The landscape of structural variation in pediatric cancer

Structural variants (SVs) account for over 60% of pediatric cancer driver variants. Pan-cancer analyses on 1,616 pediatric and 2,203 adult whole genomes show that pediatric SV burden varies ∼100-fold across cancer types, is reduced 6- to 16-fold compared to adult brain and solid tumors, but is comparable in hematological malignancies. The top-ranked SV-disrupted genes are drivers in pediatric cancers and fragile sites in adult cancers. Recurrent SV hotspots near RAG recombination signal sequences disrupt immune loci and driver genes in pediatric acute lymphoblastic leukemias, but immune loci exclusively in adult lymphoid cancers. Ten extracted SV signatures implicate RAG-mediated mutagenesis as a potential etiology for COSMIC SV7 in lymphoid cancers, while clustering of spatiotemporally distinct samples from 13 patients reveals the ongoing evolutionary contributions of SVs to intra-tumor heterogeneity and driver selection. Our study expands the known scope of RAG-mediated mutagenesis, while the curated SV dataset can guide future research and clinical testing. • A resource of curated structural variants (SVs) in 1,616 pediatric cancer genomes • Lower SV burden in brain/solid tumors but not in blood cancers compared to adults • SV hotspots enriched in pediatric cancer expand the role of RAG-mediated mutagenesis • Evolutionary contribution of SVs to intra-tumor heterogeneity and driver selection Greenhalgh et al. develop a resource of curated structural variants (SVs) from 1,616 pediatric cancer genomes for pan-cancer analyses and compared it with SVs from 2,203 adult cancers. Differences in target genes, recurrent hotspots, and SV signatures in these cohorts reveal varying mutagenesis mechanisms and their impact on tumorigenesis.