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Segmental gain of chromosome 17q is the most common genetic aberration in high-risk neuroblastoma, but its role in disease progression is poorly understood. This study aims to address the contribution of 17q gain to neuroblastoma malignancy. We analyzed the genetic and transcriptional landscape of 417 neuroblastoma patients across various risk groups and clinical stages using multi-omic approaches. Single-cell RNA/DNA sequencing and SNP arrays were combined to characterize genomic aberrations, while evolutionary trajectories were mapped to explore the accumulation of genetic changes in patients with neuroblastoma. Additionally, DNA and RNA sequencing were used to assess mutational burden and gene expression patterns. Our findings suggest that chromosome 17 gain is an early genetic event acquired during neuroblastoma development, correlating with the accumulation of additional chromosomal aberrations and poor prognosis. Increased segmental gains of chromosome 17q were observed during clonal evolution, relapse disease and metastasis. We identified PPM1D, a p53-inducible Ser/Thr phosphatase located on chr17q22.3, as a key player activated by segmental 17q-gain, gene-fusion, or gain-of-function somatic and germline mutations, further promoting neuroblastoma development/progression. Gain of chromosome 17 is an early driver of genetic instability in neuroblastoma, with PPM1D emerging as a potential candidate gene implicated in high-risk disease progression.