Origins and impact of extrachromosomal DNA

Bailey, C; Pich, O; Thol, K; Watkins, TBK; Luebeck, J; Rowan, A; Stavrou, G; Weiser, NE; Dameracharla, B; Bentham, R; Lu, WT; Kittel, J; Yang, SYC; Howitt, BE; Sharma, N; Litovchenko, M; Salgado, R; Hung, KL; Cornish, AJ; Moore, DA; Houlston, RS; Bafna, V; Chang, HY; Nik-Zainal, S; Kanu, N; McGranahan, N; Genomics England Consortium; Flanagan, AM; Mischel, PS; Jamal-Hanjani, M; Swanton, C

Author(s): Bailey, C; Pich, O; Thol, K; Watkins, TBK; Luebeck, J; Rowan, A; Stavrou, G; Weiser, NE; Dameracharla, B; Bentham, R; Lu, WT; Kittel, J; Yang, SYC; Howitt, BE; Sharma, N; Litovchenko, M; Salgado, R; Hung, KL; Cornish, AJ; Moore, DA; Houlston, RS; Bafna, V; Chang, HY; Nik-Zainal, S; Kanu, N; McGranahan, N; Genomics England Consortium; Flanagan, AM; Mischel, PS; Jamal-Hanjani, M; Swanton, C;
Details: Publication Year 2024-11,Volume 635,Issue #8037,Page 193-200
Journal Title: Nature
Publication Type: Research article
Abstract: Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer(1,2). 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.
Publisher: Springer Nature
Keywords: Humans; *Neoplasms/genetics/immunology/pathology; *Oncogenes/genetics; Mutation; Promoter Regions, Genetic/genetics; Enhancer Elements, Genetic/genetics; DNA/genetics; RNA, Long Noncoding/genetics; Female; Gene Amplification; Organ Specificity; Male
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41586-024-08107-3
Open Access at Publisher's Site: https://doi.org/10.1038/s41586-024-08107-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-11-26 06:49:08

Last Modified: 2024-11-26 06:50:57