Temporal order of mutations influences cancer initiation dynamics.

ABSTRACT

Cancer is a set of genetic diseases that are driven by mutations. It was recently discovered that the temporal order of genetic mutations affects the cancer evolution and even the nature of the decease itself. The mechanistic origin of these observations, however, remain not well understood. Here we present a theoretical model for cancer initiation dynamics that allows us to quantify the impact of the temporal order of mutations. In our approach, the cancer initiation process is viewed as a set of stochastic transitions between discrete states defined by the different numbers of mutated cells. Using a first-passage analysis, probabilities and times before the cancer initiation are explicitly evaluated for two alternative sequences of two mutations. It is found that the probability of cancer initiation is determined only by the first mutation, while the dynamics depends on both mutations. In addition, it is shown that the acquisition of a mutation with higher fitness before mutation with lower fitness increases the probability of the tumor formation but delays the cancer initiation. Theoretical results are explained using effective free-energy landscapes.