Combined gene essentiality scoring improves the prediction of cancer dependency mapsResearch in context

Abstract

Background: Probing genetic dependencies of cancer cells can improve our understanding of tumour development and progression, as well as identify potential drug targets. CRISPR-Cas9-based and shRNA-based genetic screening are commonly utilized to identify essential genes that affect cancer growth. However, systematic methods leveraging these genetic screening techniques to derive consensus cancer dependency maps for individual cancer cell lines are lacking. Finding: In this work, we first explored the CRISPR-Cas9 and shRNA gene essentiality profiles in 42 cancer cell lines representing 10 cancer types. We observed limited consistency between the essentiality profiles of these two screens at the genome scale. To improve consensus on the cancer dependence map, we developed a computational model called combined essentiality score (CES) to integrate the genetic essentiality profiles from CRISPR-Cas9 and shRNA screens, while accounting for the molecular features of the genes. We found that the CES method outperformed the existing gene essentiality scoring approaches in terms of ability to detect cancer essential genes. We further demonstrated the power of the CES method in adjusting for screen-specific biases and predicting genetic dependencies in individual cancer cell lines. Interpretation: Systematic comparison of the CRISPR-Cas9 and shRNA gene essentiality profiles showed the limitation of relying on a single technique to identify cancer essential genes. The CES method provides an integrated framework to leverage both genetic screening techniques as well as molecular feature data to determine gene essentiality more accurately for cancer cells. Keywords: Functional genetic screen, CRISPR, RNAi, Gene essentiality, Data integration