Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Abstract

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations-a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies.

Universal patterns of selection in cancer and somatic tissues

“…This negative or purifying selection will lead to dN/dS<1 in a given gene or set of genes if it occurs at appreciable rates. Negative selection on somatic mutations has been long anticipated McFarland et al, 2014;Nowell, 1976;Stratton et al, 2009), but not yet reliably documented in cancer genomes. This is due to the fact that statistical detection of lower mutation density than expected by chance requires large datasets and very careful consideration of mutation biases and germline SNP contamination.…”

“…Negative selection on somatic mutations during cancer evolution has been long anticipated McFarland et al, 2014;Nowell, 1976;Stratton et al, 2009). However, several authors have also predicted that, while present, negative selection should be weaker in somatic evolution owing to a number of factors (e.g.…”

“…The random occurrence of a very advantageous mutation, such as a cancer driver mutation, in a cell carrying weakly deleterious mutations can offset their fitness effects and lead to the fixation of deleterious mutations in a cancer. Frequent rounds of clonal expansions and hitchhiking with potent driver mutations is expected to significantly reduce the efficiency of negative selection to remove deleterious variants (McFarland et al, 2013;McFarland et al, 2014). 4.…”

“…4. Muller's ratchet: Somatic evolution is effectively asexual and so deleterious mutations will be expected to accumulate in somatic cells even in the absence of hitchhiking with driver mutations (McFarland et al, 2013;McFarland et al, 2014). Muller's ratchet is expected to be stronger the higher the mutation rate per division, which predicts that negative selection will be even weaker in hypermutator samples.…”

Dynamics and Fate of Beneficial Mutations Under Lineage Contamination by Linked Deleterious Mutations

“…Indeed, recent studies (Poon and Otto 2000;Bachtrog and Gordo 2004;Silander et al 2007;Kaiser and Charlesworth 2009;Goyal et al 2012) have indicated that beneficial mutations (including reversions of deleterious mutations) can impede or halt the fitness loss predicted in asexual populations under Muller's ratchet, as originally suggested by Haigh (1978). Moreover, a number of theoretical studies (Peck 1994;Barton 1995;Johnson and Barton 2002;Bachtrog and Gordo 2004;Jiang et al 2011;Charlesworth 2013;McFarland et al 2014) have shown that Haldane's classical fixation probability of 2s b for a beneficial mutation can be reduced by the effects of selection against linked deleterious mutations ( Birky and Walsh 1988;Campos 2004;Campos and Wahl 2010;Hartfield et al 2010;Good and Desai 2014): in principle, such effects include both background selection against deleterious mutations already present in the genome on which the beneficial mutation appears, and selection against deleterious mutations that arise and accumulate in genomes carrying the beneficial mutation. The latter form of selective effect has not previously been singled out and analyzed as a population process in its own right; it is the primary focus of the current article and will be referred to as lineage contamination.…”