Multi-cohort study identifies RASA4B and PDE4DIP as prognostic biomarkers in neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in childhood and accounts for 15% of childhood cancer deaths. Understanding the genetic landscape of neuroblastoma is crucial for unraveling its underlying mechanisms and developing targeted therapeutic approaches. Here we identified gene fusions and mutations in Western (n = 170) and Chinese (n = 69) neuroblastoma cohorts by comprehensive transcriptome and whole-exome sequencing analysis. A total of 217 high-confidence gene fusions, including ARID3B-MYCN, were identified. Transcriptome analysis further revealed 106 high-confidence mutations involving 88 genes in Chinese cohort (n = 58) and 364 high-confidence mutations involving 245 genes in Western cohort (n = 166). Mutations in RASA4B and PDE4DIP were associated with increased RNA levels of each gene, and improved overall survival across both cohorts. Overexpression of RASA4B or PDE4DIP attenuated neuroblastoma cell growth in vitro and in vivo, accompanied by suppression of the RAS-MAPK signaling pathway. These findings expand our understanding of the genetic alterations observed across the two neuroblastoma cohorts and highlight RASA4B and PDE4DIP mutation status and expression levels as potential prognostic biomarkers.