• Genetic predictors of adverse events with cutaneous melanoma systemic therapy
  • Majid Mesgar Tehrani,1,* ladan kharaz,2 mohammad mehdi eslami,3 Reza Mirlohi,4
    1. Member of the Core Committee of the National Genomics Hub, Shahid Beheshti University of Medical Sciences, Tehran, Iran
    2. Shahid Beheshti University of Medical Sciences
    3. Member of the Bioinformatics Research Group, Nasim Research Institute, Tehran, Iran
    4. Member of the Bioinformatics Research Group, Nasim Research Institute, Tehran, Iran


  • Introduction: Cutaneous melanoma is a malignant tumor of melanocytes and represents the most aggressive form of skin cancer. It accounts for the majority of skin cancer–related deaths, with approximately 325,000 new cases and 57,000 deaths reported worldwide in 2020, a number expected to rise by 2040. The disease is multifactorial, with ultraviolet (UV) radiation being the most significant risk factor, contributing to over 75% of new cases. Other risk factors include sunburn, family history, and phenotypic features. In Iran, the incidence of melanoma is increasing, particularly among young individuals, with significant impact on quality of life. The mainstay of treatment for resectable melanoma is wide local excision, while systemic therapy plays a central role in advanced stages. In recent years, targeted therapies and immunotherapies have dramatically improved survival outcomes. About half of metastatic melanomas harbor BRAF mutations, most commonly BRAF V600E, making them responsive to BRAF and MEK inhibitors. These combinations initially achieve high response rates, but resistance often develops. Immunotherapies, particularly immune checkpoint inhibitors (anti-CTLA4, anti-PD-1/PD-L1, and anti-LAG3), have shown durable responses, though up to 60% of patients eventually experience resistance or relapse. Combination strategies are being explored to overcome these limitations. Despite advances, systemic treatments are associated with adverse events (AEs), ranging from mild to severe, which may limit treatment continuation and affect outcomes. Predicting and managing these toxicities remain major challenges. As melanoma is a heterogeneous disease, genetic alterations not only shape therapeutic responses but may also influence susceptibility to AEs. Next-generation sequencing (NGS) has advanced understanding of melanoma genomics, identifying major subtypes (mutant BRAF, RAS, NF1, and Triple-WT). However, the relationship between genetic alterations and treatment-related toxicities remains underexplored. This study aims to investigate genetic predictors of AEs in cutaneous melanoma patients receiving systemic therapy, with the goal of enabling more personalized and safer treatment strategies
  • Methods: Cutaneous melanoma-associated single nucleotide polymorphisms (SNPs) with high citation frequency were identified from the NCBI database, and those directly involved in melanoma development were selected along with their related diseases. The curated dataset was imported into Megagene software to analyze the relationship between genetic polymorphism profiles and systemic treatment-related adverse events in patients with cutaneous melanoma.
  • Results: Three common SNPs associated with melanoma were identified, including RS121434595, RS121913237, and RS1126809. Among these, RS121434595 was associated with hair loss, RS1126809 with muscular pain, and RS121913237 with itching
  • Conclusion: Based on this study, genetic testing to identify common SNPs, including those in NRAS and TYR, is recommended prior to initiating systemic therapy in melanoma patients, as it may guide the selection of treatments with a lower risk of adverse events and support more personalized therapeutic strategies.
  • Keywords: Cutaneous melanoma, Single nucleotide polymorphisms, Genetic testing, Adverse events