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

TitleThe Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer.
Publication TypeJournal Article
Year of Publication2023
AuthorsLiu W, Newhall KP, Khani F, Barlow LM, Nguyen D, Gu L, Eng K, Bhinder B, Uppal M, R├ęcapet C, Sboner A, Ross SR, Elemento O, Chelico L, Faltas BM
JournalCancer Res
Volume83
Issue4
Pagination506-520
Date Published2023 Feb 15
ISSN1538-7445
KeywordsAnimals, APOBEC-3G Deaminase, Clonal Evolution, Cytidine Deaminase, Genomic Instability, Humans, Mice, Minor Histocompatibility Antigens, Mutagenesis, Mutagens, Urinary Bladder Neoplasms
Abstract

UNLABELLED: 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 that it contributes to genomic instability, tumor mutational burden, copy-number loss events, and clonal diversity.

SIGNIFICANCE: APOBEC3G plays a role in cancer mutagenesis and clonal heterogeneity, which can potentially inform future therapeutic efforts that restrict tumor evolution. See related commentary by Caswell and Swanton, p. 487.

DOI10.1158/0008-5472.CAN-22-2912
Alternate JournalCancer Res
PubMed ID36480186
Grant ListR01 AI085015 / AI / NIAID NIH HHS / United States
R56 AI085015 / AI / NIAID NIH HHS / United States
Related Faculty: 
Andrea Sboner, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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