Enhancer Coamplification and Hijacking Promote Oncogene Expression in Liposarcoma

Liposarcoma (LPS) is the most common soft-tissue sarcoma in adults with two major subtypes, well differentiated and dedifferentiated. Both subtypes are characterized with the pathognomonic giant ring or marker chromosomes that harbor high copy numbers of known oncogenes. Here, we reported a comprehensive molecular characterization of both tumor and normal tissues from the same patients with LPS, including whole-genome sequencing (WGS), transcriptome, enhancer landscape, and genome-wide three-dimensional (3D) genome structure by Hi-C. Tumor-specific transcripts and regulatory elements were identified, and enhancer coamplification and hijacking events were discovered as novel mechanisms upregulating oncogenes such as MDM2, CDK4, and HMGA2. Combining Hi-C, optical mapping, nanopore long reads, and WGS data partially resolved complex structural variations and reconstructed the local genome and the giant chromosome. Overall, this study provides a comprehensive resource for LPS research and offers insights into how altered enhancers and the 3D genome contribute to gene dysregulation in cancer. SIGNIFICANCE: Comprehensive profiling of the enhancer landscape and 3D genome structure in liposarcoma identifies extensive enhancer-oncogene coamplification and enhancer hijacking events, deepening the understanding of how oncogenes are regulated in cancer.