Origins and impact of extrachromosomal DNA

Chris Bailey, Oriol Pich, Kerstin Thol, Thomas B. K. Watkins, Jens Luebeck, Andrew Rowan, Georgia Stavrou, Natasha E. Weiser, Bhargavi Dameracharla, Robert Bentham, Wei-Ting Lu, Jeanette Kittel, S. Y. Cindy Yang, Brooke E. Howitt, Natasha Sharma, Maria Litovchenko, Roberto Salgado, King L. Hung, Alex J. Cornish, David A. Moore, Richard S. Houlston, Vineet Bafna, Howard Y. Chang, Serena Nik-Zainal, Nnennaya Kanu, Nicholas McGranahan, Adrienne M. Flanagan, Paul S. Mischel (), Mariam Jamal-Hanjani () and Charles Swanton ()
Additional contact information
Chris Bailey: The Francis Crick Institute
Oriol Pich: The Francis Crick Institute
Kerstin Thol: University College London Cancer Institute
Thomas B. K. Watkins: Stanford University
Jens Luebeck: University of California at San Diego
Andrew Rowan: The Francis Crick Institute
Georgia Stavrou: University College London Cancer Institute
Natasha E. Weiser: Stanford University
Bhargavi Dameracharla: Stanford University
Robert Bentham: University College London Cancer Institute
Wei-Ting Lu: The Francis Crick Institute
Jeanette Kittel: University College London Cancer Institute
S. Y. Cindy Yang: Stanford University
Brooke E. Howitt: Stanford University
Natasha Sharma: University College London Cancer Institute
Maria Litovchenko: University College London Cancer Institute
Roberto Salgado: ZAS Hospitals
King L. Hung: Stanford University
Alex J. Cornish: The Institute of Cancer Research
David A. Moore: The Francis Crick Institute
Richard S. Houlston: The Institute of Cancer Research
Vineet Bafna: University of California at San Diego
Howard Y. Chang: Stanford University
Serena Nik-Zainal: University of Cambridge
Nnennaya Kanu: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute
Adrienne M. Flanagan: UCL Cancer Institute
Paul S. Mischel: Stanford University
Mariam Jamal-Hanjani: University College London Cancer Institute
Charles Swanton: The Francis Crick Institute

Nature, 2024, vol. 635, issue 8037, 193-200

Abstract: Abstract Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system.

Date: 2024
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DOI: 10.1038/s41586-024-08107-3

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