EcDNA-borne structural variants drive oncogenic fusion transcript amplification

Hyerim Yi; Shu Zhang; Jason Swinderman; Yanbo Wang; Vishnupriya Kanakaveti; 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

doi:10.1016/j.cell.2025.12.009

EcDNA-borne structural variants drive oncogenic fusion transcript amplification

Cell. 2026 Feb 5;189(3):906-921.e20. doi: 10.1016/j.cell.2025.12.009. Epub 2026 Jan 7.

Authors

Hyerim Yi¹, Shu Zhang¹, Jason Swinderman², Yanbo Wang¹, Vishnupriya Kanakaveti³, King L Hung⁴, Ivy Tsz-Lo Wong⁵, Suhas Srinivasan⁶, Ellis J Curtis⁷, Aarohi Bhargava-Shah⁸, Rui Li⁶, Matthew G Jones⁶, Jens Luebeck⁹, Chris Bailey¹⁰, Yanding Zhao⁶, Julia A Belk⁶, Katerina Kraft⁶, Quanming Shi⁶, Xiaowei Yan¹, Simon K Pritchard¹¹, Kabir S Mahajan¹¹, Frances Liang¹¹, Mariam Jamal-Hanjani¹², Dean W Felsher³, Luke A Gilbert², Vineet Bafna¹³, Paul S Mischel¹⁴, Howard Y Chang¹⁵

Affiliations

¹ RNA Medicine Program, Stanford University, Stanford, CA, USA; Departments of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
² Arc Institute, Palo Alto, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Departments of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁶ RNA Medicine Program, Stanford University, Stanford, CA, USA; Departments of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; School of Medicine, University of California at San Diego, La Jolla, CA, USA.
⁸ RNA Medicine Program, Stanford University, Stanford, CA, USA; Departments of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA; School of Medicine, Stanford University, Stanford, CA, USA.
⁹ Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA.
¹⁰ Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute, London, UK.
¹¹ RNA Medicine Program, Stanford University, Stanford, CA, USA.
¹² Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK.
¹³ Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA; Halıcıoğlu Data Science Institute, University of California at San Diego, La Jolla, CA, USA.
¹⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA. Electronic address: psmischel@stanford.edu.
¹⁵ RNA Medicine Program, Stanford University, Stanford, CA, USA; Departments of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: howchang@stanford.edu.

PMID: 41506267
DOI: 10.1016/j.cell.2025.12.009

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.

Keywords: PVT1; RNA fusion; RNA stability; SRSF1; cancer; ecDNA; extrachromosomal DNA; oncogene.

MeSH terms

Cell Line, Tumor
DNA Copy Number Variations
Gene Amplification*
Genomic Instability
Humans
Neoplasms* / genetics
Oncogene Fusion* / genetics
Oncogene Proteins, Fusion / genetics
RNA Stability
RNA, Long Noncoding / genetics
RNA, Long Noncoding / metabolism

Substances

RNA, Long Noncoding
Oncogene Proteins, Fusion

Abstract

MeSH terms

Substances

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