Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity

Cancers evolve in rapidly changing environments from single cells into genetically heterogeneous masses. Darwinian evolution selects for survival of the fittest cells, that is, those that are best suited to their environment. Heterogeneity provides a pool of mutations upon which selection can act 1, 5–9. Cells that acquire fitness-enhancing mutations are more likely to pass these mutations on to daughter cells, driving neoplastic progression and therapeutic resistance 10,11. One common type of cancer mutation, oncogene amplification, can be found either in chromosomes or in nuclear ecDNA elements, including double minutes 2– 4, 12–14. Relative to chromosomal amplicons, ecDNA is less stable, segregating unequally to daughter cells 15, 16. Double minutes are reported to occur in 1.4% of cancers with a maximum of 31.7% in neuroblastoma, based on the Mitelman database 4,17. However, the scope of ecDNA in cancer has not been accurately quantified, the oncogenes contained therein have not been systematically examined and the impact of ecDNA on tumour evolution has yet to be determined.

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