CDK4is co-amplified with eitherTP53promoter gene fusions orMDM2through distinct mechanisms in osteosarcoma

Abstract

AbstractAmplification of theMDM2andCDK4genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases withMDM2and/orCDK4amplification. We identified four major subgroups: (i) low-grade osteosarcoma with chromosome 12 amplicons as the sole acquired alteration, (ii) high- and low-grade tumours withCDK4andMDM2amplification along with few changes affecting other chromosomes, (iii) high-grade osteosarcomas with heavily rearranged genomes including eitherCDK4andMDM2amplification or (iv)CDK4amplification andTP53structural alterations. The amplicons involvingMDM2exhibited signs of an initial chromothripsis event affecting chromosome 12. In contrast, there was no indication of a chromothripsis event on chromosome 12 inTP53-rearranged cases. Instead, the initial disruption of theTP53locus resulted in breakage and repair processes that co-amplified theCDK4locus. Furthermore, our investigation revealed recurring promoter swapping events that involved the regulatory regions of theFRS2,PLEKHA5, andTP53genes. These events led to the ectopic expression of partner genes, with theELF1gene being upregulated by theFRS2andTP53promoter regions, respectively, in two distinct cases.