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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\u00a039 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\u00a0a 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\n                    <jats:italic>trans<\/jats:italic>\n                    . We also\u00a0identify 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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-08107-3","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T12:03:10Z","timestamp":1730894590000},"page":"193-200","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":209,"title":["Origins and impact of extrachromosomal DNA"],"prefix":"10.1038","volume":"635","author":[{"given":"Chris","family":"Bailey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1956-1882","authenticated-orcid":false,"given":"Oriol","family":"Pich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4624-118X","authenticated-orcid":false,"given":"Kerstin","family":"Thol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B. 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C.S. is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the steering committee chair. C.S. is also co-chief investigator of the NHS Galleri trial financed by GRAIL and a paid member of GRAIL\u2019s scientific advisory board (SAB). C.S. receives consultant fees from Achilles Therapeutics (also a SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, the China Innovation Centre of Roche (formerly the Roche Innovation Centre\u2014Shanghai), Metabomed (until July 2022) and the Sarah Cannon Research Institute. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience and Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. C.S. declares patent applications on methods to detect lung cancer (PCT\/US2017\/028013), targeting neoantigens (PCT\/EP2016\/059401), identifying patient response to immune checkpoint blockade (PCT\/EP2016\/071471), determining HLA loss of heterozygosity (PCT\/GB2018\/052004), predicting survival rates of patients with cancer (PCT\/GB2020\/050221), identifying patients who respond to cancer treatment (PCT\/GB2018\/051912) and methods for lung cancer detection (US20190106751A1). C.S. is an inventor on a European patent application (PCT\/GB2017\/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity, and under their terms of employment, C.S. is due a revenue share of any revenue generated from such licence(s). N.M. has stock options in and has consulted for Achilles Therapeutics and holds European patents relating to targeting neoantigens (PCT\/EP2016\/059401), identifying patient response to immune checkpoint blockade (PCT\/ EP2016\/071471), determining HLA loss of heterozygosity (PCT\/GB2018\/052004) and predicting survival rates of patients with cancer (PCT\/GB2020\/050221). P.S.M. is a co-founder, chairs the SAB of and has equity interest in Boundless Bio. P.S.M. is also an advisor with equity for Asteroid Therapeutics and is an advisor to Sage Therapeutics. V.B. is a co-founder, consultant, SAB member and has equity interest in Boundless Bio and Abterra, and the terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Bio and Orbital Therapeutics, and is an advisor to 10X Genomics, Arsenal Biosciences, Chroma Medicine and Spring Discovery.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}