Modelling the evolution of genetic instability during tumour progression

Ruchira S. Datta, Alice Gutteridge, Charles Swanton, Carlo Maley, Trevor A. Graham

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The role of genetic instability in driving carcinogenesis remains controversial. Genetic instability should accelerate carcinogenesis by increasing the rate of advantageous driver mutations; however, genetic instability can also potentially retard tumour growth by increasing the rate of deleterious mutation. As such, it is unclear whether genetically unstable clones would tend to be more selectively advantageous than their genetically stable counterparts within a growing tumour. Here, we show the circumstances where genetic instability evolves during tumour progression towards cancer. We employ a Wright-Fisher type model that describes the evolution of tumour subclones. Clones can acquire both advantageous and deleterious mutations, and mutator mutations that increase a cell's intrinsic mutation rate. Within the model, cancers evolve with a mutator phenotype when driver mutations bestow only moderate increases in fitness: very strong or weak selection for driver mutations suppresses the evolution of a mutator phenotype. Genetic instability occurs secondarily to selectively advantageous driver mutations. Deleterious mutations have relatively little effect on the evolution of genetic instability unless selection for additional driver mutations is very weak or if deleterious mutations are very common. Our model provides a framework for studying the evolution of genetic instability in tumour progression. Our analysis highlights the central role of selection in shaping patterns of mutation in carcinogenesis.

Original languageEnglish (US)
Pages (from-to)20-33
Number of pages14
JournalEvolutionary Applications
Volume6
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Molecular Evolution
tumor
mutation
Mutation
neoplasms
modeling
Neoplasms
Carcinogenesis
carcinogenesis
Mutation Rate
Clone Cells
phenotype
clone
cancer
Phenotype
clones
fitness

Keywords

  • Carcinogenesis
  • Clonal expansion
  • Genetic instability
  • Mathematical biology
  • Selection

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Ecology, Evolution, Behavior and Systematics
  • Genetics

Cite this

Modelling the evolution of genetic instability during tumour progression. / Datta, Ruchira S.; Gutteridge, Alice; Swanton, Charles; Maley, Carlo; Graham, Trevor A.

In: Evolutionary Applications, Vol. 6, No. 1, 01.2013, p. 20-33.

Research output: Contribution to journalArticle

Datta, Ruchira S. ; Gutteridge, Alice ; Swanton, Charles ; Maley, Carlo ; Graham, Trevor A. / Modelling the evolution of genetic instability during tumour progression. In: Evolutionary Applications. 2013 ; Vol. 6, No. 1. pp. 20-33.
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