Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mutations to whole-genome duplications, in tumour initiation and progression is lacking. We posit that different genomic aberrations generally exhibit a temporal order, shaped by a balance between the levels of mutations and selective pressures. Repeat instability emerges first, followed by larger aberrations, with compensatory effects leading to robust tumour fitness maintained throughout the tumour progression. A better understanding of the interplay between genetic aberrations, the microenvironment, and epigenetic and metabolic cellular states is essential for early detection and prevention of cancer as well as development of efficient therapeutic strategies.
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The authors thank members of the Koonin group at the National Center for Biotechnology Information (NCBI) and members of the Moffitt Cancer Center for useful discussions and feedback. E.P. and E.V.K. are supported by intramural funds from the US Department of Health and Human Services (to the National Library of Medicine). R.J.G. and R.A.G. acknowledge support from the Physical Sciences in Oncology Program U54CA193489. F.D. is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 648670).
The authors declare no competing interests.
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Persi, E., Wolf, Y.I., Horn, D. et al. Mutation–selection balance and compensatory mechanisms in tumour evolution. Nat Rev Genet 22, 251–262 (2021). https://doi.org/10.1038/s41576-020-00299-4
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