Multi-omic measurement of mutually exclusive loss-of-function enriches for candidate synthetic lethal gene pairs
Abstract
Identification of synthetic lethal interactions in cancer cells could offer promising new therapeutic targets. Large-scale functional genomic screening presents an opportunity to test large numbers of cancer synthetic lethal hypotheses. Methods enriching for candidate synthetic lethal targets in molecularly defined cancer cell lines can steer effective design of screening efforts. Loss of one partner of a synthetic lethal gene pair creates a dependency on the other, thus synthetic lethal gene pairs should never show simultaneous loss-of-function. We have developed a computational approach to mine large multi-omic cancer data sets and identify gene pairs with mutually exclusive loss-of-function. Since loss-of-function may not always be genetic, we look for deleterious mutations, gene deletion and/or loss of mRNA expression by bimodality defined with a novel algorithm BiSEp. Applying this toolkit to both tumour cell line and patient data, we achieve statistically significant enrichment for experimentally validated tumour suppressor genes and synthetic lethal gene pairings. Notably non-reliance on genetic loss reveals a number of known synthetic lethal relationships otherwise missed, resulting in marked improvement over genetic-on...Continue Reading
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A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells
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