Chromosomal instability and hopeful monsters: A driving force for cancer heterogeneity and evolution


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Charles Swanton1
1Cancer Research UK London Research Institute and University College London Cancer Institute, London, UK

Abstract

Extensive evidence over the last four decades has demonstrated that two fundamental principles of Darwinian evolution are likely to operate within solid tumours, diversity and natural selection. Extensive somatic mutational heterogeneity has been described within solid tumours, with evidence of spatial intratumour heterogeneity emerging in most solid tumours. Recurrent mutations in driver genes between tumours of the same subtype and parallel evolution of subclones within the same tumour, where inactivation of the same tumour suppressor gene may occur across spatially separated regions provides further evidence of natural selection occurring within a patient's lifetime.

Modern Darwinian views of evolution assert that evolutionary change is gradual and continuous. However, such gradualist views of evolution have had their detractors. Goldschmidt argued that discontinuous variation or macromutation might give rise to new species, whilst emphasising that most macromutations would have disastrous consequences on the organism, resulting in ‘monsters'. However, he argued that rarely a ‘macromutation' may give rise to a new form of life, coining the phrase ‘hopeful monster'.

Cancer chromosomal instability can be considered a macromutational event, generating large leaps in phenotypic and adaptive change in daughter cells. In this talk both gradualist and macromutational views on cancer evolution will be highlighted. The role of tetraploidy and chromosomal instability in initiating such macromutational events in human tumours together with genetic mechanisms contributing to chromosomal instability and intratumour heterogeneity will be discussed.