Beyond synthetic lethality: multiple gene interaction types play a key functional role in cancer

The phenotypic effect of perturbing a gene9s activity depends on the activity state of other genes, reflecting the fundamental notion that genotype to phenotype linkage is mediated by a network of functionally interacting genes. The vast majority of contemporary investigations have focused on just one type of genetic interactions (GI) - synthetic lethality (SL). However, there may be additional types of GIs whose systematic identification may markedly enrich the molecular and functional characterization of cancer. Here, based on a novel data-driven approach, we identify ~72K GIs of 11 new types, shared across cancers. These GIs are highly predictive of patient survival, stratify breast cancer tumors into refined subtypes, and explain differences in patients9 response to drugs and cancer driver genes9 tissue-specificity. These results markedly expand the scope of cancer GIs and lay a strong conceptual and computational basis for future studies of additional types of GIs and for their translational applications.