Integrating multiple key molecules in uveal melanoma to uncover metastatic and immune microenvironment-related gene signatures.

AIMTo identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma (UVM) patients.

METHODSTranscriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas (TCGA)-UVM cohort and an external Gene Expression Omnibus (GEO) microarray dataset (GSE73652; 8 non-metastatic vs 5 metastatic cases) were analyzed to identify differentially expressed genes (DEGs). Functional enrichment, protein-protein interaction (PPI) network construction, and survival analyses identified seven metastasis- and prognosis-related genes. Their expression was further examined using public single-cell RNA-seq data (GSE139829; 11 tumors). Experimental validation was performed in UVM cell lines (92.1, OMM1, MEL270) and adult retinal pigment epithelial (ARPE-19) cells using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting to confirm transcriptomic trends. A LASSO Cox model was applied to construct a metastasis-related risk Score signature. Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE. Somatic mutation and copy number variation (CNV) profiles were also examined.

RESULTSSeven key genes (UBE2T, KIF20A, DLGAP5, KLC3, TPX2, UBE2C, AURKA) were significantly associated with overall survival and used to construct a metastasis-related riskScore signature, which effectively stratified patients into high- and low-risk groups and served as an independent prognostic factor. qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells, which were largely consistent with the transcriptomic findings. The high-risk group exhibited reduced immune infiltration and stromal activity. Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential. Mutation and CNV analyses further supported the relevance of these genes to UVM progression.

CONCLUSIONThis study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM. The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations, and may offer guidance for future mechanistic studies and therapeutic exploration.