The cytidine deaminase APOBEC3G contributes to cancer mutagenesis and clonal evolution in bladder cancer.

Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we showed that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increased the clonal diversity of bladder cancer, driving divergent cancer evolution. Characterization of the single base substitution signature induced by APOBEC3G in vivo established the induction of a mutational signature distinct from those caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers revealed the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Overall, this study dissects the mutagenic impact of APOBEC3G on the bladder cancer genome, identifying it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity.

Cancer research. 2022 Dec 08 [Epub ahead of print]

Weisi Liu, Kevin P Newhall, Francesca Khani, LaMont Barlow, Duy Nguyen, Lilly Gu, Ken Eng, Bhavneet Bhinder, Manik Uppal, Charlotte Récapet, Andrea Sboner, Susan R Ross, Olivier Elemento, Linda Chelico, Bishoy M Faltas

Weill Cornell Medicine, New York, United States., Case Western Reserve University, Cleveland, Ohio, United States., Weill Cornell Medicine, New York, NY, United States., New York University Grossman School of Medicine, New York, NY, United States., Weill Cornell Medicine, United States., Universite de Pau et des Pays de l'Adour, E2S UPPA, INRAE, Saint-Pée-sur-Nivelle, France., University of Illinois at Chicago College of Medicine, Chicago, United States., Weill Cornell Medicine, New York, New York, United States., University of Saskatchewan, Saskatoon, Saskatchewan, Canada.