Beyond synthetic lethality: charting the landscape of clinically relevant genetic interactions in cancer

Abstract

28The phenotypic effect of perturbing a gene's activity depends on the activity level of other genes, 29 reflecting the notion that phenotypes are emergent properties of a network of functionally interacting 30 genes. In the context of cancer, contemporary investigations have primarily focused on just one type of 31 functional genetic interaction (GI) -synthetic lethality (SL). However, there may be additional types of 32 GIs whose systematic identification would enrich the molecular and functional characterization of cancer. 33Here, we describe a novel data-driven approach called EnGIne, that applied to TCGA data identifies 34 71,946 GIs spanning 12 distinct types, only a small minority of which are SLs. The detected GIs explain 35 cancer driver genes' tissue-specificity and differences in patients' response to drugs, and stratify breast 36 cancer tumors into refined subtypes. These results expand the scope of cancer GIs and lay a conceptual 37 and computational basis for future studies of additional types of GIs and their translational applications. 38The GI network is accessible online via a web portal [https://amagen.shinyapps.io/cancerapp/]. 39 40