High DNA mutation rate in SSc cells may promote cancer: Study

Researchers sequence lung fibroblasts to test hypothesis by Steve Bryson, PhD | November 19, 2024

​Cells derived from people with systemic sclerosis (SSc) had widespread DNA mutations compared with healthy cells, which may explain the higher risk of cancer in this patient population, according to a study.

Changes included mutational patterns found solely in the genomes of certain cancers, as well as changes in one or two DNA building blocks, insertions and deletions of DNA segments, and alterations in whole chromosomes.

The study, “Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis,” was published in Nature Communications.

SSc, or scleroderma, is an autoimmune disorder that affects the skin and connective tissue. It’s marked by the build-up of scar tissue in the skin and potentially various organs, including the heart and blood vessels, as well as the lungs, stomach, and kidneys.
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Studies suggest that the incidence of cancer in people with SSc is higher than in the general population, with up to about one in five patients developing cancer. Because the abnormal immune response in SSc can damage a wide range of tissues, it’s been suspected that this damage may extend to DNA, thus giving rise to cancer-causing mutations.

‘Genome-wide DNA damage’​
A team led by researchers at the Medical University of South Carolina hypothesized that “recurrent SSc-associated inflammation and auto-immune responses trigger genome-wide DNA damage, which could propagate systemic [body-wide] widespread mutagenesis [mutations] across various tissue types.”

To test this hypothesis, the researchers conducted whole-genome sequencing (WGS) on lung fibroblasts derived from SSc patients and healthy individuals.
Fibroblasts are the most common type of cell in connective tissue and are known to be involved in SSc development. WGS is a method to determine the whole DNA sequence of a genome, or the entire set of DNA instructions found in a cell.

Analysis revealed an increase in the mutational load of SSc samples compared with healthy samples. In particular, patient samples had elevated levels of single base substitutions (SBS), meaning single changes in one of the four DNA building blocks: adenine, thymine, guanine, or cytosine.

SSc samples were enriched in a specific mutational signature called SBS93. This signature, which has been linked with cancers affecting the digestive system, predominantly consists of mutations in which a thymine or cytosine is changed to one of the other DNA building blocks.

The change from thymine in SBS93 has also been associated with an error-prone DNA polymerase, an enzyme that copies DNA. Although this enzyme is needed to copy DNA damaged by ultraviolet rays from sunlight, it often inserts an incorrect DNA building block — a mutation — when it bypasses damaged DNA.

When the researchers focused on other types of mutations, they discovered higher levels of double base substitutions (DBS), or changes in two DNA building blocks, as well as insertions or deletions of longer DNA segments, in patient samples. One DBS signature, prominent in a healthy sample from a heavy smoker, was present in almost all SSc samples.

“Overall, our data strongly suggests the involvement of multiple different mutational processes in SSc,” the team wrote.

The scientists examined samples for kataegis, a feature in cancer genomes characterized by at least four single mutations in a relatively short region on the DNA strand. One of the five healthy samples showed limited kataegis on one chromosome, whereas five of nine SSc samples had kataegis across different chromosomes.

Looking more broadly at whole chromosomes, three SSc samples had large-scale amplifications or deletions of individual chromosome arms, which were not found in healthy samples. Likewise, large structural variations called chromosomal rearrangements were detected solely in SSc samples.
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“Our work offers a snapshot into the mutational landscape of SSc and highlights some of the mechanisms that could drive inflammation-associated genomic instability in SSc,” the researchers wrote. Larger studies with more genes and different tissue types may “shed further light on the central players involved in SSc-specific inflammation, immune response, and mutagenesis.”