Psoriasis Not Linked to Spontaneous Mutations in Skin Cells, Study Finds

Psoriasis is not caused or spread by spontaneous genetic mutations in the skin, according to a new study. These findings allow for researchers to examine other avenues that may play a part in the development and presence of psoriasis.

This analysis study is published in Nature Genetics.¹

“Studying somatic mutations in noncancerous conditions has only become possible recently thanks to technological advancements, said lead author Sigurgeir Olafsson, PhD, deCODE genetics, in a statement.² “Genetic analysis of noncancerous diseases can help identify new driver mutations, such as those we describe. This adds to our growing collective knowledge about the impact of mutations on cancer and other diseases, as well as showing that certain treatments can influence the mutational landscape of a tissue.”

Somatic mutations occur over time in all cells in our bodies and can arise from replication errors, chemicals, or environmental factors, the study authors wrote. Although many of these mutations are harmless, some can lead to cancer. Recent studies have aimed to understand the possibility of driver mutations causing noncancerous diseases by adversely affecting the function of the tissue or influencing the spread of disease throughout the body.

In a previous study conducted by Wellcome Sanger Institute, these mutations were found to have an impact on inflammatory bowel disease, and therefore, the researchers aimed to examine if the same was true for psoriasis.

The researchers obtained 111 forearm skin samples from patients with psoriasis, taking samples from both psoriatic patches and healthy skin. Using a laser capture microdissection, they were able to isolate 1182 samples, which were then analyzed using whole genome or exome sequencing.

Minimal differences were identified in the types of mutations observed in healthy skin samples compared with psoriasis samples, with only a slight increase in the number of mutations. Moreover, no functional differences were observed between psoriasis and nonpsoriasis tissue samples, and the authors found no connection between psoriasis and specific somatic mutation in the skin.

In addition to evidence of positive selection in previously reported driver genes (NOTCH1, NOTCH2, TP53, FAT1, and PPM1D), 4 new driver mutations (GXYLT1, CHEK2, ZFP36L2, and EEF1A1) were identified that gave skin cells an advantage over their neighbors. However, these driver mutations were found in both psoriasis patches and other skin tissue and the researchers hypothesized these mutations were selected for in squamous epithelium irrespective of disease status.

Furthermore, the researchers found a mutational signature linked with the use of psoralens, "a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis," and sometimes as part of a treatment for flare-ups. However, these mutations were found in patients who had been prescribed psoralens along with patients who had not, which suggests these mutations could have come from environmental exposure, such as sunscreens.

“Psoriasis is a condition that affects millions of people around the world, impacting their quality of life, and very little is known about why it happens and how we can treat it,” said Carl Anderson, PhD, head of human genetics, Wellcome Sanger Institute, and senior author of the study, in the statement.² “While our research did not find a gene where somatic mutations increase susceptibility to psoriasis, we were able to quantify the mutational consequences of psoralens exposure on the skin, defining a mutational signature that may help future research. We also found that the way in which skin cells develop from stem cells is, reassuringly, unaltered by psoriasis.”

References

1. Olafsson S, Rodriguez E, Lawson AR, et al. Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin. Nature Genetics. Published online October 26, 2023. doi:10.1038/s41588-023-01545-1

2. Wellcome Trust Sanger Institute. Psoriasis not caused by spontaneous mutations in skin cells. News release. EurekAlert! October 26, 2023. Accessed October 31, 2023. https://www.eurekalert.org/news-releases/1005852