Extrachromosomal DNA—relieving heredity constraints, accelerating tumour evolution

• Published in: Annals of oncology Vol. 31; no. 7; pp. 884 - 893
• Main Authors: Bailey, C., Shoura, M.J., Mischel, P.S., Swanton, C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2020
• Subjects: DNA; double minutes; extrachromosomal circular DNA; extrachromosomal DNA; Gene Amplification; Heredity; Humans; Neoplasms - genetics; Oncogenes; Tumor Microenvironment - genetics; tumour evolution; extrachromosomal DNA; double minutes; extrachromosomal circular DNA; tumour evolution
• ISSN: 0923-7534; 1569-8041; 1569-8041
• DOI: 10.1016/j.annonc.2020.03.303

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. •Extrachromosomal DNA (ecDNA) provides a mechanism by which cancer cells can accelerate intratumour heterogeneity.•ecDNA contain favourable epigenetic modifications that further fuel positive selection.•Tumours with ecDNA formation are frequently more aggressive, related to poorer survival outcomes and provide mechanisms of drug resistance.