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

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  • Ming Jun Shi, PSL Research University, Université Paris-Sud 11, Beijing Friendship Hospital
  • ,
  • Xiang Yu Meng, PSL Research University, Université Paris-Sud 11, Wuhan University
  • ,
  • Philippe Lamy
  • A. Rouf Banday, National Cancer Institute, Bratislava, Slovakia
  • ,
  • Jie Yang, Université Paris—Denis Diderot
  • ,
  • Aura Moreno-Vega, PSL Research University, Université Paris-Sud 11
  • ,
  • Chun Long Chen, Institut Curie, Sorbonne Université
  • ,
  • Lars Dyrskjøt
  • Isabelle Bernard-Pierrot, PSL Research University
  • ,
  • Ludmila Prokunina-Olsson, National Cancer Institute, Bratislava, Slovakia
  • ,
  • François Radvanyi, PSL Research University

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. 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 molecular mechanisms of bladder cancer.

Original languageEnglish
JournalEuropean Urology
Volume76
Issue1
Pages (from-to)9-13
Number of pages5
ISSN0302-2838
DOIs
Publication statusPublished - 2019

    Research areas

  • APOBEC, Bladder cancer, FGFR3 mutation, Lynch syndrome, Upper urinary tract cancer

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