Illuminating HLA-DPA1 and HSH2D as Potential Prognostic Biomarkers by Weighted Gene Co-Expression Network Analysis for NRAS-Mutant Skin Cutaneous Melanoma

Abstract

Abstract Background NRAS-mutant skin cutaneous melanoma (NRAS-MT SKCM) poses clinical challenges due to its aggressive progression and unfavorable outcomes compared to other subtypes. NRAS mutations, present in around 26% of cases, play a significant role in cutaneous melanoma. However, targeted therapies tailored to NRAS mutations are currently lacking, highlighting an unmet need. Our study aimed to identify hub/key genes specifically associated with NRAS-MT SKCM prognosis. The identification of prognostic biomarkers for survival prediction is essential to enhance patient care and facilitate the development of personalized treatment strategies. Methods We comprehensively analyzed RNA-seq data from The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM) and Genotype-Tissue Expression (GTEx) for NRAS-MT SKCM and normal skin tissues. Our analyses included weighted gene co-expression network analysis (WGCNA), differential gene expression analysis, functional enrichment analysis, construction of a protein-protein interaction (PPI) network, identification of hub genes, survival analysis, and external validation using the microarray dataset GSE65904 from the Gene Expression Omnibus (GEO) database. Results The analysis of differential gene expression revealed 6,577 differentially expressed genes (DEGs) with significant changes in NRAS-mutant SKCM, including 3,823 up-regulated and 2,754 down-regulated genes. WGCNA highlighted a noteworthy blue module consisting of 248 genes strongly correlated with NRAS-mutant SKCM. An intersection analysis identified 211 genes common to both the DEGs and the blue module. Through PPI network analysis and survival analysis, key hub genes within the blue module were identified, including HLA-DPA1, SIGLEC1, HSH2D, and TNFSF8. Survival analysis indicated that lower expression of these genes was associated with poorer overall survival in NRAS-mutant SKCM patients. External validation confirmed the prognostic significance of two survival-related hub genes, namely HLA-DPA1 and HSH2D. Conclusion Our study identified HLA-DPA1 and HSH2D as potential prognostic biomarkers in NRAS-MT SKCM. These findings contribute to a better understanding of the disease's molecular mechanisms and have implications for personalized treatment strategies.