Identifying actionable synthetically lethal cancer gene pairs using mutual exclusivity

Mutually exclusive loss-of-function alterations in gene pairs are those that occur together less frequently than may be expected and may denote a synthetically lethal relationship (SSL) between the genes. SSLs can be exploited therapeutically to selectively kill cancer cells. Here, we analysed mutation, copy number variation, and methylation levels in samples from The Cancer Genome Atlas, using the hypergeometric and the Poisson binomial tests to identify mutually exclusive inactivated genes. We focused on gene pairs where one is an inactivated tumour suppressor and the other a gene whose protein product can be inhibited by known drugs. This provided an abundance of potential targeted therapeutics and repositioning opportunities for several cancers. These data are available on the MexDrugs website, https://bioinformaticslab.sussex.ac.uk/mexdrugs.