Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis

Area of Science:

• Genetics
• Immunology
• Oncology

Background:

• Systemic sclerosis is a fibrotic connective tissue disease primarily affecting women.
• Cancer develops in 4-22% of systemic sclerosis patients, worsening prognosis.
• Mechanisms linking systemic sclerosis, inflammation, and cancer are poorly understood.

Purpose of the Study:

• To investigate if inflammation in systemic sclerosis causes DNA damage and somatic mutations.
• To compare mutation burdens and spectra in fibroblasts from systemic sclerosis patients and controls.

Main Methods:

• Cultured clonal fibroblast lineages from lung tissues of systemic sclerosis patients and controls.
• Analyzed mutation types, including single base substitutions, indels, copy-number changes, and structural variants.
• Identified mutation signatures and genomic regions with kataegis.

Main Results:

• Systemic sclerosis fibroblasts exhibited increased mutation burdens across all major types compared to controls.
• Evidence of somatic hypermutation and kataegis, typically found in cancer genomes, was observed.
• Mutation signatures resembling Polη activity and activation-induced deaminase were identified.

Conclusions:

• Inflammation in systemic sclerosis may drive significant genomic instability.
• Elevated somatic mutagenesis in systemic sclerosis could contribute to cancer development.
• Further research is warranted to explore therapeutic strategies targeting DNA damage in systemic sclerosis.