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Free keywords:
synthetic sickness or lethality; combination therapy; glioblastoma
Abstract:
Synthetic lethal interactions in cancer hold the potential for successful combined therapies, which would avoid the difficulties of single molecule-targeted treatment. Identification of interactions that are specific for human tumors is an open problem in cancer research. This work aims at deciphering synthetic sick or lethal interactions directly from somatic alteration, expression and survival data of cancer patients. To this end, we look for pairs of genes and their alterations or expression levels that are "avoided" by tumors and "beneficial" for patients. Thus, candidates for synthetic sickness or lethality (SSL) interaction are identified as such gene pairs whose combination of states is under-represented in the data. Our main methodological contribution is a quantitative score that allows ranking of the candidate SSL interactions according to evidence found in patient survival. Applying this analysis to glioblastoma data, we collect 1,956 synthetic sick or lethal partners for 85 abundantly altered genes, most of which show extensive copy number variation across the patient cohort. We rediscover and interpret known interaction between TP53 and PLK1, as well as provide insight into the mechanism behind EGFR interacting with AKT2, but not AKT1 nor AKT3. Cox model analysis determines 274 of identified interactions as having significant impact on overall survival in glioblastoma, which is more informative than a standard survival predictor based on patient's age.
