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.

在过去的二十年里，技术进步为儿科癌症基因组带来了前所未有的见解，揭示了与成人癌症不同的特征。儿科癌症起源于发育中的组织，通常具有较低的突变负荷，并且由破坏转录活性、染色质状态、非编码顺式调节区域和其他生物学功能的变异驱动。在每个肿瘤中，有多个状态不同的细胞群，其中一些细胞的谱系可以追溯到它们的胎儿起源。全基因组基因筛选已经确定了与儿科癌症中起源细胞和转录失调相关的脆弱性，这已成为设计新治疗方法的宝贵资源，包括小分子、免疫疗法和靶向蛋白质降解的方法。在本综述中，我们从泛癌的角度介绍了儿科癌症这些方面的最新发现，并对未来的研究进行了展望。