Genetic and chromosomal dysregulations of progenitor cells in the etiology and pathogenesis of pediatric cancers.

Pediatric cancers (PCs) differ significantly from adult cancers in terms of etiology and response to treatment. Although environmental factors have been implicated in the development of some PCs, accumulating evidence indicates that these cancers may arise from genetic dysregulation, which introduces errors within the precursor cells and the progenitor cell machinery during the early developmental stages. Such dysregulations are often explained by a "multi-hit model", in which progenitor cells acquire an initial prenatal mutation that predisposes them to subsequent postnatal hits, eventually driving malignant transformation. This review aims to consolidate emerging evidence on the role of these dysregulated progenitor cells (dPCs) as tumor cells of origin in PCs and to examine how their identity and developmental timing shape tumor phenotype, latency, and clinical behavior. Evidence drawn from monozygotic twin studies, germline predisposition syndromes, and genetically engineered mouse models were discussed for selected PC categories. This review also analyzes the current targeted therapeutic approaches. Such evidences indicate a firm and recurring role for dPCs across diverse PC subtypes, though a complete functional understanding of their dysregulation and the identification of reliable therapeutic targets remain in their early stages. Unlike adult cancers, therapeutic strategies for PCs should account for developmentally timed vulnerabilities intrinsic to their cells of origin, positioning dPCs as a potential therapeutic target.