Mutation–selection balance and compensatory mechanisms in tumour evolution

Erez Persi*, Yuri I. Wolf, David Horn, Eytan Ruppin, Francesca Demichelis, Robert A. Gatenby, Robert J. Gillies*, Eugene V. Koonin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish
Pages (from-to)251-262
Number of pages12
JournalNature Reviews Genetics
Issue number4
StatePublished - Apr 2021


FundersFunder number
US Department of Health and Human Services
National Cancer InstituteZIABC011802
U.S. National Library of MedicineU54CA193489
Horizon 2020 Framework Programme648670
European Research Council


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