Gene set enrichment analysis of melanoma primary tumor transcriptome to identify pathways associated with lymph node metastasis.

e21572 Background: Lymph node metastasis (LNM) is a critical prognostic indicator in melanoma, guiding clinical decisions regarding staging, treatment, and surveillance. Despite its importance, the molecular mechanisms driving LNM remain poorly understood. Identifying gene sets and pathways associated with LNM could provide valuable insights into the biology of metastasis and highlight potential therapeutic targets. In this study, we performed gene set enrichment analysis (GSEA) on data from The Cancer Genome Atlas (TCGA) melanoma cohort to identify pathways significantly enriched in lymph node-positive melanoma patients compared to lymph node-negative patients. Methods: Primary tumor transcriptome data from the TCGA melanoma dataset were analyzed, including 87 patients, of whom 29 were lymph node positive and 58 were lymph node negative. Gene expression profiles were ranked based on their correlation with lymph node status, and GSEA was conducted using Python 3.7 to evaluate the enrichment of curated gene sets from The Molecular Signatures Database. Pathways were ranked by their normalized enrichment scores (NES), and statistical significance was assessed using false discovery rate (FDR) q-values. Results: The analysis identified several pathways significantly associated with lymph node metastasis (LNM). The Myc Targets pathway showed the highest level of enrichment (NES = 1.61, FDR q-val = 0.001), followed by the DNA Repair pathway (NES = 1.51, FDR q-val = 0.005), the Oxidative Phosphorylation pathway (NES = 1.49, FDR q-val = 0.011), and the Unfolded Protein Response pathway (NES = 1.35, FDR q-val = 0.040), all of which were enriched in cases with lymph node metastasis. Conclusions: These findings reveal key molecular mechanisms driving lymph node metastasis in melanoma, with potential applications for staging and treatment. Enriched pathways like Myc Targets, DNA Repair, and Oxidative Phosphorylation could help stratify metastatic risk and guide the use of advanced imaging or sentinel lymph node biopsies. These signatures may also inform immunotherapy decisions, leading to more personalized staging and treatment strategies that improve melanoma outcomes.