Abstract A007: EcDNA-derived structural variants: A common pathway to oncogenic fusion transcript amplification in cancer

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 1,825 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, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation under strong selection in cancer. Citation Format: Shu Zhang, Hyerim Yi, Jason Swinderman, Yanbo Wang, Vishnupriya Kanakaviti, King L. Hung, Ivy Tsz-Lo. Wong, Suhas Srinivasan, Ellis J. Curtis, Aarohi Bhargava-Shah, Rui Li, Matthew G. Jones, Jens Luebeck, Chris Bailey, Yanding Zhao, Julia A. Belk, Katerina Kraft, Quanming Shi, Xiaowei Yan, Simon K. Pritchard, Kabir S. Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W. Felsher, Luke A. Gilbert, Vineet Bafna, Paul S. Mischel, Howard Y. Chang. EcDNA-derived structural variants: A common pathway to oncogenic fusion transcript amplification in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A007.