FGFR3 is one of the most frequently mutated genes in bladder cancer and a driver of an oncogenic dependency. Here we report that only the most common recurrent FGFR3 mutation, S249C (TCC ! TGC), represents an APOBEC-type motif and is probably caused by the APOBEC-mediated mutagenic process, accounting for its over-representation. We observed significant enrichment of the APOBEC mutational signature and overexpression of AID/APOBEC gene family members in bladder tumors with S249C compared to tumors with other recurrent FGFR3 mutations. Analysis of replication fork directionality suggests that the coding strand of FGFR3 is predominantly replicated as a lagging strand template that could favor the formation of hairpin structures, facilitating mutagenic activity of APOBEC enzymes. In vitro APOBEC deamination assays confirmed S249 as an APOBEC target. We also found that the FGFR3 S249C mutation was common in three other cancer types with an APOBEC mutational signature, but rare in urothelial tumors without APOBEC mutagenesis and in two diseases probably related to aging. Patient summary: We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within suboptimal motifs, such as in the case of FGFR3 S249C, one of the most common mutations in bladder cancer. Knowledge about the etiology of this mutation will improve our understanding of the molecular mechanisms of bladder cancer.

Ming-Jun Shi a,b,i,y , Xiang-Yu Meng a,b,c,y , Philippe Lamy d,y , A. Rouf Banday e,y , Jie Yang f , Aura Moreno-Vega a,b , Chun-Long Chen g,h , Lars Dyrskjøt d,z , Isabelle Bernard-Pierrot a,z , Ludmila Prokunina-Olsson e,z , Franc¸ ois Radvanyi a,z, a Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, Paris, France; b Paris-Sud University, Paris-Saclay University, Paris, France; cDepartment of Urology, Zhongnan Hospital, Wuhan University, Wuhan, China; dDepartment of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; e Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; f Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Diderot, Paris, France; g Institut Curie, CNRS, UMR3244, PSL Research University, Paris, France; h Sorbonne Université, Paris, France; i Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China

Shi M-J, et al. APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Overrepresentation in Bladder Cancer. Eur Urol (2019), https://doi.org/10.1016/j.eururo.2019.03.032

Read an Expert Commentary by Bishoy M. Faltas, MD