The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer-Reference-Cited by-同舟云学术

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

Published:2022-12-08 Issue:4 Volume:83 Page:506-520
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Liu Weisi¹^ORCID,Newhall Kevin P.¹²^ORCID,Khani Francesca³⁴^ORCID,Barlow LaMont⁵⁶⁷^ORCID,Nguyen Duy¹^ORCID,Gu Lilly¹^ORCID,Eng Ken⁷⁸^ORCID,Bhinder Bhavneet⁷⁸^ORCID,Uppal Manik¹⁷⁸^ORCID,Récapet Charlotte⁹^ORCID,Sboner Andrea³⁴⁷⁸^ORCID,Ross Susan R.¹⁰^ORCID,Elemento Olivier⁴⁷⁸^ORCID,Chelico Linda¹¹^ORCID,Faltas Bishoy M.¹⁴⁷¹²^ORCID

Affiliation:

1. 1Department of Medicine, Weill Cornell Medicine, New York, New York.

2. 2Case Western Reserve University, School of Medicine, Cleveland, Ohio.

3. 3Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

4. 4Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.

5. 5Department of Urology, Grossman School of Medicine, New York University, New York, New York.

6. 6Department of Pathology, Grossman School of Medicine, New York University, New York, New York.

7. 7Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York.

8. 8Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York.

9. 9Universite de Pau et des Pays de l'Adour, E2S UPPA, INRAE, ECOBIOP, Saint-Pée-sur-Nivelle, France.

10. 10Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.

11. 11University of Saskatchewan, College of Medicine, Department of Biochemistry, Microbiology, and Immunology, Saskatoon, Saskatchewan, Canada.

12. 12Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, New York.

Abstract

AbstractMutagenic 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

Funder

C.V. Starr Center for the Study of the American Experience, Washington College

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/cancerres/article-pdf/doi/10.1158/0008-5472.CAN-22-2912/3229781/can-22-2912.pdf

Reference90 articles.

1. The repertoire of mutational signatures in human cancer;PCAWG Mutational Signatures Working Group, PCAWG Consortium;Nature,2020

2. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity;Swanton;Cancer Discov,2015

3. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers;Roberts;Nat Genet,2013