Funder: Bone Cancer Research Trust; Id: http://dx.doi.org/10.13039/100011719Funder: The Tom Prince Cancer TrustFunder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269Funder: Jean Shanks Foundation – Pathological Society Clinical FellowshipFunder: UCL Experimental Cancer CentreFunder: UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272Osteosarcoma, the most common primary malignant tumour of bone, affects both children and adults. No fundamental biological differences between paediatric and adult osteosarcoma are known. Here, we apply multi-region whole-genome sequencing to an index case of a 4-year-old child whose aggressive tumour harboured high-level, focal amplifications of MYC and CCNE1 connected by translocations. We reanalysed copy number readouts of 258 cases of high-grade osteosarcoma from three different cohorts and identified a significant enrichment of focal MYC, but not CCNE1, amplifications in children. Furthermore, we identified four additional cases of MYC and CCNE1 coamplification, highlighting a rare driver event which warrants further investigation. Our findings indicate that amplification of the MYC oncogene is a major driver of childhood osteosarcoma, while CCNE1 appears recurrently amplified independent of age
