Recurrent activating mutations in AHR act as drivers of urinary tract cancer

Bladder cancer is a common cancer with a high recurrence rate and with limited progress in treatment and survival of patients with advanced stages of the disease. The tumorigenesis of bladder cancer is still poorly understood, but identification of genetic contributors to its development may provide leads for targeted therapeutic approaches. By an in-depth analysis of whole-genome sequencing data of metastasized urinary tract cancer samples, we identified a novel recurrent in-frame deletion of exons 8 and 9 in the aryl hydrocarbon receptor (AHR) gene, encoding a ligand-activated transcription factor with context-specific physiological functions. The deletion (AHRΔe8-9) is highly specific to urinary tract cancer and occurs in 10.7% of metastatic lesions. Additionally, a recurrent AHR hotspot point mutation and AHR gene amplifications were identified indicating that alterations in the AHR gene are a key cancer driver event for urinary tract cancer adding up to a prevalence of ~19% (40 out of 206). The hotspot point mutation results in an amino acid change (AHRQ383H) in the ligand-binding domain of the protein and causes altered ligand affinities such as AHRQ383H activation upon incubation with the AhR antagonist CH-2233191. The in-frame deletion of exons 8 and 9 disrupt the ligand-binding domain and result in a constitutive nuclear localization of the protein and ligand-independent transcriptional activation. The constitutive activation of the AhR pathway by the hAHRΔe8-9 mutant in mouse bladder organoids induces dedifferentiation and enables anchorage independent growth. In conclusion, our results indicate that AhR is a key proto-oncogene and cancer driver gene in urinary tract cancer and emphasize the potential of the AhR pathway as a target for therapeutic interventions.