FGFR3 mutations are common in urothelial carcinoma. The APOBEC mutational process is the dominant mutational mechanism in bladder cancer. The relationship between the overexpression of FGFR3 S249C mutation and APOBEC mutagenesis is not well understood. A new study published by Shi et al. in European Urology examined the link between the APOBEC mutational load and different FGFR3 recurrent mutations in bladder cancer.

The investigators initially made the observation S249C occurs in a common APOBEC targeted motif (TCC -> TGC). After analysis of fork directionality, they found that the FGFR3 sense strand is mainly replicated as a lagging strand template. The authors predicted that this could allow single-stranded DNA structures to make hairpin structures exposing S249 to APOBEC enzymes mutagenesis. This is consistent with recent work suggesting that “hairpin” (stem-loop)

single-stranded DNA structures are the seat of enhanced APOBEC mutagenesis. Although they commonly detected FGFR3 S249C mutation in three different cancers (head and neck cancer, cervical cancer and non-small-cell lung cancer).

The importance of this study is that it shows that APOBEC3 mutagenesis can potentially occur in non-canonical motifs which expands the repertoire of possible APOBEC-induced mutations. It is likely that different mutagenic mechanisms produce distinct hotspot FGFR3 mutations.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

Shi MJ, Meng XY, Lamy P, Banday AR, Yang J, Moreno-Vega A, Chen CL, Dyrskjøt L, Bernard-Pierrot I, Prokunina-Olsson L, Radvanyi F. APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer. Eur Urol. 2019 Jul;76(1):9-13. doi: 10.1016/j.eururo.2019.03.032. Epub 2019 Apr 8. PMID: 30975452

Buisson R, Langenbucher A, Bowen D, Kwan EE, Benes CH, Zou L, Lawrence MS. Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science. 2019 Jun 28;364(6447). pii: eaaw2872. doi: 10.1126/science.aaw2872. PMID:31249028