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...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2023-02, Vol.83 (4), p.506-520 |
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| creator | Liu, Weisi Newhall, Kevin P Khani, Francesca Barlow, LaMont Nguyen, Duy Gu, Lilly Eng, Ken Bhinder, Bhavneet Uppal, Manik Récapet, Charlotte Sboner, Andrea Ross, Susan R Elemento, Olivier Chelico, Linda Faltas, Bishoy M |
| description | 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.
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. |
| doi_str_mv | 10.1158/0008-5472.CAN-22-2912 |
| format | Article |
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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.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-22-2912</identifier><identifier>PMID: 36480186</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; APOBEC-3G Deaminase - genetics ; APOBEC-3G Deaminase - metabolism ; Cancer ; Clonal Evolution - genetics ; Cytidine Deaminase - genetics ; Cytidine Deaminase - metabolism ; Genomic Instability ; Humans ; Life Sciences ; Mice ; Minor Histocompatibility Antigens - genetics ; Mutagenesis - genetics ; Mutagens ; Urinary Bladder Neoplasms - genetics</subject><ispartof>Cancer research (Chicago, Ill.), 2023-02, Vol.83 (4), p.506-520</ispartof><rights>2022 American Association for Cancer Research.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-51a5488bafc8f6b2a9a81742dee0ac7bf60f91997320c5f419114879093ce5d3</citedby><cites>FETCH-LOGICAL-c390t-51a5488bafc8f6b2a9a81742dee0ac7bf60f91997320c5f419114879093ce5d3</cites><orcidid>0000-0002-4226-718X ; 0000-0002-8061-9617 ; 0000-0001-6685-8761 ; 0000-0003-4673-8978 ; 0000-0002-0271-1880 ; 0000-0001-6915-3070 ; 0000-0001-7238-8604 ; 0000-0002-4730-5448 ; 0000-0002-6432-1693 ; 0000-0002-7343-8017 ; 0000-0001-5414-8412 ; 0000-0002-3094-3769 ; 0000-0003-3628-1716 ; 0000-0002-3404-3610 ; 0000-0001-7605-3035</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36480186$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.inrae.fr/hal-04144654$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Weisi</creatorcontrib><creatorcontrib>Newhall, Kevin P</creatorcontrib><creatorcontrib>Khani, Francesca</creatorcontrib><creatorcontrib>Barlow, LaMont</creatorcontrib><creatorcontrib>Nguyen, Duy</creatorcontrib><creatorcontrib>Gu, Lilly</creatorcontrib><creatorcontrib>Eng, Ken</creatorcontrib><creatorcontrib>Bhinder, Bhavneet</creatorcontrib><creatorcontrib>Uppal, Manik</creatorcontrib><creatorcontrib>Récapet, Charlotte</creatorcontrib><creatorcontrib>Sboner, Andrea</creatorcontrib><creatorcontrib>Ross, Susan R</creatorcontrib><creatorcontrib>Elemento, Olivier</creatorcontrib><creatorcontrib>Chelico, Linda</creatorcontrib><creatorcontrib>Faltas, Bishoy M</creatorcontrib><title>The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>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.
APOBEC3G plays a role in cancer mutagenesis and clonal heterogeneity, which can potentially inform future therapeutic efforts that restrict tumor evolution. 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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.
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.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>36480186</pmid><doi>10.1158/0008-5472.CAN-22-2912</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4226-718X</orcidid><orcidid>https://orcid.org/0000-0002-8061-9617</orcidid><orcidid>https://orcid.org/0000-0001-6685-8761</orcidid><orcidid>https://orcid.org/0000-0003-4673-8978</orcidid><orcidid>https://orcid.org/0000-0002-0271-1880</orcidid><orcidid>https://orcid.org/0000-0001-6915-3070</orcidid><orcidid>https://orcid.org/0000-0001-7238-8604</orcidid><orcidid>https://orcid.org/0000-0002-4730-5448</orcidid><orcidid>https://orcid.org/0000-0002-6432-1693</orcidid><orcidid>https://orcid.org/0000-0002-7343-8017</orcidid><orcidid>https://orcid.org/0000-0001-5414-8412</orcidid><orcidid>https://orcid.org/0000-0002-3094-3769</orcidid><orcidid>https://orcid.org/0000-0003-3628-1716</orcidid><orcidid>https://orcid.org/0000-0002-3404-3610</orcidid><orcidid>https://orcid.org/0000-0001-7605-3035</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals APOBEC-3G Deaminase - genetics APOBEC-3G Deaminase - metabolism Cancer Clonal Evolution - genetics Cytidine Deaminase - genetics Cytidine Deaminase - metabolism Genomic Instability Humans Life Sciences Mice Minor Histocompatibility Antigens - genetics Mutagenesis - genetics Mutagens Urinary Bladder Neoplasms - genetics |
| title | The Cytidine Deaminase APOBEC3G Contributes to Cancer Mutagenesis and Clonal Evolution in Bladder Cancer |
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