Blood, CSF, and Urine Biomarkers for Paediatric Brain Tumours: A Systematic Review of Liquid Biopsy Approaches
Jack Read, Jinyue Yu, Craig Paterson, Farhad Shokraneh, Phillipa Davies, Julian P T Higgins, Kathreena M KurianAbstract
Background
Identification of non-invasive biomarkers in blood, cerebrospinal fluid (CSF), or urine could aid diagnosis and monitoring in paediatric brain tumours.
Methods
We searched MEDLINE, Embase, SCIE, and Cochrane Database of Systematic Reviews. Data on tumour type, biomarkers and biofluid were extracted. Diagnostic performance (sensitivity, specificity, and area under the curve (AUC)) for discrimination between tumour and comparator groups was summarised. Risk of bias was assessed using QUADAS-2.
Results
25 studies were included (1025 patients: including medulloblastoma, diffuse midline glioma H3K27-altered (DMG), pilocytic astrocytoma (PA)/optic pathway glioma, ependymoma, high-grade gliomas and 842 controls). Diagnostic performance relative to study-specific comparator groups (eg, healthy controls, non-tumour neurological conditions) was summarised. In medulloblastoma, blood miR-15a-5p (18-fold increase, P = .049) and IL-7 (P < .0001) were elevated, while CSF 14-3-3 and HSP90-alpha achieved AUCs 0.96-0.97. Urinary Netrin-1 showed 81% sensitivity and AUC 0.875, and panels combining CADH1, FIBB, and FGFR4 reached AUC 0.973. DMG was detectable via H3K27M ctDNA in blood and CSF, with altered circulating and extracellular histones (P < .01). In PA, blood miR-222-3p (≥21.9; sensitivity 88.9%, specificity 72%, AUC 0.796) and miR-26a-5p (≥387; sensitivity 100%, specificity 64%, AUC 0.751) and neuron-specific enolase (AUC 0.89) were elevated. CSF CPXM2 distinguished PA from controls (AUC 0.91; sensitivity 100%, specificity 71%), with downregulated AQP4 (P < .05). Ependymomas exhibited elevated blood miR-93-5p (≥154.48; sensitivity 80%, specificity 100%, AUC 0.821) and miR-138-5p (≥16.06; sensitivity 80%, specificity 67%, AUC 0.817). High-grade gliomas had reduced TNF-β. CSF proteomic studies identified S100B, PGD2S, ApoE, and cyclophilin A (sensitivities up to 100% and AUCs approaching 1.0). Across studies, CSF biomarkers generally showed the highest diagnostic accuracy, while blood and urine offered greater clinical feasibility.
Conclusions
Paediatric tumour-specific liquid biopsy biomarkers hold promise for non-invasive clinical management. However, future research with larger prospective longitudinal validation cohorts is required.