Origins and impact of extrachromosomal DNA

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer<sup>1,2</sup>. 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.

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Publication Details

Journal
Nature
Published
2024-11-06
DOI
https://doi.org/10.1038/s41586-024-08107-3
Citations
122
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
34.79
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article

Origins and impact of extrachromosomal DNA

D. Kasperaviciute, Bhargavi Dameracharla, S. R. Thompson, R. Bevers et al.
122 citations
Nature
Cancer Genomics and Diagnostics
34.79
article

Origins and impact of extrachromosomal DNA

D. Kasperaviciute, Bhargavi Dameracharla, S. R. Thompson, R. Bevers, Matthew A. Brown, Tim Hubbard, Anna C. Need, J. Pullinger, Federico Minneci, Nirupa Murugaesu, Ana Lisa Taylor Tavares, Melis Kayikci, Wei-Ting Lu, Roberto Salgado, N. Sharma, Tim Rogers, Charles Swanton, S.Y. Cindy Yang, Maria Litovchenko, M. Tanguy, L. Lahnstein, Richard H. Scott, Magdalena Zarowiecki, Richard S. Houlston, Oriol Pich, Jeanette Kittel, Melanie Mueller, M. J. Welland, Jonathan S. Mitchell, Vineet Bafna, Ivone Leong, D. Perez-Gil, A. Lakey, Robert B. Bentham, Seton Henderson, John N. Griffin, Howard Y. Chang, A. Kousathanas, Paul S. Mischel, Brooke E. Howitt, K. Sawant, Georgia Stavrou, Robert Wilson Jackson, Adam Giess, Marta Bleda, Adrienne M. Flanagan, Mariam Jamal‐Hanjani, Afshan Siddiq, Alex J. Cornish, Peter O’Donovan, L. J. Jones, Kerstin Thol, Andrew Rowan, Nicholas McGranahan, F. J. Lopez, Anne Thomas, Jens Luebeck, Nnennaya Kanu, Helen Brittain, S. E. A. Leigh, Angela Hamblin, T. Rahim, Christopher A. Odhams, M. J. Caulfield, Chris Bailey, Sean Smith, G. C. Chan, Natasha E. Weiser, David Allan Moore, A. Sosinsky, A. Stuckey, A. Sieghart, Serena Nik‐Zainal, F. Maleady-Crowe, Meriel McEntagart, S. M. Wood, Kate Witkowska, King L. Hung, A. Rendon, Christine Patch, L. Moutsianas, Arianna Tucci, Elaine Thomas, C. R. Boustred, M. B. Pereira, P. Arumugam, Eric O. Williams, J. C. Ambrose, K. Savage, F. Boardman-Pretty
article en
122 citations

Abstract

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer<sup>1,2</sup>. 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.

NatureVol. 635(8037)
University College Hospital (GB), Institute of Cancer Research (GB), Queen Mary University of London (GB), Palo Alto University (US), University of Cambridge (GB), Peter MacCallum Cancer Centre (AU), The Francis Crick Institute (GB), Royal London Hospital (GB), Cancer Research UK (GB), Royal National Orthopaedic Hospital (GB), University of California San Diego (US), London Cancer (GB), Stanford Medicine (US), Genomics England (GB), CRUK Lung Cancer Centre of Excellence (GB), William Harvey Research Institute (GB), University College London (GB), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 0%
Cancer Genomics and Diagnostics
34.79
DOIOpen Access PDFOpenAlex
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