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Exploiting synthetic lethal vulnerabilities for cancer therapy

Synthetic lethality refers to a combination of two or more genetic events (typically affecting different genes) in which the co-occurrence of the events results in cell or organismal lethality, but the cell or organism remains viable when only one of the events occurs. Synthetic lethality has gained attention in the last few years for its value in selective killing of cancer cells: by targeting the synthetic lethal partner of an altered gene in cancer, only the cancer cells can be killed while sparing normal cells. In a recent study, we showed that mutual exclusive combinations of genetic events in cancer hint at naturally occurring synthetic lethal combinations, and therefore by systematically mining for these combinations we can identify novel therapeutic targets for cancer. Based on this, we had identified a list of 718 genes that are mutually exclusive to six DNA-damage response genes in cancer. Here, we extend these results to identify a subset of 43 genes whose over-expression correlates with significantly poor survival in estrogen receptor-negative breast cancers, and thus provide a promising list of potential therapeutic targets and/or biomarkers.