12 号染色体上的 MDM2 和 CDK4 基因扩增通常与低度恶性骨肉瘤相关。在这项研究中，我们对来自 25 个骨肉瘤的 33 个样本进行了高分辨率基因组和转录组分析，包括具有 MDM2 和/或 CDK4 扩增的高级别和低级别病例。我们识别出四个主要亚组，从几乎完整的基因组到严重重排的基因组，每个亚组都包含 CDK4 和 MDM2 扩增或带有 TP53 结构改变的 CDK4 扩增。虽然涉及 MDM2 的扩增子表现出初始染色体碎裂事件的迹象，但在 TP53 重排病例中没有发现染色体碎裂的证据。相反，TP53 基因座的最初破坏导致了 CDK4 基因座的共同扩增。此外，我们观察到涉及 FRS2、PLEKHA5 和 TP53 基因调控区域的重复启动子交换事件。这些事件导致伙伴基因异位表达，在两种不同的情况下，ELF1 基因被 FRS2 和 TP53 启动子区域上调。© 2024。作者。

Amplification of the MDM2 and CDK4 genes 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 with MDM2 and/or CDK4 amplification. We discerned four major subgroups, ranging from nearly intact genomes to heavily rearranged ones, each harbouring CDK4 and MDM2 amplification or CDK4 amplification with TP53 structural alterations. While amplicons involving MDM2 exhibited signs of an initial chromothripsis event, no evidence of chromothripsis was found in TP53-rearranged cases. Instead, the initial disruption of the TP53 locus led to co-amplification of the CDK4 locus. Additionally, we observed recurring promoter swapping events involving the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events resulted in ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions in two distinct cases.© 2024. The Author(s).