Tug of war between driver and passenger mutations in cancer and other adaptive processes
Significance During rapid adaptation, populations start in hostile conditions and must evolve new traits to survive. Development of cancer from a population of precancerous cells within a body is an example of such rapid adaptation. New traits required for cancer progression are acquired by driver mutations in a few key genes. Most mutations, however, are unimportant for progression and can be damaging to cancer cells, termed "passengers." The role these damaging passengers play in cancer and other adaptive processes is unknown. Here we show that driver mutations engage in a tug of war with damaging passengers. This tug of war explains many phenomena in oncology, suggesting how to develop new therapies and target existing therapies to exploit damaging passengers. 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.
Proceedings of the National Academy of Sciences