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Abstract Neuroblastoma (NB) is one of the most lethal childhood cancers due to its propensity to become treatment resistant. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicate these two contrasting scenarios and show branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

Natalie Andersson et al. present DEVOLUTION, an algorithm and tool that allows researchers to reconstruct tumor clonal lineages from copy number and/or sequencing data. They validate this method on a diverse cohort of pediatric cancers, demonstrating its potential applications for cancer research.

Clonal evolution and heterogeneity has strong implications for treatment response in acute myeloid leukemia. Here, the authors use patient derived in vivo modelling to highlight the complex clonal and evolutionary dynamics underpinning acute myeloid leukemia progression.