Pan-cancer genome and transcriptome analyses of 1,699 pediatric leukemias and solid tumors

Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult(1–4) but not pediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues(5). Here we present a pan-cancer study of somatic alterations, including single nucleotide variants (SNVs), small insertion/deletions (indels), structural variations (SVs), copy number alterations (CNAs), gene fusions and internal tandem duplications (ITDs), in 1,699 pediatric leukemia and solid tumours across six histotypes, with whole-genome (WGS), whole-exome (WES) and transcriptome (RNA-seq) sequencing data processed under a uniform analytical framework (Online Methods and Extended Data Fig. 1). We report 142 driver genes in pediatric cancers, of which only 45% matched those found in adult pan-cancer studies and CNAs and SVs constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for pediatric cancers and emphasize the need for pediatric cancer-specific development of precision therapies.