Developmental origins shape the paediatric cancer genome

In the past two decades, technological advances have brought unprecedented insights into the paediatric cancer genome revealing characteristics distinct from those of adult cancer. Originating from developing tissues, paediatric cancers generally have low mutation burden and are driven by variants that disrupt the transcriptional activity, chromatin state, non-coding cis-regulatory regions and other biological functions. Within each tumour, there are multiple populations of cells with varying states, and the lineages of some can be tracked to their fetal origins. Genome-wide genetic screening has identified vulnerabilities associated with both the cell of origin and transcription deregulation in paediatric cancer, which have become a valuable resource for designing new therapeutic approaches including those for small molecules, immunotherapy and targeted protein degradation. In this Review, we present recent findings on these facets of paediatric cancer from a pan-cancer perspective and provide an outlook on future investigations. In this Review, Zhang and colleagues provide an overview of the molecular characteristics of paediatric cancer and highlight how these malignancies arise from developmental aberrations resulting in paediatric-specific cancer genomes that influence both the initiation and progression of cancer. Additionally, they discuss genetic vulnerabilities within these cancer genomes that present opportunities for therapeutic interventions.