Enhancer co-amplification 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 LPS patients, including whole genome sequencing (WGS), transcriptome, enhancer landscape, and genome-wide 3D genome structure by Hi-C. Tumor-specific transcripts and regulatory elements were identified, and enhancer co-amplification 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.