Cancer evolution: Darwin and beyond

EMBO J. 2021 Sep 15;40(18):e108389. doi: 10.15252/embj.2021108389. Epub 2021 Aug 30.


Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution.

Keywords: cancer; cancer evolution; cancer therapy; tumour heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Plasticity
  • Cell Transformation, Neoplastic* / genetics
  • Cell Transformation, Neoplastic* / metabolism
  • Clonal Evolution
  • Disease Management
  • Disease Susceptibility*
  • Evolution, Molecular
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Genomics / methods
  • Humans
  • Neoplasms / diagnosis
  • Neoplasms / etiology*
  • Neoplasms / metabolism*
  • Neoplasms / therapy
  • Selection, Genetic
  • Tumor Microenvironment