Recent large-scale tumor resequencing studies have identified a number of 
mutations that might be involved in tumorigenesis. Analysis of the frequency of 
specific mutations across different tumors has been able to identify some, but 
not all of the mutated genes that contribute to tumor initiation and 
progression. One reason for this is that other functionally important genes are 
likely to be mutated more rarely and only in specific contexts. Thus, for 
example, mutation in one member of a collection of functionally related genes 
may result in the same net effect, and/or mutations in certain genes may be 
observed less frequently if they play functional roles in later stages of tumor 
development, such as metastasis. We modified and applied a network 
reconstruction and coexpression module identification-based approach to identify 
functionally related gene modules targeted by somatic mutations in cancer. This 
method was applied to available breast cancer, colorectal cancer, and 
glioblastoma sequence data, and identified Wnt/TGF-beta cross-talk, Wnt/VEGF 
signaling, and MAPK/focal adhesion kinase pathways as targets of rare driver 
mutations in breast, colorectal cancer, and glioblastoma, respectively. These 
mutations do not appear to alter genes that play a central role in these 
pathways, but rather contribute to a more refined shaping or "tuning" of the 
functioning of these pathways in such a way as to result in the inhibition of 
their tumor-suppressive signaling arms, and thereby conserve or enhance 
tumor-promoting processes.