Sequence, Structure and Network Methods to Uncover Cancer Genes

A major aim of cancer genomics is to pinpoint which somatically mutated genes are involved in tumor initiation and progression. This is a difficult task, as numerous somatic mutations are typically observed in each cancer genome, only a subset of which are cancer-relevant, and very few genes are found to be somatically mutated across large numbers of individuals. In this talk, I will overview three methods my group has introduced for identifying cancer genes. First, I will present a framework for uncovering cancer genes, differential mutation analysis, that compares the mutational profiles of genes across cancer genomes with their natural germline variation across healthy individuals. Next, I will show how to leverage per-individual mutational profiles within the context of protein-protein interaction networks in order to identify small connected subnetworks of genes that, while not individually frequently mutated, comprise pathways that are altered across (i.e., "cover") a large fraction of individuals. Finally, I will demonstrate that cancer genes can be discovered by identifying genes whose interaction interfaces are enriched in somatic mutations. Overall, these methods recapitulate known cancer driver genes, and discover novel, and sometimes rarely-mutated, genes with likely roles in cancer.