TARGET-SL: precision essential gene prediction using driver prioritisation and synthetic lethality.

Abstract

The ability to identify patient-specific vulnerabilities to guide cancer treatments is a vital area of research. However, predictive bioinformatics tools are difficult to translate into clinical applications due to a lack of in vitro and in vivo validation. While the increasing number of personalised driver prioritisation algorithms (PDPAs) report powerful patient-specific information, the results do not easily translate into treatment strategies. Critical in addressing this gap is the ability to meaningfully benchmark and validate PDPA predictions. To address this, we developed Tumour-specific Algorithm for Ranking GEnetic Targets via Synthetic Lethality (TARGET-SL), which utilises PDPA predictions to produce a ranked list of predicted essential genes that can be validated in vitro and in vivo. This framework employs a novel strategy to benchmark PDPAs, by comparing predictions with ground truth gene essentiality data from large-scale CRISPR-knockout and drug sensitivity screens. Importantly TARGET-SL identifies vulnerabilities that are more exclusive to individual tumours than predictions based on canonical driver genes. We further find that TARGET-SL is better at identifying sample-specific vulnerabilities than other similar tools.