title: Selective pressures for and against genetic instability in cancer: a time-dependent problem.
abstract: Genetic instability in cancer is a two-edge sword. It can both increase the rate of cancer progression (by increasing the probability of cancerous mutations) and decrease the rate of cancer growth (by imposing a large death toll on dividing cells). Two of the many selective pressures acting upon a tumour, the need for variability and the need to minimize deleterious mutations, affect the tumour's 'choice' of a stable or unstable 'strategy'. As cancer progresses, the balance of the two pressures will change. In this paper, we examine how the optimal strategy of cancerous cells is shaped by the changing selective pressures. We consider the two most common patterns in multistage carcinogenesis: the activation of an oncogene (a one-step process) and an inactivation of a tumour-suppressor gene (a two-step process). For these, we formulate an optimal control problem for the mutation rate in cancer cells. We then develop a method to find optimal time-dependent strategies. It turns out that for a wide range of parameters, the most successful strategy is to start with a high rate of mutations and then switch to stability. This agrees with the growing biological evidence that genetic instability, prevalent in early cancers, turns into stability later on in the progression. We also identify parameter regimes where it is advantageous to keep stable (or unstable) constantly throughout the growth.
authors.affiliation: Department of Mathematics, University of California, Irvine, CA 92697, USA. komarova@math.uci.edu
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Komarova
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Sadovsky
authors.forename: Frederic Y M
authors.initials: FY
authors.lastname: Wan
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes