Impact of deleterious passenger mutations on cancer progression

Abstract

Cancer progression is driven by the accumulation of a small number of genetic alterations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional mutations termed passengers. Passengers are widely believed to have no role in cancer, yet many passengers fall within protein-coding genes and other functional elements that can have potentially deleterious effects on cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter the course of neoplastic progression. Our approach combines evolutionary simulations of cancer progression with an analysis of cancer sequencing data. From simulations, we find that passengers accumulate and largely evade natural selection during progression. Although individually weak, the collective burden of passengers alters the course of progression, leading to several oncological phenomena that are hard to explain with a traditional driver-centric view. We then tested the predictions of our model using cancer genomics data and confirmed that many passengers are likely damaging and have largely evaded negative selection. Finally, we use our model to explore cancer treatments that exploit the load of passengers by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Though both approaches lead to cancer regression, the latter is a more effective therapy. Our results suggest a unique framework for understanding cancer progression as a balance of driver and passenger mutations.

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

“…Hence, we varied each parameter by 1,000-fold (SI Appendix, Table S1) and found that dynamics varied considerably over this range but fell into two broad categories: adaptation (cancer) and extinction (no progression). Previous studies have concluded that passengers minimally affect progression when lethal (7) or if only deleterious in a few housekeeping genes (24); however, we previously presented genomic evidence that cancers accumulate myriad mildly deleterious passengers (12).…”

“…All trajectories follow a reversed sawtoothed pattern (Fig. 1B), resulting from a tug-of-war between drivers and passengers (12). When a new driver arises and fixates in the population, the population size increases to a new stationary value.…”

“…Simulations used a first-order Gillespie algorithm (12). Drivers and passengers were classified in the studies where they were first identified.…”

“…Previously, we showed that deleterious passengers readily accumulate during tumor progression and exhibit signatures of damaging mutations (12). Passenger mutations and chromosomal abnormalities, including aneuploidy, can be deleterious via a variety of mechanisms such as direct loss-of-function (13), cytotoxicity from protein disbalance and aggregation (14), or by eliciting an immune response (15).…”

Cancer evolution and heterogeneity

“…This is negative or purifying selection, which leads to a dN/dS <1 in a given gene or set of genes, if it occurs at appreciable rates 47, 48, 49, 50. If the negatively selected genes are 0.02%‐0.5% of all genes, the dN/dS <1, and clones with coding mutations will be lost per tumor.…”