Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer
Vlaar, Judith M; Borgman, Anouska; Kalkhoven, Eric; Westland, Denise; Besselink, Nicolle; Shale, Charles; Faltas, Bishoy M; Priestley, Peter; Kuijk, Ewart; Cuppen, Edwin
(2022) Scientific Reports, volume 12, issue 1, pp. 1 - 12
(Article)
Abstract
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
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deletions of exons 8 and 9 in the aryl hydrocarbon receptor gene (AHR Δe8-9), which codes for a ligand-activated transcription factor. Pan-cancer analyses show that AHR Δe8-9 is highly specific to urinary tract cancer and mutually exclusive with other bladder cancer drivers. The ligand-binding domain of the AHR Δe8-9 protein is disrupted and we show that this results in ligand-independent AHR-pathway activation. In bladder organoids, AHR Δe8-9 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 Δe8-9 expression results in anchorage independent growth of bladder organoids, indicating tumorigenic potential. DNA-binding deficient AHR Δe8-9 fails to induce transformation, suggesting a role for AHR target genes in the acquisition of the oncogenic phenotype. In conclusion, we show that AHR Δe8-9 is a novel driver of urinary tract cancer and that the AHR pathway could be an interesting therapeutic target.
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Keywords: Exons/genetics, Humans, Ligands, Mutation, Receptors, Aryl Hydrocarbon/metabolism, Urinary Bladder Neoplasms/genetics, General, Journal Article
ISSN: 2045-2322
Publisher: Nature Publishing Group
Note: Funding Information: We are grateful to Jasper Mullenders and Hans Clevers for providing the mouse bladder organoids. We thank Livio Kleij for his support with microscopy, Single Cell Discoveries for support with single cell RNA sequencing, the Utrecht Sequencing Facility for providing sequencing service, and the UMC Utrecht Bioinformatics Expertise Core for data analysis and data handling. The Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University, and The Netherlands X-omics Initiative (NWO project 184.034.019). The UMC Utrecht Bioinformatics Expertise Core is subsidized by the University Medical Center Utrecht, Center for Molecular Medicine. This publication and the underlying study have been made possible partly based on the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study. Publisher Copyright: © 2022, The Author(s).
(Peer reviewed)