Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer
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RESEARCH
Open Access
Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer Ming-Jun Shi1,2,3†, Xiang-Yu Meng2,3,4*†, Jacqueline Fontugne2,3, Chun-Long Chen5,6, François Radvanyi2† and Isabelle Bernard-Pierrot2*†
Abstract Background: APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. Methods: We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBECmediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. Results: We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-offunction mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT. We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. (Continued on next page)
* Correspondence: [email protected]; [email protected] † Ming-Jun Shi and Xiang-Yu Meng contributed equally to this work. † François Radvanyi and Isabelle Bernard-Pierrot are joint senior authors. 2 Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d’Ulm, 75005 Paris, France Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) a
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