Effects of ordered mutations on dynamics in signaling networks

Many previous clinical studies have found that accumulated sequential mutations are statistically related to tumorigenesis. However, they are limited in fully elucidating the significance of the ordered-mutation because they did not focus on the network dynamics. Therefore, there is a pressing need to investigate the dynamics characteristics induced by ordered-mutations.

To quantify the ordered-mutation-inducing dynamics, we defined the mutation-sensitivity and the order-specificity that represent if the network is sensitive against a double knockout mutation and if mutation-sensitivity is specific to the mutation order, respectively, using a Boolean network model.

Through intensive investigations, we found that a signaling network is more sensitive when a double-mutation occurs in the direction order inducing a longer path and a smaller number of paths than in the reverse order. In addition, feedback loops involving a gene pair decreased both the mutation-sensitivity and the order-specificity. Next, we investigated relationships of functionally important genes with ordered-mutation-inducing dynamics. The network is more sensitive to mutations subject to drug-targets, whereas it is less specific to the mutation order. Both the sensitivity and specificity are increased when different-drug-targeted genes are mutated. Further, we found that tumor suppressors can efficiently suppress the amplification of oncogenes when the former are mutated earlier than the latter.

Taken together, our results help to understand the importance of the order of mutations with respect to the dynamical effects in complex biological systems.