Oncodriver genes are usually identified when mutations recur in multiple tumours. Different drivers often converge in the activation or repression of key cancer-relevant pathways. However, as many pathways contain multiple members of the same gene family, individual mutations might be overlooked, as each family member would necessarily have a lower mutation frequency and thus not identified as significant in any one-gene-at-a-time analysis. Here, we looked for mutated, functional sequence positions in gene families that were mutually exclusive (in patients) with another gene in the same pathway, which identified both known and new candidate oncodrivers. For instance, many inactivating mutations in multiple G-protein (particularly Gi/o) coupled receptors, are mutually exclusive with Gαs oncogenic activating mutations, both of which ultimately enhance cAMP signalling. By integrating transcriptomics and interaction data, we show that the Gs pathway is upregulated in multiple cancer types, even those lacking known GNAS activating mutations. This suggests that cancer cells may develop alternative strategies to activate adenylate cyclase signalling in multiple cancer types. Our study provides a mechanistic interpretation for several rare somatic mutations in multi-gene oncodrivers, and offers possible explanations for known and potential off-label cancer treatments, suggesting new therapeutic opportunities.

RNA editing has been described to promote heterogeneity leading to the development of multiple disorders including cancer. The cytosine deaminase APOBEC3B is known to fuel tumor evolution through DNA mutagenesis, but whether it may also function as an RNA editing enzyme has not been studied. Here, we engineered a novel doxycycline-inducible mouse model of human APOBEC3B-overexpression to understand the impact of this enzyme in tissue homeostasis and address a potential role in C-to-U RNA editing. Elevated and sustained levels of APOBEC3B led to rapid alteration of cellular fitness, major organ dysfunction, and ultimately lethality in mice. Importantly, extensive analyses of RNA-sequencing and WES from mouse tissues expressing high APOBEC3B levels reveal frequent UCC-to-UUC RNA editing events mainly localized in a specific hotspot. This work identifies, for the first time, a new function for APOBEC3B in RNA editing and presents a valuable preclinical tool to understand the emerging role of APOBEC3B as a potent driver of cancer and other diseases.