EcDNA-borne structural variants drive oncogenic fusion transcript amplification
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.
Authors
- Dean W. Felsher (ORCID: https://orcid.org/0000-0003-2496-523X)
- Shu Zhang (ORCID: https://orcid.org/0000-0002-2680-255X)
- Vishnupriya Kanakaveti (ORCID: https://orcid.org/0000-0001-9965-2858)
- Quanming Shi (ORCID: https://orcid.org/0000-0003-2109-5048)
- Suhas Srinivasan (ORCID: https://orcid.org/0000-0001-8309-9648)
- Luke A. Gilbert (ORCID: https://orcid.org/0000-0001-5854-0825)
- Ellis J. Curtis (ORCID: https://orcid.org/0000-0003-3751-9968)
- Paul S. Mischel (ORCID: https://orcid.org/0000-0002-4560-2211)
- Ivy Tsz-Lo Wong (ORCID: https://orcid.org/0000-0002-9761-3422)
- H J Chang
- Julia A. Belk (ORCID: https://orcid.org/0000-0003-4724-6158)
- Hyerim Yi (ORCID: https://orcid.org/0000-0001-6456-4743)
- Mariam Jamal‐Hanjani (ORCID: https://orcid.org/0000-0003-1212-1259)
- Y. Zhao
- Xiaowei Yan (ORCID: https://orcid.org/0000-0003-4215-1395)
- Fei Liang (ORCID: https://orcid.org/0000-0002-8887-9536)
- Katerina Kraft (ORCID: https://orcid.org/0000-0002-2011-6946)
- Chris Bailey (ORCID: https://orcid.org/0000-0002-1602-8396)
- King L. Hung (ORCID: https://orcid.org/0000-0002-3662-4662)
- Jason Swinderman (ORCID: https://orcid.org/0000-0002-4268-9788)
- Matthew G. Jones (ORCID: https://orcid.org/0000-0002-1850-9644)
- Yanbo Wang
- Aarohi Bhargava-Shah
- Vineet Bafna
- Simon K. Pritchard
- Rui Li
- Jens Luebeck
- Kabir S. Mahajan
Institutions
- University of California, San Francisco (US)
- The Francis Crick Institute (GB)
- University of California San Diego (US)
- Stanford Medicine (US)
- Pediatrics and Genetics (US)
- CRUK Lung Cancer Centre of Excellence (GB)
- University College London (GB)
- Stanford University (US)
Publication Details
- Journal
- Cell
- Published
- 2026-01-07
- DOI
- https://doi.org/10.1016/j.cell.2025.12.009
- Citations
- 1
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 24.82