Genomic rearrangements define a distinct biological state in neuroblastoma.
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Neuroblastoma is a heterogeneous pediatric cancer whose behavior is shaped by diverse genomic alterations. While previous genomic studies have identified recurrent drivers and mutational processes, whether large-scale genome architecture actively contributes to defining tumor states has not yet been fully investigated. How translocations and inversions integrate somatic instability, transcriptional programs and inherited susceptibility in neuroblastoma has not been systematically explored. Here, we leverage a whole-genome sequencing dataset of 316 neuroblastoma tumors with matched normal samples from two independent cohorts, complemented by transcriptomic profiling in a large subset of cases. We show that tumors harbouring translocations and inversions, operationally defined here as genomic rearrangements, represent a distinct biological state characterized by increased genomic instability, enrichment of focal copy number alterations and inferior clinical outcome. These tumors exhibit consistent enrichment of the oxidative stress-associated mutational signature SBS18, supporting a link between mutational processes and chromosomal instability. Transcriptomic analyses reveal coordinated activation of DNA repair and cell cycle programs alongside repression of neuronal differentiation pathways, independently of established clinical risk factors. In parallel, stringent variant interpretation delineates a high-confidence catalogue of rare but biologically and clinically relevant somatic point mutations, while germline analyses uncover enrichment of pathogenic variants in DNA damage response pathways, particularly ATR-mediated signaling, among tumors with genomic rearrangements. Together, these findings highlight genomic rearrangements as defining features of tumor state and as a central organizing principle of neuroblastoma biology, linking somatic genomic instability, transcriptional reprogramming and germline susceptibility.