Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution

Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA…