Genetic Risk Profiling Reveals Altered Glycosyltransferase Expression as a Predictor for Patient Outcome in Neuroblastoma.
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Background/Objectives: Neuroblastoma is a highly aggressive pediatric cancer that arises from immature nerve cells and exhibits a broad spectrum of clinical presentations. While low- and intermediate-risk neuroblastomas often have favorable outcomes, high-risk neuroblastomas are associated with poor prognosis and significant treatment challenges. The complex genetic networks driving these high-risk cases remain poorly understood. This study aims to investigate differences in gene expression patterns that may contribute to disease outcomes. Methods: We employed an in silico approach to analyze a cohort of 493 neuroblastoma tumor samples that underwent mRNA sequencing (GSE49711). This dataset was reanalyzed in depth with a non-hypothesis-driven approach to identify the expression patterns and regulatory mechanisms associated with a poor prognosis. Results: By exploring global gene expression and the integration of clinical parameters, we stratified the samples into two groups with highly distinct gene expression profiles. MYCN amplification emerged as a major driver not only of poor prognosis but also of specific gene regulatory patterns. Notably, tumors with MYCN amplification exhibited the strong regulation of immune response genes and less immune infiltration, suggesting potential immune evasion. However, while we observed only minor changes in immune checkpoint expression, there was a strong modulation of glycosyltransferase genes in MYCN-amplified tumors. Using this information, we were able to construct a risk profile based on 12 glycosylation-related genes, which correlates with the survival outcomes of neuroblastoma patients. Conclusions: This study highlights the role of MYCN amplification in driving a poor prognosis in neuroblastoma through the regulation of immune response and glycosylation-related genes. Based on this finding, we developed a genetic risk profile that correlates with survival outcomes in neuroblastoma patients.