SuperDendrix algorithm integrates genetic dependencies and genomic alterations across pathways and cancer types

Recent genome-wide CRISPR-Cas9 loss-of-function screens have identified genetic dependencies across many cancer cell lines. Associations between these dependencies and genomic alterations in the same cell lines reveal phenomena such as oncogene addiction and synthetic lethality. However, comprehensive identification of such associations is complicated by complex interactions between genes across genetically heterogeneous cancer types. We introduce and apply the algorithm SuperDendrix to CRISPR-Cas9 loss-of-function screens from 769 cancer cell lines, to identify differential dependencies across cell lines and to find associations between differential dependencies and combinations of genomic alterations and cell-type-specific markers. These associations respect the position and type of interactions within pathways: for example, we observe increased dependencies on downstream activators of pathways, such as NFE2L2, and decreased dependencies on upstream activators of pathways, such as CDK6. SuperDendrix also reveals dozens of dependencies on lineage-specific transcription factors, identifies cancer-type-specific correlations between dependencies, and enables annotation of individual mutated residues.