Precise Characterization of Genetic Interactions in Cancer via Molecular Network Refining Processes

Abstract

<jats:p> Genetic interactions (GIs), such as the synthetic lethal interaction, are promising therapeutic targets in precision medicine. However, despite extensive efforts to characterize GIs by large-scale perturbation screening, considerable false positives have been reported in multiple studies. We propose a new computational approach for improved precision in GI identification by applying constraints that consider actual biological phenomena. In this study, GIs were characterized by assessing mutation, loss of function, and expression profiles in the DEPMAP database. The expression profiles were used to exclude loss-of-function data for nonexpressed genes in GI characterization. More importantly, the characterized GIs were refined based on Kyoto Encyclopedia of Genes and Genomes (KEGG) or protein–protein interaction (PPI) networks, under the assumption that genes genetically interacting with a certain mutated gene are adjacent in the networks. As a result, the initial GIs characterized with CRISPR and RNAi screenings were refined to 65 and 23 GIs based on KEGG networks and to 183 and 142 GIs based on PPI networks. The evaluation of refined GIs showed improved precision with respect to known synthetic lethal interactions. The refining process also yielded a synthetic partner network (SPN) for each mutated gene, which provides insight into therapeutic strategies for the mutated genes; specifically, exploring the SPN of mutated BRAF revealed ELAVL1 as a potential target for treating BRAF-mutated cancer, as validated by previous research. We expect that this work will advance cancer therapeutic research.</jats:p>