Abstract
Extrachromosomal DNA (ecDNA) can arise early in the development of aggressive tumors or later upon progression, but the impact of chronology on patient outcome is not known. Currently, it is not possible to determine when an ecDNA arose in the course of tumor development and progression, based on genome sequencing data. Here, we develop an analytic method, ecEvol, to infer ecDNA emergence time, selection strength, mutation rate, and clonal dominance from allele frequency spectra in bulk whole-genome sequencing. EcEvol outperforms other methods and predicts parameters with high accuracy across a wide range of parameter values. Applying ecEvol to primary, treatment-naive tumors, we find that ecDNA typically emerges early and undergoes strong positive selection, albeit with substantial variation across cancer types. EcDNAs carrying known oncogenes emerge earlier and reach greater clonal dominance than ecDNAs lacking known oncogenes. In advanced and predominantly treated tumors, ecDNA emerges substantially later than in matched primary tumors, consistent with the generation and selection of new ecDNA during tumor progression and therapy. Longitudinal samples further support continued expansion of ecDNA-bearing lineages. Finally, earlier ecDNA emergence is associated with poorer overall survival. These results provide insight into the chronology of ecDNA formation from a single tumor biopsy taken at any point during the course of the disease, revealing that allele-frequency spectra encode the evolutionary history of ecDNA and provide a quantitative framework for reconstructing its emergence and expansion.