Abstract 4065: EcDNA-borne structural variants drive oncogenic fusion transcript amplification

Abstract Extrachromosomal DNA (ecDNA) amplifications are key drivers of human cancers. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. By integrating analysis of whole genome and transcriptome sequences from tumor samples and cancer cell lines of a wide variety of tissue types, we reveal that ecDNAs have the highest rate of oncogene fusion events of any copy number alteration. Focusing on the most common ecDNA fusion hotspot, we find that fusion of the 5' end of the long noncoding RNA gene, PVT1-with exon 1 joined to diverse 3' partners-confers increased RNA stability, potentially via an SRSF1-dependent mechanism, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation in cancer. Citation Format: Hyerim Yi, Shu Zhang, Jason Swinderman, Yanbo Wang, Vishnupriya Kanakaveti, King L. Hung, Ivy T.-L. Wong, Suhas Srinivasan, Ellis J. Curtis, Aarohi Bhargava-Shah, Rui Li, Matthew G. Jones, Jens Luebeck, Chris Bailey, Yanding Zhao, Julia Belk, Katerina Kraft, Quanming Shi, Xiaowei Yan, Simon K. Pritchard, Kabir S. Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W. Felsher, Luke Gilbert, Vineet Bafna, Paul S. Mischel, Howard Y. Chang. EcDNA-borne structural variants drive oncogenic fusion transcript amplification abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4065.