Abstract 3887: The origins and clinical impact of extrachromosomal DNA across 39 cancers

Abstract Extrachromosomal DNA (ecDNA) is emerging as a major contributor to cancer drug resistance and poor outcome in many cancer types. To understand the underlying genetic and mutational processes associated with ecDNA formation and presence, we conducted an analysis of whole-genome sequencing data from 14, 778 cancer patients representing 39 tumor types from the Genomics England cohort. Our findings revealed focal amplifications driven by ecDNA in 17. 1% of tumor samples, exhibiting varying frequencies across tissues. Notably, liposarcomas (55. 4%) and HER2+ breast cancers (46. 4%) displayed higher rates compared to lower rates found in pancreatic adenocarcinomas (2%). In addition to oncogenic amplifications such as HER2 derived from ecDNA during cancer evolution, ecDNAs that did not contain oncogenes were enriched for immunomodulatory genes (e. g. , CXCL6, LRRC32, and HLA-G). Immunomodulatory ecDNAs exhibited reduced T cell infiltration. In the context of intrinsic and environmental mutational processes, deamination clock-like, tobacco smoking, and APOBEC cytidine deaminase signatures positively correlated with ecDNA presence. Conversely, mismatch repair deficiency (MMRd) and POLD1/POLE deficiency signatures exhibited a negative correlation. Mutational processes associated with tobacco exposure, UV light, and spontaneous deamination primarily occurred before ecDNA formation, while signatures of homologous recombination repair deficiency tended to manifest post-ecDNA formation. Notably, ecDNA was enriched at metastatic sites and significantly associated with shorter overall survival in multivariable analysis (HR 1. 31, 95% CI 1. 17-1. 47), underscoring its clinical relevance. This study enhances our understanding of the mutational processes and tissue contexts that shape the ecDNA landscape in human cancer and highlights its implications for clinical outcomes. Citation Format: Chris Bailey, Oriol Pich, Kerstin Thol, Jens Luebeck, Georgia Stavrou, Thomas B. Watkins, Natasha E. Weiser, Wei-Ting Lu, Jeanette Kittel, Robert Bentham, Natasha Sharma, Roberto Salgado, Dave Moore, Maria Litovchenko, King L. Hung, Alex J. Cornish, Bhargavi Dameracharla, Serena Nik-Zainal, Vineet Bafna, Howard Chang, Nicholas McGranahan, Nnennaya Kanu, Genomics England Consortium, Paul S. Mischel, Mariam Jamal-Hanjani, Charles Swanton. The origins and clinical impact of extrachromosomal DNA across 39 cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3887.