Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion
Summary: Environmental exposures significantly influence cancer risk, but their mutational impact remains unclear. We perform whole-exome sequencing of hepatocellular carcinomas (HCCs) from B6C3F1/N mice that arise spontaneously with age (2 years old) or following chronic exposure to one of ten pote...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725007491 |
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| author | Miaofei Xu Jianying Li Yun-Chung Hsiao Ramesh C. Kovi Jian-Liang Li Leszek J. Klimczak Laura Riva David Adams Pierre R. Bushel B. Alex Merrick Dmitry Gordenin John R. Bucher Robert C. Sills Arun R. Pandiri |
| author_facet | Miaofei Xu Jianying Li Yun-Chung Hsiao Ramesh C. Kovi Jian-Liang Li Leszek J. Klimczak Laura Riva David Adams Pierre R. Bushel B. Alex Merrick Dmitry Gordenin John R. Bucher Robert C. Sills Arun R. Pandiri |
| author_sort | Miaofei Xu |
| collection | DOAJ |
| description | Summary: Environmental exposures significantly influence cancer risk, but their mutational impact remains unclear. We perform whole-exome sequencing of hepatocellular carcinomas (HCCs) from B6C3F1/N mice that arise spontaneously with age (2 years old) or following chronic exposure to one of ten potential human carcinogens that operate through genotoxic or non-genotoxic mechanisms. HCCs from mice exposed to drinking water disinfection byproducts, such as bromochloroacetic acid (BCA) and bromodichloroacetic acid (BDCA), show dose-dependent increases in mutational burden, distinct mutational signatures (BCA-mSBS12 and BDCA-mSBS25), and enrichment of the aTn→aCn mutational motif. In contrast, HCCs from other exposures, as well as from spontaneous tumors, show comparable mutational burdens, mutational signatures, and enrichment of the nCg→nTg mutational motif. These findings suggest that many environmental carcinogens promote tumorigenesis by amplifying endogenous mutagenic processes rather than initiating distinct mutational events. Our results highlight the utility of rodent models for investigating environmental carcinogenesis and provide insights relevant to human cancer risk assessment. |
| format | Article |
| id | doaj-art-bf50c2ed4f374abe927a113c05c460f2 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-bf50c2ed4f374abe927a113c05c460f22025-08-20T03:17:25ZengElsevierCell Reports2211-12472025-07-0144711597810.1016/j.celrep.2025.115978Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotionMiaofei Xu0Jianying Li1Yun-Chung Hsiao2Ramesh C. Kovi3Jian-Liang Li4Leszek J. Klimczak5Laura Riva6David Adams7Pierre R. Bushel8B. Alex Merrick9Dmitry Gordenin10John R. Bucher11Robert C. Sills12Arun R. Pandiri13Division of Translational Toxicology, NIEHS, Research Triangle Park, NC, USABiostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC, USAGenomic Integrity and Structural Biology Laboratory, NIEHS, Research Triangle Park, NC, USADivision of Translational Toxicology, NIEHS, Research Triangle Park, NC, USABiostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC, USABiostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC, USAWellcome Trust Sanger Institute, Cambridge, UKWellcome Trust Sanger Institute, Cambridge, UKBiostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC, USADivision of Translational Toxicology, NIEHS, Research Triangle Park, NC, USAGenomic Integrity and Structural Biology Laboratory, NIEHS, Research Triangle Park, NC, USADivision of Translational Toxicology, NIEHS, Research Triangle Park, NC, USADivision of Translational Toxicology, NIEHS, Research Triangle Park, NC, USADivision of Translational Toxicology, NIEHS, Research Triangle Park, NC, USA; Corresponding authorSummary: Environmental exposures significantly influence cancer risk, but their mutational impact remains unclear. We perform whole-exome sequencing of hepatocellular carcinomas (HCCs) from B6C3F1/N mice that arise spontaneously with age (2 years old) or following chronic exposure to one of ten potential human carcinogens that operate through genotoxic or non-genotoxic mechanisms. HCCs from mice exposed to drinking water disinfection byproducts, such as bromochloroacetic acid (BCA) and bromodichloroacetic acid (BDCA), show dose-dependent increases in mutational burden, distinct mutational signatures (BCA-mSBS12 and BDCA-mSBS25), and enrichment of the aTn→aCn mutational motif. In contrast, HCCs from other exposures, as well as from spontaneous tumors, show comparable mutational burdens, mutational signatures, and enrichment of the nCg→nTg mutational motif. These findings suggest that many environmental carcinogens promote tumorigenesis by amplifying endogenous mutagenic processes rather than initiating distinct mutational events. Our results highlight the utility of rodent models for investigating environmental carcinogenesis and provide insights relevant to human cancer risk assessment.http://www.sciencedirect.com/science/article/pii/S2211124725007491CP: Cancer |
| spellingShingle | Miaofei Xu Jianying Li Yun-Chung Hsiao Ramesh C. Kovi Jian-Liang Li Leszek J. Klimczak Laura Riva David Adams Pierre R. Bushel B. Alex Merrick Dmitry Gordenin John R. Bucher Robert C. Sills Arun R. Pandiri Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion Cell Reports CP: Cancer |
| title | Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion |
| title_full | Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion |
| title_fullStr | Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion |
| title_full_unstemmed | Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion |
| title_short | Environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion |
| title_sort | environmental carcinogens often exacerbate endogenous mutagenic processes to enhance tumor promotion |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725007491 |
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