Genetic heterogeneity within a single tumour is the breeding ground for cancer progression and treatment failure. We study the highly malignant bone tumour osteosarcoma, which has one of the most rearranged genomes of all cancers and a high cell-to-cell variability. This is surprising because osteosarcoma primarily affects children and adolescents. These patients have not had the long life behind them thought necessary for the accumulation of massive amounts of somatic mutations. We believe that this paradox is key in understanding what is required of a cell to allow rapid manifestation as a high-grade malignancy. Our ultimate aim is to develop new treatment strategies for patients with osteosarcoma and other high-grade malignancies. To this end, we screen primary tumour material for pathogenetic aberrations using next-generation sequencing technology and we manipulate genes of interest in cancer model systems using the CRISPR/Cas9 gene editing system.