Psoriasis, a chronic skin condition affecting an estimated 125 million people globally, has long puzzled researchers with its elusive origins and mechanisms. Recent research led by the Wellcome Sanger Institute challenges the conventional wisdom surrounding psoriasis, revealing that somatic mutations are not responsible for either the onset or the propagation of this debilitating skin disorder.
The findings, published in Nature Genetics on October 26, shed new light on the understanding of psoriasis, redirecting scientific focus toward alternative avenues for exploration.
Somatic Mutations and Their Role in Diseases:
Somatic mutations, alterations in the DNA of non-reproductive cells, naturally accumulate over time due to replication errors, exposure to chemicals, or environmental factors. While some mutations contribute to the development of cancer, many are innocuous. In certain cases, mutations can confer a selective advantage to the affected cells, leading to their proliferation and potential contribution to disease. Previous research, particularly in inflammatory diseases like inflammatory bowel disease, has highlighted the role of somatic mutations in disease initiation and progression.
The Psoriasis Puzzle:
Psoriasis, characterized by flaky and sore skin patches, has long remained an enigma in terms of its causative factors. The Wellcome Sanger Institute, known for groundbreaking genetic research, aimed to investigate whether somatic mutations played a role in the development and spread of psoriasis, similar to their impact on other inflammatory diseases.
Study Design and Methodology:
The research team, in collaboration with other institutions, sequenced skin samples from 111 individuals diagnosed with psoriasis. Crucially, they compared mutated genes in psoriatic patches with those in unaffected skin tissue from the same individuals. The technique of laser capture microdissection enabled the isolation of 1,182 samples, which were subjected to whole genome or exome sequencing.
Contrary to expectations, the study revealed no significant differences in mutated genes between psoriatic patches and healthy skin. The team identified only a marginal increase in the number of mutations in psoriasis-affected tissue, dispelling the notion that somatic mutations drive the development or spread of psoriasis.
Moreover, functional analysis demonstrated no distinctive differences between psoriatic and non-psoriatic tissue, indicating that psoriasis is not linked to a specific somatic mutation in the skin.
New Insights and Intriguing Discoveries:
In a noteworthy revelation, the research team identified four new driver mutations that provided skin cells with a competitive advantage, occurring in both psoriasis patches and healthy skin. Additionally, a mutational signature associated with psoralen use, a compound sometimes used in psoriasis treatment, was identified. However, this signature was present in patients both with and without prescribed psoralens, suggesting a potential environmental origin for these mutations.
Dr. Sigurgeir Olafsson, the first author of the study, emphasized the significance of recent technological advancements enabling the study of somatic mutations in non-cancerous conditions. He highlighted that understanding the impact of mutations on diseases, including psoriasis, contributes to the collective knowledge about the role of mutations in various health conditions.
Implications for Psoriasis Research and Treatment:
While the study dispels the notion of somatic mutations as the primary driver of psoriasis, it opens new avenues for research into alternative causes and mechanisms underlying the condition. The findings emphasize the need to explore factors beyond genetic mutations to unravel the mysteries of psoriasis.
Discussion: Unveiling the Genomic Landscape of Psoriasis
In this comprehensive investigation employing whole-exome sequencing (WES) of microbiopsies from the epidermis of 111 patients with psoriasis vulgaris, we sought to elucidate the impact of this chronic disease on the somatic mutation landscape of the skin. Our findings challenge established notions regarding the role of psoriasis in keratinocyte clone spread, mutation burden, and the potential influence of treatment on the increased risk of keratinocyte cancers associated with the condition.
Minimal Impact on Keratinocyte Clone Spread:
Contrary to expectations, our analysis suggests that psoriasis does not exert a significant influence on the lateral spread of keratinocyte clones in the skin. This implies that the somatic mutation landscape of psoriatic patches closely resembles that of unaffected skin, challenging the conventional belief that psoriasis triggers extensive mutations leading to the spread of affected cells.
