A Modular Master Regulator Landscape Determines the Impact of Genetic Alterations on the Transcriptional Identity of Cancer Cells

Abstract

Despite considerable pan-cancer efforts, the link between genomics and transcriptomics in cancer remains relatively weak and mostly based on statistical rather than mechanistic principles. By performing integrative analysis of transcriptomic and mutational profiles on a sample-by-sample basis, via regulatory/signaling networks, we identified a repertoire of 407 Master-Regulator proteins responsible for canalizing the genetics of 20 TCGA cohorts into 112 transcriptionally-distinct tumor subtypes. Further analysis highlighted a highly-recurrent regulatory architecture (oncotecture) with Master-Regulators organized into 24 modular MR-Blocks, regulating highly-specific tumor-hallmark functions and predictive of patient outcome. Critically, >50% of the somatic alterations identified in individual samples were in proteins affecting Master-Regulator activity, thus yielding novel insight into mechanisms linking tumor genetics and transcriptional identity and establishing novel non-oncogene dependencies. Experimental validation of functional mutations upstream of the most conserved MR-Block confirmed their ability to affect MR-protein activity, suggesting that the proposed methodology may effectively complement and extend current pan-cancer knowledge.