Origins and impact of extrachromosomal DNA

• 成果类型: Article
• 署名作者: Bailey, Chris; Pich, Oriol; Thol, Kerstin; Watkins, Thomas B. K.; Luebeck, Jens; Rowan, Andrew; Stavrou, Georgia; Weiser, Natasha E.; Dameracharla, Bhargavi; Bentham, Robert; Lu, Wei-Ting; Kittel, Jeanette; Yang, S. Y. Cindy; Howitt, Brooke E.; Sharma, Natasha; Litovchenko, Maria; Salgado, Roberto; Hung, King L.; Cornish, Alex J.; Moore, David A.; Houlston, Richard S.; Bafna, Vineet; Chang, Howard Y.; Nik-Zainal, Serena; Kanu, Nnennaya; McGranahan, Nicholas; Flanagan, Adrienne M.; Mischel, Paul S.; Jamal-Hanjani, Mariam; Swanton, Charles
• 署名单位: Francis Crick Institute; Cancer Research UK; University of London; University College London; University of London; University College London; Cancer Research UK; Stanford University; Stanford University; University of California System; University of California San Diego; University of London; University College London; Stanford University; Stanford University; Peter Maccallum Cancer Center; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University College London Hospitals NHS Foundation Trust; University of London; University College London; University of Cambridge; University of London; University College London; University of London; University College London; Royal National Orthopaedic Hospital NHS Trust; University College London Hospitals NHS Foundation Trust; University of London; University College London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4559
• DOI: 10.1038/s41586-024-08107-3
• 发表日期: 2024-11-07
• 关键词: cancer

摘要

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. A study examines the diversity of extrachromosomal DNA elements in cancer, and provides details on the frequency and origin of extrachromosomal DNA and its role in the development of different types of cancer.