Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis
Abstract Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as a multisystem pathology. Roughly 4-22% of patients with systemic sclerosis develop cancer, which drastically worsens prognosis. However, the mechanisms und...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53332-z |
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| author | Sriram Vijayraghavan Thomas Blouin James McCollum Latarsha Porcher François Virard Jiri Zavadil Carol Feghali-Bostwick Natalie Saini |
| author_facet | Sriram Vijayraghavan Thomas Blouin James McCollum Latarsha Porcher François Virard Jiri Zavadil Carol Feghali-Bostwick Natalie Saini |
| author_sort | Sriram Vijayraghavan |
| collection | DOAJ |
| description | Abstract Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as a multisystem pathology. Roughly 4-22% of patients with systemic sclerosis develop cancer, which drastically worsens prognosis. However, the mechanisms underlying systemic sclerosis initiation, propagation, and cancer development are poorly understood. We hypothesize that the inflammation and immune response associated with systemic sclerosis can trigger DNA damage, leading to elevated somatic mutagenesis, a hallmark of pre-cancerous tissues. To test our hypothesis, we culture clonal lineages of fibroblasts from the lung tissues of controls and systemic sclerosis patients and compare their mutation burdens and spectra. We find an overall increase in all major mutation types in systemic sclerosis samples compared to control lung samples, from small-scale events such as single base substitutions and insertions/deletions, to chromosome-level changes, including copy-number changes and structural variants. In the genomes of patients with systemic sclerosis, we find evidence of somatic hypermutation or kategis (typically only seen in cancer genomes), we identify mutation signatures closely resembling the error-prone translesion polymerase Polη activity, and observe an activation-induced deaminase-like mutation signature, which overlaps with genomic regions displaying kataegis. |
| format | Article |
| id | doaj-art-9922427373d4473b9e26d8079f0b5aff |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9922427373d4473b9e26d8079f0b5aff2025-02-09T12:43:51ZengNature PortfolioNature Communications2041-17232024-10-0115111410.1038/s41467-024-53332-zWidespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosisSriram Vijayraghavan0Thomas Blouin1James McCollum2Latarsha Porcher3François Virard4Jiri Zavadil5Carol Feghali-Bostwick6Natalie Saini7Department of Biochemistry and Molecular Biology, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaUniversity Claude Bernard Lyon 1, INSERM U1052–CNRS UMR5286, Cancer Research Center, Centre Léon BérardInternational Agency for Research on Cancer WHO, Epigenomics and Mechanisms BranchDepartment of Medicine, Division of Rheumatology, Medical University of South CarolinaDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaAbstract Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as a multisystem pathology. Roughly 4-22% of patients with systemic sclerosis develop cancer, which drastically worsens prognosis. However, the mechanisms underlying systemic sclerosis initiation, propagation, and cancer development are poorly understood. We hypothesize that the inflammation and immune response associated with systemic sclerosis can trigger DNA damage, leading to elevated somatic mutagenesis, a hallmark of pre-cancerous tissues. To test our hypothesis, we culture clonal lineages of fibroblasts from the lung tissues of controls and systemic sclerosis patients and compare their mutation burdens and spectra. We find an overall increase in all major mutation types in systemic sclerosis samples compared to control lung samples, from small-scale events such as single base substitutions and insertions/deletions, to chromosome-level changes, including copy-number changes and structural variants. In the genomes of patients with systemic sclerosis, we find evidence of somatic hypermutation or kategis (typically only seen in cancer genomes), we identify mutation signatures closely resembling the error-prone translesion polymerase Polη activity, and observe an activation-induced deaminase-like mutation signature, which overlaps with genomic regions displaying kataegis.https://doi.org/10.1038/s41467-024-53332-z |
| spellingShingle | Sriram Vijayraghavan Thomas Blouin James McCollum Latarsha Porcher François Virard Jiri Zavadil Carol Feghali-Bostwick Natalie Saini Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis Nature Communications |
| title | Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis |
| title_full | Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis |
| title_fullStr | Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis |
| title_full_unstemmed | Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis |
| title_short | Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis |
| title_sort | widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis |
| url | https://doi.org/10.1038/s41467-024-53332-z |
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