Circulating MicroRNAs as Diagnostic and Prognostic Biomarkers for Neuroblastoma: A Systematic Review and Exploratory...

Neuroblastoma is a leading cause of pediatric cancer deaths. Accurate and early risk stratification is crucial; however, current approaches rely on invasive biopsies. MicroRNAs have shown promise as non-invasive biomarkers. PubMed and EMBASE were systematically searched for studies evaluating circulating microRNAs in patients with neuroblastoma until April 2025. Eligible studies were included in a narrative synthesis. If raw expression data were available, a standardized re-analysis was performed to assess diagnostic and prognostic performance using differential expression, receiver operating characteristic (ROC) curve, and Cox regression analyses. Nine studies comprising 385 patients were included. Narrative synthesis identified four microRNAs consistently associated with high-risk disease: miR-375, miR-124-3p, miR-218-5p, and miR-490-5p. In our re-analysis, the findings were largely driven by a single cohort of 185 patients, with limited contributions from smaller studies, and should therefore be interpreted as exploratory. We identified nine microRNAs that were associated with poor prognosis. MiR-9-3p demonstrated the most promising performance for identifying high-risk disease (sensitivity = 0.95; specificity = 0.89) and the strongest association with poor overall survival (hazard ratio [HR] = 14.80). In multivariable analyses, miR-9-3p remained an independent predictor of poor survival (HR = 5.48) after controlling for MYCN amplification (HR = 2.08), metastatic disease (HR = 1.62), and age ≥ 18 months at diagnosis (HR = 2.30). While miR-9-3p may serve as a promising candidate biomarker for high-risk disease, there are several limitations to this study. Prospective multicenter validation is required before clinical implementation.