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Abstract Extrachromosomal DNA (ecDNA) are acentric, circular DNA fragments which form after DNA double strand breaks. They segregate randomly during mitosis, promoting high-level amplifications of positively selected oncogenes such as EGFR and MYC. The prevalence of ecDNA across several cancer types, such as glioblastoma and sarcoma, has made promising therapeutic targets. However, while DNA damage is a hallmark of nearly all cancers, the formation of ecDNA is not, and the determinants for ecDNA acquisition are unclear. Furthermore, whether the timing of tumors’ acquisition of ecDNA (i. e. , early or late clonal or sub-clonal) affects patient survival and drug resistance is unclear. Here, we leverage orthoganol information from ecDNA amplicons, such as mutation allele frequency and sequence synteny, to develop computational methods for elucidating the evolutionary history of ecDNA. Applying these to several cancer subtypes in TCGA, we find that most ecDNAs arise early in tumor evolution. We expect these results will help identify determinants of ecDNA acquisition and its temporal influence on patient survival. Citation Format: Andrew R. Lynch, Peter Van Loo. Timing ecDNA acquisition across cancer 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 1612.
Lynch et al. (Fri,) studied this question.
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