Dysregulation of Extracellular Matrix Genes Identifies Neuroblastoma Patients at High Risk of Recurrence and Poor Outcome

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children and exhibits substantial clinical heterogeneity. Although key genetic alterations such as N-Myc proto-oncogene protein amplification and anaplastic lymphoma kinase mutations are known drivers of neuroblastoma, their clinical utility is limited by population-specific genetic diversity. To address this, we propose a "function-over-gene" strategy by evaluating extracellular matrix (ECM)-related gene sets as molecular biomarkers, aiming to overcome the limitations posed by genetic heterogeneity and provide novel prognostic insights. METHODS: We integrated data from a single-center cohort and the TARGET database. Cox regression models were used to assess the prognostic value of ECM gene alterations and their association with clinical outcomes. Gene set enrichment analysis (GSEA) was employed to identify ECM-related gene sets, followed by transcriptomic analysis to explore downstream regulatory pathways. RESULTS: In the single-center cohort, ECM gene mutations were potentially associated with bone and lymph node metastases and emerged as an independent predictor of poor prognosis (HR=2.7, P =0.02) in multivariate analysis. Validation using the TARGET cohort confirmed the prognostic relevance of the ECM gene set (HR=1.55, P =0.0083) and revealed its involvement in modulating the tumor microenvironment via immune and complement pathways. CONCLUSION: ECM gene signatures serve as robust prognostic markers across populations. This function-based approach offers a novel perspective to address genetic heterogeneity and provides a theoretical foundation for ECM-targeted combination therapies.