Modest Effect on Mutation Burden:
While psoriasis is associated with a modestly increased risk of keratinocyte cancers, our results indicate that this elevation may predominantly stem from the effects of treatment rather than inherent features of the disease. We observed a minimal impact on the mutation burden in psoriatic tissue, reinforcing the idea that factors beyond somatic mutations contribute to the increased cancer risk in psoriasis patients.
Inflammation and Mutation Burden:
Our study explored the relationship between psoriasis duration, a proxy for inflammation exposure, and mutation burden. The observed association between disease duration and an increased mutation burden of clock-like signatures SBS1 and SBS5 suggests a potential link between inflammation and mutation accumulation. However, further validation and exploration are warranted to solidify this connection.
Positive Selection of Genes:
Intriguingly, our investigation identified four genes not previously reported in studies of normal epidermis that are under positive selection in psoriasis. We propose that nonsynonymous mutations in these genes are not specific to psoriasis but are rather under positive selection in squamous epithelia in general. This discovery adds complexity to our understanding of the genetic landscape associated with psoriasis.
Psoralen Exposure and Mutational Signatures:
We unveiled a distinct mutational signature associated with psoralen exposure, a known mutagen used in psoriasis treatment. While the correlation with PUVA treatment was not flawless, our findings align with experimental evidence demonstrating psoralens’ mutagenic effects. The potential exposure routes, including sunscreen or dietary sources, offer intriguing avenues for further exploration and highlight the need for cautious consideration of mutagenic effects in various contexts.
Contrasting Somatic Mutation Landscapes with IBD:
Comparison with our earlier work on inflammatory bowel disease (IBD) reveals notable differences in the somatic mutation landscapes of affected tissues. Despite both being Th17-mediated chronic inflammatory diseases sharing common genetic loci, IBD and psoriasis exhibit distinct effects on immune-related genes. The absence of positive selection for IL-17 pathway genes in psoriasis underscores the differential role of this cytokine in the two diseases. Our data emphasizes the importance of discerning the unique somatic mutation profiles in different autoimmune conditions and directs attention to potential divergences in underlying pathogenic mechanisms.
While our study provides crucial insights into the somatic mutation landscape of psoriasis-affected skin, avenues for future research abound. The potential role of somatic mutations in immune cells in psoriasis pathogenesis remains open, aligning with emerging data from other autoimmune diseases. Investigating whether somatic mutations enable lymphocytes to bypass tolerance checkpoints and foster autoreactive clone expansion represents a promising direction for future exploration. Our study lays the foundation for a nuanced understanding of the genomic intricacies associated with psoriasis, paving the way for more targeted and effective therapeutic interventions.
In the quest to decipher the complexities of psoriasis, the Wellcome Sanger Institute’s research challenges the prevailing belief that somatic mutations are intricately linked to the development and spread of this chronic skin condition. By demonstrating minimal differences in mutated genes between psoriatic and healthy skin, the study paves the way for a fresh perspective in psoriasis research. While the genetic analysis didn’t uncover a specific somatic mutation responsible for psoriasis, it provides valuable insights into the mutational consequences of psoralen exposure, urging researchers to consider environmental factors in their quest to unlock the secrets of psoriasis.
- The replacement of non-mutated cells with those containing an advantage could have an impact on the functioning of the tissue, potentially contributing to common complex disease risk or influencing the disease progression or response to treatment.
- Previous work by the Wellcome Sanger Institute found mutations that could be linked to the development of IBD. https://pubmed.ncbi.nlm.nih.gov/32697969/
- National Psoriasis Foundation. Available at https://www.psoriasis.org/psoriasis-statistics/#:~:text=Prevalence&text=125%20million%20people%20worldwide%20%E2%80%94%202,the%20World%20Psoriasis%20Day%20consortium. [Accessed October 2023]
- Exome sequencing targets and sequences coding regions of the genome, referred to as “the exome”. Whole genome sequencing captures and sequences the entire genome.
S. Olafsson, E. Rodriguez, A. Lawson, et al. (2023) Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin. Nature Genetics. DOI: 10.1038/s41588-023-01545-1