Abstract
Achilles' heel relationships arise when the status of one gene exposes a cell's vulnerability to perturbation of a second gene, such as chemical inhibition, providing therapeutic opportunities for precision oncology. SynLeGG (www.overton-lab.uk/synlegg) identifies and visualizes mutually exclusive loss signatures in 'omics data to enable discovery of genetic dependency relationships (GDRs) across 783 cancer cell lines and 30 tissues. While there is significant focus on genetic approaches, transcriptome data has advantages for investigation of GDRs and remains relatively underexplored. SynLeGG depends upon the MultiSEp algorithm for unsupervised assignment of cell lines into gene expression clusters, which provide the basis for analysis of CRISPR scores and mutational status in order to propose candidate GDRs. Benchmarking against SynLethDB demonstrates favourable performance for MultiSEp against competing approaches, finding significantly higher area under the Receiver Operator Characteristic curve and between 2.8-fold to 8.5-fold greater coverage. In addition to pan-cancer analysis, SynLeGG offers investigation of tissue-specific GDRs and recovers established relationships, including synthetic lethality for SMARCA2 with SMARCA4. Proteomics, Gene Ontology, protein-protein interactions and paralogue information are provided to assist interpretation and candidate drug target prioritization. SynLeGG predictions are significantly enriched in dependencies validated by a recently published CRISPR screen.