APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer

Publication date: Available online 8 April 2019Source: European UrologyAuthor(s): Ming-Jun Shi, Xiang-Yu Meng, Philippe Lamy, A. Rouf Banday, Jie Yang, Aura Moreno-Vega, Chun-Long Chen, Lars Dyrskjøt, Isabelle Bernard-Pierrot, Ludmila Prokunina-Olsson, François RadvanyiAbstractFGFR3 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 summaryWe propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within subop...
Source: European Urology - Category: Urology & Nephrology Source Type: research