RB1 mutations are seen in 40–60% of sporadic osteosarcoma5–7, making it the second most commonly mutated gene in this disease after TP53. Studies of osteosarcoma genomic evolution invariably report RB1 mutations as early, truncal events8,9 and germline mutations in RB1 increase the risk of osteosarcoma development10, denoting a causal role of RB1 defects during disease initiation. Here, TP53 is linked to osteosarcoma.