Can Next-Generation Sequencing Revolutionize Dermatology?

by Haroon Ahmad, MD 2025-01-01 00:00

PhysicianMedical

🔍 Key Finding Next-generation sequencing (NGS) has advanced dermatology by improving diagnosis and management of genodermatoses, cutaneous squamous cell carcinoma, melanoma, and cutaneous T-cell lymphoma. NGS allows for faster and more comprehensive genetic analysis compared to traditional methods, leading to improved diagnostic yields, personalized therapies, and a deeper understanding of disease pathogenesis.

🔬 Methodology Overview

Design: Narrative review.
Data Sources: Published literature on applications of Next-Generation Sequencing (NGS) in dermatology.
Selection Criteria: Focus on clinical studies utilizing NGS in genodermatoses (specifically epidermolysis bullosa and ichthyosis), melanoma, cutaneous squamous cell carcinoma, and cutaneous T-cell lymphoma.
Analysis Approach: Qualitative synthesis of findings from clinical NGS studies, highlighting diagnostic yield, mutational landscapes, and therapeutic implications.
Scope: Diagnostic and management applications of NGS in specific dermatological conditions, emphasizing the impact of NGS on the field.

📊 Results

Genodermatoses: NGS achieved 84-100% diagnostic yield for epidermolysis bullosa (EB) across multiple studies, significantly higher than traditional methods like immunofluorescence antigen mapping (IFM) which had frequent equivocal findings. For ichthyosis, NGS yielded a diagnostic rate of 79-91% in ARCI cohorts, with larger gene panels ( > 50 genes) generally showing higher yields.
Cutaneous Squamous Cell Carcinoma (cSCC): UV signature C-to-T transitions are the most common mutations. TP53 is an early and frequent driver mutation, particularly in metastatic cSCC (80-100%). NOTCH1 mutations also occur early and frequently (82% in one study).
Melanoma: NGS panels achieved 70-92% yield in identifying pathogenic mutations in melanoma, with many being actionable. In a real-world study, 76% of melanomas had actionable alterations. BRAF mutations are most common in low cumulative sun damage skin, while NRAS and KIT mutations are more frequent in high sun damage skin.
Cutaneous T-cell Lymphoma (CTCL): NGS showed 85% clonality detection compared to 44% with traditional PCR-CE methods. Recurrent mutations were found in tumor suppressor genes (TP53, FAT1, FAT3), chromatin remodeling genes (ARID1B, MLL2, MLL3, KDM6A), and DNA damage response genes (ATM, MDC1). UV-induced mutational signature 7 was prevalent in MF (52%) and SS (23%).

💡 Clinical Impact Next-generation sequencing (NGS) has improved diagnosis and management of genetic skin diseases, melanoma, and cutaneous squamous cell carcinoma by identifying causative mutations and informing treatment selection. NGS also shows promise in enhancing cutaneous T-cell lymphoma diagnosis, potentially improving patient management.

🤔 Limitations

Turnaround time for NGS is longer than IFM for EB diagnosis.
Large copy number variations may be missed with NGS.
Difficulty detecting structural variants in melanoma with targeted NGS panels.
Choice between whole exome versus targeted panels for melanoma poses challenges.
NGS testing requires specialized infrastructure and bioinformatic support, limiting availability.
Cost of NGS testing, though comparable to conventional methods, can still be a barrier.
Throughput limitations of smaller sequencing platforms can impact turnaround time for rare conditions.

✨ What It Means For You Next-generation sequencing (NGS) offers dermatologists a powerful tool for diagnosing genetic skin diseases and cancers, guiding treatment decisions based on identified mutations, and monitoring therapeutic responses. NGS improves diagnostic accuracy and identifies potential therapeutic targets, particularly in heterogeneous diseases like epidermolysis bullosa, ichthyosis, melanoma, and cutaneous T-cell lymphoma, paving the way for personalized dermatologic care. While cost and turnaround time have been limitations, ongoing technological advancements are making NGS increasingly accessible and efficient for routine clinical use.

Reference King AD, Deirawan H, Klein PA, Dasgeb B, Dumur CI, Mehregan DR. Next-generation sequencing in dermatology. Frontiers in Medicine. 2023;10:1218404. https://doi.org/10.3389/fmed.2023.1218404