"Evolution of extrachromosomal DNA in non-growing populations"Scaramangas, AlanIn this presentation I will explore the evolution of extrachromosomal DNA (ecDNA) in cell populations of fixed size. ecDNA is typically manifest as circular fragments of genetic material containing fitness-conferring genes (such as oncogenes) and is not bound to a (histone) protein structure like chromosomal DNA. Because of this lack of attachment, ecDNA is randomly segregated during mitosis and can accrue in impressively large numbers. While ecDNA is seldom found in healthy tissue it features in approximately one third of all cancers and is linked with worse outcomes across patients. Interestingly, early research indicates that even non-growing premalignant lesions, which may or may not develop into cancer, contain ecDNA (though in smaller amounts). There are a multitude of of precancer conditions (including Barrett’s oesophagus, colon polyps, Bowen’s disease, and ductal carcinoma in situ to name a few) several of which are becoming increasingly common. This makes accurate early-stage diagnosis especially important and the inclusion of ecDNA analysis during this stage particularly relevant. We model the dynamics of ecDNA in the precancerous state, by considering a population of cells containing a small initial amount of ecDNA. The population evolves through random but equiprobable birth and death events, where during mitosis the total amount of ecDNA is doubled, allowing for varied inheritance patterns among daughter cells. Assuming that ecDNA which is lost cannot be recovered, some of the questions we address are: (a) What is the probability that ecDNA goes extinct in the population? (b) If not extinct, what is the probability that ecDNA exceeds a certain detectable threshold? (c) How do we expect the number of cells carrying a given number of ecDNA copies (i.e. the copy number distribution) to evolve over time? This analysis sheds light on the potential impact of ecDNA in cancer progression and highlights the importance of its early detection and monitoring. |
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