The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Mutational signatures are key to understanding cancer development.
• APOBEC3 cytidine deaminases are implicated in human cancers, but in vivo roles of individual proteins are unclear.

Purpose of the Study:

• To investigate the in vivo mutagenic impact of human APOBEC3G in a murine bladder cancer model.
• To characterize the specific mutational signature induced by APOBEC3G.

Main Methods:

• Transgenic expression of human APOBEC3G in a murine bladder cancer model.
• Analysis of single-base substitution signatures.
• Genomic instability and kataegis assessment.
• Comparative analysis of human cancer datasets.

Main Results:

• APOBEC3G expression promoted mutagenesis, genomic instability, and kataegis, reducing survival.
• APOBEC3G increased bladder cancer clonal diversity and drove divergent tumor evolution.
• APOBEC3G induced a distinct in vivo mutational signature, different from APOBEC3A/B.
• APOBEC3G contributes to genomic instability, tumor mutational burden, copy-number loss, and clonal diversity in human cancers.

Conclusions:

• APOBEC3G is a significant mutagen in bladder cancer, driving genomic instability and tumor evolution.
• The distinct mutational signature of APOBEC3G provides insights into its specific role in cancer mutagenesis.
• Understanding APOBEC3G's contribution to cancer heterogeneity may inform future therapeutic strategies targeting tumor evolution.