RESUMO
Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give rise to skin cancer. Early mutation accumulation is a crucial first step in photocarcinogenesis. Therefore, a sufficient understanding of the process may help predict disease onset and identify avenues for skin cancer prevention. Early epidermal mutation profiles are typically established using high-depth targeted next-generation sequencing. However, there is currently a lack of tools for designing custom panels to capture mutation-enriched genomic regions efficiently. To address this issue, we created a computational algorithm that implements a pseudo-exhaustive approach to identify the best genomic areas to target. We benchmarked the current algorithm in three independent mutation datasets of human epidermal samples. Compared to the sequencing panel designs originally used in these publications, the mutation capture efficacy (number of mutations/base pairs sequenced) of our designed panel improved 9.6-12.1-fold. Mutation burden in the chronically sun-exposed and intermittently sun-exposed normal epidermis was measured within genomic regions identified by hotSPOT based on cutaneous squamous cell carcinoma (cSCC) mutation patterns. We found a significant increase in mutation capture efficacy and mutation burden in cSCC hotspots in chronically sun-exposed vs. intermittently sun-exposed epidermis (p < 0.0001). Our results show that our hotSPOT web application provides a publicly available resource for researchers to design custom panels, enabling efficient detection of somatic mutations in clinically normal tissues and other similar targeted sequencing studies. Moreover, hotSPOT also enables the comparison of mutation burden between normal tissues and cancer.
RESUMO
Psoriasis is a lifelong disease and its prevalence in older adults continues to increase as the population ages. Therefore, it is important for physicians to understand the management of the disease in this population. While the management of psoriasis in older adults is similar to the management of patients below the age of 65 years, there are special considerations when treating older patients. Older patients may have more comorbidities, more immunosuppression, and are often taking additional medications that can interact with those being used to treat psoriasis. Safer and more effective treatment options for psoriasis have been introduced in recent years, particularly injectable biological agents. Unfortunately, older patients with psoriasis are oftentimes underrepresented in the clinical trials for these new medications. Subsequent studies have focused on the safety and efficacy of these medications in older adults. The results of these studies demonstrate that biologic agents are well tolerated in older patients and are more effective in treating psoriasis than conventional systemic therapies. In addition, new small-molecule agents such as apremilast also offer an effective and safe treatment option for older patients with psoriasis. The results of these studies can help guide physicians with incorporating these newer medications into the treatment regimen of older psoriasis patients. Despite the proven safety and efficacy of biologic agents, their frequency of use in elderly patients is still almost half of that in non-elderly patients.
