Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs.

Pancancer studies have identified many genes that are frequently somatically altered across multiple tumour types, suggesting that pathway-targeted therapies can be deployed across diverse cancers. However, the same 'actionable mutation' impacts distinct context-specific gene regulatory programs and signalling networks-and interacts with different genetic backgrounds of co-occurring alterations-in different cancers. Here we apply a computational strategy for integrating parallel (phospho)proteomic and mRNA sequencing data across 12 TCGA tumour data sets to interpret the context-specific impact of somatic alterations in terms of functional signatures such as (phospho)protein and transcription factor (TF) activities. Our analysis predicts distinct dysregulated transcriptional regulators downstream of somatic alterations in different cancers, and we validate the context-specific differential activity of TFs associated to mutant PIK3CA in isogenic cancer cell line models. These results have implications for the pancancer use of targeted drugs and potentially for the design of combination therapies.