AbstractCancer aggressiveness and its effect on patient survival depends on mutations in the tumor genome. Epistatic interactions between the mutated genes may guide the choice of anticancer therapy and set predictive factors of its success. Inhibitors targeting synthetic lethal partners of genes mutated in tumors are already utilized for efficient and specific treatment in the clinic. The space of possible epistatic interactions, how-ever, is overwhelming, and computational methods are needed to limit the experimental effort of validating the interactions for therapy and characterizing their biomarkers. Here, we introduce SurvLRT, a statistical likelihood ratio test for identifying epistatic gene pairs and triplets from cancer patient genomic and survival data. Compared to established approaches, SurvLRT performed favorable in predicting known, experimentally verified synthetic lethal partners of PARP1 from TCGA data. Our approach is the first to test for epistasis between triplets of genes to identify biomarkers of synthetic lethality-based therapy. SurvLRT proved successful in identifying the known gene TP53BP1 as the biomarker of success of the therapy targeting PARP in BRCA1 deficient tumors. Search for other biomarkers for the same interaction revealed a region whose deletion was a more significant biomarker than deletion of TP53BP1. With the ability to detect not only pairwise but twelve different types of triple epistasis, applicability of SurvLRT goes beyond cancer therapy, to the level of characterization of shapes of fitness landscapes.Author SummaryGenomic alterations in tumors affect the fitness of tumor cells, controlling how well they replicate and survive compared to other cells. The landscape of tumor fitness is shaped by epistasis. Epistasis occurs when the contribution of gene alterations to the total fitness is non-linear. The type of epistatic genetic interactions with great potential for cancer therapy is synthetic lethality. Inhibitors targeting synthetic lethal partners of genes mutated in tumors can selectively kill tumor and not normal cells. Therapy based on synthetic lethality is, however, context dependent, and it is crucial to identify its biomarkers. Unfortunately, the space of possible interactions and their biomarkers is overwhelming for experimental validation. Computational pre-selection methods are required to limit the experimental effort. Here, we introduce a statistical approach called SurvLRT, for the identification of epistatic gene pairs and triplets based on patient genomic and survival data. First, we show that using SurvLRT, we can deliver synthetic lethal interactions of pairs of genes that are specific to cancer. Second, we demonstrate the applicability of SurvLRT to identify biomarkers for synthetic lethality, such as mutational status of other genes that can alleviate the synthetic effect.
Using Yeast Synthetic Lethality To Inform Drug Combination for Malaria
