Passenger mutations can accelerate tumor suppressor gene inactivation in cancer evolution

Abstract

Carcinogenesis is an evolutionary process whereby cells accumulate multiple mutations. Besides the "driver mutations" that cause the disease, cells also accumulate a number of other mutations with seemingly no direct role in this evolutionary process. They are called passenger mutations. While it has been argued that passenger mutations render tumors more fragile due to reduced fitness, the role of passenger mutations remains understudied. Using evolutionary computational models, we demonstrate that in the context of tumor suppressor gene inactivation (and hence fitness valley crossing), the presence of passenger mutations can accelerate the rate of evolution by reducing overall population fitness and increasing the relative fitness of intermediate mutants in the fitness valley crossing pathway. Hence, the baseline rate of tumor suppressor gene inactivation might be faster than previously thought. Conceptually, parallels are found in the field of turbulence and pattern formation, where instabilities can be driven by perturbations that are damped (disadvantageous), but provide a richer set of pathways such that a system can achieve some desired goal more readily. This highlights, through a number of novel parallels, the relevance of physical sciences in oncology.peer-reviewed)

TrackSig: reconstructing evolutionary trajectories of mutations in cancer

“…If overall rate of generating mutations in tumour was constant, our timeline would correspond to the real time. However, tumour mutation rate often accelerates throughout development 29,30 . Although the changing rate does not affect our analysis, the estimates of the pseudo-time might not be linearly related to real time.…”