Neuroblastoma RAS viral oncogene homolog (NRAS) mutations occur in 20–30% of cutaneous melanomas, defining a distinct molecular subtype. While NRAS mutations drive unique gene expression programs, locus-specific transcriptional regulation has not been systematically explored. This study characterized coordinated transcriptional upregulation in NRAS-mutant melanoma, focusing on chromosome 1p13.2. RNA-seq and mutation data for 472 melanoma samples from The Cancer Genome Atlas Skin Cutaneous Melanoma were analyzed. Differential expression, coexpression assessment, and copy number variation (CNV) correlation were performed for 45 protein-coding genes within 1p13.2. Findings were validated in MSK-IMPACT 2021 ( n = 696). In NRAS-mutant melanomas, 56% of 1p13.2 genes were upregulated (false discovery rate < 0.05) versus 12% genome-wide ( P < 0.001), including TRIM33, AMPD1, GNAI3, and SLC25A24. Upregulation was NRAS-specific: 84% showed higher expression versus BRAF-mutant tumors. Six of the 10 most NRAS-correlated genes localized to 1p13.2. CNV gains showed dose-dependent effects (gains: 1.8–3.2 fold; amplifications: 3.5–5.4 fold), with strong correlations (AMPD1 ρ = 0.68, GNAI3 ρ = 0.62, TRIM33 ρ = 0.58; P < 0.001). MSK-IMPACT validation confirmed 1p13.2 upregulation. As these findings are based on transcriptomic and copy number analyses, additional protein-level and functional studies across independent cohorts are required to confirm biological significance. NRAS-mutant melanomas harbor a coordinated transcriptional program within 1p13.2, driven by CNV gains. This locus contains genes with potential druggability, offering new avenues for combinatorial targeting alongside mitogen-activated protein kinase pathway inhibition.
Bilik et al. (Thu,) studied this question.
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