBB) [25] , the CSF and interstitial spaces, theoretically, should be the most rich in cytologic, genetic, and protein markers of tumor growth [16] . Most CSF based biomarker studies have focused on detecting: (1) tumor cells; (2) cellfree tumor DNA; (3) non-coding RNA; or (4) tumor-related metabolites.…”

“…A myriad of miRNA have been detected in the CSF of adult brain tumor patients, most prominently miR-21, miR-15b, miR-125b, and miR-223 [16,44,48,49] . These markers individually or in combination with other miRNA have demonstrated high levels of specificity and sensitivity for gliomas and medulloblastomas [47,49] .…”

“…Aberrations in tumor metabolism and cell signaling pathways relative to normal tissues tends to lead to an accumulation of well-characterized small molecules that can be used to predict the presence of a malignancy; and in certain instances, even predict the molecular signature of that malignancy [51] . Dyscrasias have been identified in all of the major metabolic cycles employed by cancer cells, including glucose metabolism, the pentose phosphate pathway, amino acid metabolism, and fatty acid metabolism, as well as many proliferative signaling pathways, such as the PI3K/AKT and WNT/β-catenin pathways [8,16] . Lactate, isocitrate, citrate, and D-2-hydroxyglutarate are metabolites known to accumulate in gliomas utilizing aerobic glycolysis as their dominant ATP source [52] .…”