Integrative analysis of cancer genes in a functional interactome

The post-genomic era has resulted in the accumulation of high-throughput cancer data from a vast array of genomic technologies including next-generation sequencing and microarray. As such, the large amounts of germline variant and somatic mutation data that have been generated from GWAS and sequencing projects, respectively, show great promise in providing a systems-level view of these genetic aberrations. In this study, we analyze publicly available GWAS, somatic mutation, and drug target data derived from large databanks using a network-based approach that incorporates directed edge information under a randomized network hypothesis testing procedure. We show that these three classes of disease-associated nodes exhibit non-random topological characteristics in the context of a functional interactome. Specifically, we show that drug targets tend to lie upstream of somatic mutations and disease susceptibility germline variants. In addition, we introduce a new approach to measuring hierarchy between drug targets, somatic mutants, and disease susceptibility genes by utilizing directionality and path length information. Overall, our results provide new insight into the intrinsic relationships between these node classes that broaden our understanding of cancer. In addition, our results align with current knowledge on the therapeutic actionability of GWAS and somatic mutant nodes, while demonstrating relationships between node classes from a global network perspective.