Relationship between cancer mutations and parameter sensitivity in Rb pathway

It has long been known that formation of all sorts of tumors is largely owing to the genomic variations. Oncogenic mutations are often found focused on one or more important pathways which indicate that it is meaningful to investigate oncogenic mutations and oncogenic mechanisms from the point of view of biological network. Recently, we found that in apoptosis pathway of mammalian cell, mutations that cause large variations on the bifurcation point are more probably oncogenic mutations. Here, we used the Rb-E2F pathway in mammalian cell in response to growth factor as another example to verify this correlation. To conduct this study, nonlinear dynamics equations that describe the behavior of the Rb-E2F pathway was first constructed. Then we identified sensitive parameters which have a great influence on the system’s bifurcation point. And we found that the sensitive parameters are highly related to high-frequency oncogenic mutations after comparing the results of parameter sensitivity analysis with profile of known cancer mutations. Moreover, the position of bifurcation point rather than concentration of a certain protein is a better measurement to determine biological network's function. Our results further confirm that nonlinear dynamics analysis of biological networks is an important way to understand oncogenesis. And the analysis method can become a powerful tool to understand and analyze the function of biological network.