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 characterization of such associations is complicated by complex interactions between genes across genetically heterogeneous cancer types. We introduce SuperDendrix, an algorithm to identify differential dependencies across cell lines and to find associations between differential dependencies and combinations of genetic alterations and cell-type-specific markers. Application of SuperDendrix to CRISPR-Cas9 loss-of-function screens from 554 cancer cell lines reveals a landscape of associations between differential dependencies and genomic alterations across multiple cancer pathways in different combinations of cancer types. We find that these associations respect the position and type of interactions within pathways with 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. ### Competing Interest Statement B.J.R. is a founder of Medley Genomics and a member of its board of directors.
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