Extrachromosomal DNA—relieving heredity constraints, accelerating tumour evolution

Abstract

Oncogene amplification on extrachromosomal DNA (ecDNA) provides a mechanism by which cancer cells can rapidly adapt to changes in the tumour microenvironment. These circular structures contain oncogenes and their regulatory elements, and, lacking centromeres, they are subject to unequal segregation during mitosis. This non-Mendelian mechanism of inheritance results in increased tumour heterogeneity with daughter cells that can contain increasingly amplified oncogene copy number. These structures also contain favourable epigenetic modifications including transcriptionally active chromatin, further fuelling positive selection. ecDNA drives aggressive tumour behaviour, is related to poorer survival outcomes and provides mechanisms of drug resistance. Recent evidence suggests one in four solid tumours contain cells with ecDNA structures. The concept of tumour evolution is one in which cancer cells compete to survive in a diverse tumour microenvironment under the Darwinian principles of variation and fitness heritability. Unconstrained by conventional segregation constraints, ecDNA can accelerate intratumoral heterogeneity and cellular fitness. In this review, we highlight some of the recent discoveries underpinning this process.

EcDNA hubs drive cooperative intermolecular oncogene expression

“…The copyright holder for this preprint this version posted November 20, 2020. ; https://doi.org/10.1101/2020. 11.19.390278 doi: bioRxiv preprint Hung, Yost, Xie et al, (CHANG), p. 4 suggesting that they are composed of many ecDNA molecules clustering tightly in space. We used the pair autocorrelation function g(r) (Methods) to measure the spatial distribution of ecDNA hubs.…”

“…Circular ecDNA encoding oncogenes is a prevalent feature of cancer genomes and potent driver of human cancer progression [4][5][6][7] . EcDNAs are covalently closed, double-stranded, and range from ~100 kilobases to several megabases in size 1,[8][9][10][11] .…”

Molecular structure and evolution mechanism of two populations of double minutes in human colorectal cancer cells

“…Based on FISH method, the wide exist of subpopulations of DMs had been demonstrated in cancer cells 10 . Understanding the heterogeneity of DMs will enhance our understanding of cancer evolution and potential treatment strategies 25 . Thus, it is very important for us to examine the number of subpopulations and its composition of high‐amplification regions before constructing the molecular structure.…”

Drug efficacy and toxicity prediction: an innovative application of transcriptomic data

“…A multitude of diversifying lineages has been reported in tumors (Bailey et al 2020;Turajlic et al 2019;Wu et al 2016), which can complicate transcriptomic data analysis (Xia 2017;Navin 2015). It would be interesting to know if a certain anti-cancer drug will perturb all different cancer cell lineages or just a subset of the lineages.…”