Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

Genome Medicine

Ming-Jun Shi¹  Isabelle Bernard-Pierrot²  François Radvanyi²  Jacqueline Fontugne³  Xiang-Yu Meng⁴  Chun-Long Chen⁵ 

[1] Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China;Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d’Ulm, 75005, Paris, France;Paris-Saclay University, Paris, France;Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d’Ulm, 75005, Paris, France;Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d’Ulm, 75005, Paris, France;Paris-Saclay University, Paris, France;Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, 26 Rue d’Ulm, 75005, Paris, France;Paris-Saclay University, Paris, France;Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China;Institut Curie, CNRS, UMR3244, PSL Research University, Paris, France;Sorbonne Université, Paris, France;

关键词: Bladder cancer;    APOBEC;    Mutagenesis;    Stem-loop;    Driver mutation;    Passenger mutation;    Oncogene;    Tumour suppressor gene;    Aryl hydrocarbon receptor;   

DOI  :  10.1186/s13073-020-00781-y

来源: Springer

【 摘 要 】

BackgroundAPOBEC-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.MethodsWe 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 APOBEC-mediated 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.ResultsWe 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-of-function 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.ConclusionsOur study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes.

【 授权许可】

CC BY