Development of a 3-MicroRNA Signature and Nomogram for Predicting the Survival of Patients with Uveal Melanoma Based on TCGA and GEO Databases

Abstract

Background. The aim of this study was to apply bioinformatic analysis to develop a robust miRNA signature and construct a nomogram model in uveal melanoma (UM) to improve prognosis prediction. Methods. miRNA and mRNA sequencing data for 80 UM patients were obtained from The Cancer Genome Atlas (TCGA) database. The patients were further randomly assigned to a training set (n = 40, used to identify key miRNAs) and a testing set (n = 40, used to internally verify the signature). Then, miRNAs data of GSE84976 and GSE68828 were downloaded from Gene Expression Omnibus (GEO) database for outside verification. Combining univariate analysis and LASSO methods for identifying a robust miRNA biomarker in training set and the signature was validated in testing set and outside dataset. A prognostic nomogram was constructed and combined with decision curve as well as reduction curve analyses to assess the application of clinical usefulness. Finally, we constructed a miRNA-mRNA regulator network in UM and conducted pathway enrichment analysis according to the mRNAs in the network. Results. In total, a 3-miRNA was identified and validated that can robustly predict UM patients’ survival. According to univariate and multivariate cox analyses, age at diagnosis, tumor node metastasis (TNM) classification, stage, and the 3-miRNA signature significantly correlated with the survival outcomes. These characteristics were used to establish nomogram. The nomogram worked well for predicting 1 and 3 years of overall survival time. The decision curve of nomogram revealed a good clinical usefulness of our nomogram. What’s more, a miRNA-mRNA network was constructed. Pathway enrichment showed that this network was largely involved in mRNA processing, the mRNA surveillance pathway, the spliceosome, and so on. Conclusions. We developed a 3-miRNA biomarker and constructed a prognostic nomogram, which may afford a quantitative tool for predicting the survival of UM. Our finding also provided some new potential targets for the treatment of UM.

Genetics and RNA Regulation of Uveal Melanoma

“…Sun et al re-analyzed TCGA expression data and identified a signature including five miRNAs (miR-513a-5p, miR-506-3p, miR-508-3p, miR-140-3p, miR-103a-2-5p) representing an independent prognostic factor able to predict the prognosis of UM patients [216]. Another signature comprising three miRNAs (miR-1296, miR-199a, miR-508) was identified by using TCGA expression data and validated in two GEO datasets (GSE84976 [203] and GSE68828 [224]); the authors suggested the prognostic application of this signature in predicting OS [222].…”

“…Upregulated in high-risk tumors [201] Upregulated in advanced tumors [222] Upregulated in tumors with chromosome 3 monosomy [224] miR-199a-5p…”

“…PTEN [254] miR-372 NA SRC3/NCOA3 [217] miR-378* hsa-miR-378a-5p Downregulated in tumors with chromosome 3 monosomy [221] miR-378d hsa-miR-378d Downregulated in high-risk tumors [202] Upregulated in tumor tissues [228] miR-378g hsa-miR-378g Upregulated in tumor tissues [228] miR-429 hsa-miR-429 Regulation of cell proliferation in vitro SRC3/NCOA3 [217] miR-452 hsa-miR-452-5p Associated with high risk [238] miR-4709 NA Associated with high risk [238] miR-506 hsa-miR-506-3p Downregulated in tumors with chromosome 3 monosomy; upregulated in tumors with chromosome 3 monosomy and metastatic disease [221] Downregulated in metastatic tumors [220] miR-506-3p Downregulated in metastatic tumors [240] High levels associated with better survival outcomes [216] miR-507 hsa-miR-507 Downregulated in tumors with chromosome 3 monosomy [221] Low expression associated with poor prognosis [235] miR-508 hsa-miR-508-3p Downregulated in advanced tumors [222] miR-508-3p Downregulated in tumors with chromosome 3 monosomy; upregulated in tumors with chromosome 3 monosomy and metastatic disease [221] miR-508-3p Downregulated in high-vs. low-grade tumors and deceased vs. alive patients; associated with poor prognosis and worse overall survival [239] Downregulated in metastatic tumors [240] High levels associated with better survival outcomes [216] miR-508-5p hsa-miR-508-5p Downregulated in metastatic tumors [240] miR-509-3-5p hsa-miR-509-3-5p Downregulated in tumors with chromosome 3 monosomy; upregulated in tumors with chromosome 3 monosomy and metastatic disease [221] Downregulated in high-vs. low-grade tumors and deceased vs. alive patients; associated with poor prognosis and worse overall survival [239] Downregulated in metastatic tumors [240] miR-509-3p hsa-miR-509-3p Downregulated in tumors with chromosome 3 monosomy; upregulated in tumors with chromosome 3 monosomy and metastatic disease [221] Downregulated in metastatic tumors [240] Downregulated in metastatic tumors [240] miR-513a-5p hsa-miR-513a-5p High levels associated with better survival outcomes...…”

Recent Advances in Molecular and Genetic Research on Uveal Melanoma

“…For example, nine differentially expressed miRNAs found in MUM exosomes, i.e., downregulated hsa-miR-191-5p and -223-3p and upregulated hsa-miR-203a, 139-3p, -122-5p, -486-5p, -144-5p, -10b-5p and -483-5p, were identified as potential progression indicators [ 121 ]. Three miRNAs, particularly the upregulation of hsa-miR-199a-3p and the downregulation of hsa-miR-1296-3p and -508-3p, were also found in high-risk UM patients [ 136 ].…”