Label propagation defines signaling networks associated with recurrently mutated cancer genes

Abstract

Human tumors have distinct profiles of genomic alterations, and each of these alterations has the potential to cause unique changes to cellular homeostasis. Detailed analyses of these changes could reveal downstream effects of genomic alterations, contributing to our understanding of their roles in tumor development and progression. Across a range of tumor types, including bladder, lung, and endometrial carcinoma, we determined genes that are frequently altered in The Cancer Genome Atlas patient populations, then examined the effects of these alterations on signaling and regulatory pathways. To achieve this, we used a label propagation-based methodology to generate networks from gene expression signatures associated with defined mutations. Individual networks offered a large-scale view of signaling changes represented by gene signatures, which in turn reflected the scope of molecular events that are perturbed in the presence of a given genomic alteration. Comparing different networks to one another revealed common biological pathways impacted by distinct genomic alterations, highlighting the concept that tumors can dysregulate key pathways through multiple, seemingly unrelated mechanisms. Finally, altered genes inducing common changes to the signaling network were used to search for genomic markers of drug response, connecting shared perturbations to differential drug sensitivity.