Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer.

Bladder cancer has a high recurrence rate and low survival of advanced stage patients. Few genetic drivers of bladder cancer have thus far been identified. We performed in-depth structural variant analysis on whole-genome sequencing data of 206 metastasized urinary tract cancers. In ~ 10% of the patients, we identified recurrent in-frame deletions of exons 8 and 9 in the aryl hydrocarbon receptor gene (AHR), which codes for a ligand-activated transcription factor. Pan-cancer analyses show that AHR is highly specific to urinary tract cancer and mutually exclusive with other bladder cancer drivers. The ligand-binding domain of the AHR protein is disrupted and we show that this results in ligand-independent AHR-pathway activation. In bladder organoids, AHR induces a transformed phenotype that is characterized by upregulation of AHR target genes, downregulation of differentiation markers and upregulation of genes associated with stemness and urothelial cancer. Furthermore, AHR expression results in anchorage independent growth of bladder organoids, indicating tumorigenic potential. DNA-binding deficient AHR fails to induce transformation, suggesting a role for AHR target genes in the acquisition of the oncogenic phenotype. In conclusion, we show that AHR is a novel driver of urinary tract cancer and that the AHR pathway could be an interesting therapeutic target.