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Abstract:
Nuclear extra-chromosomal DNA (ecDNA) is highly prevalent in human tumours. ecDNA amplifica-tions can promote accessible chromatin, oncogen over-expression and imply a worse clinical prognosis.Yet, little is known about the evolutionary process of ecDNA in human cancers. Here, we develop thetheoretical foundation of the ecDNA somatic evolutionary process combining mathematical, compu-tational and experimental approaches. We show that random ecDNA segregation leads to unintuitivedynamics even if ecDNA is under very strong positive selection. Patterns of inter- and intra-tumourecDNA and chromosomal heterogeneity differ markedly and standard approaches are not directly ap-plicable to quantify ecDNA evolution. We show that evolutionary informed modelling leads to testablepredictions on how to distinguish positively selected from neutral ecDNA dynamics. Our predictionsdescribe the dynamics of circular amplicons in GBM39 cell line experiments, suggesting a 300% fit-ness increase due to circular extra-chromosomalEGFRvI I Iamplifications. Our work lies the basis forfurther studies to quantitate ecDNA somatic evolutionary processes.
