Abstract
Uveal melanoma (UVM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic disease and have a poor prognosis. The need for immunotherapies has rapidly emerged, and recent research has yielded impressive results. Emerging evidence has implicated ferroptosis as a novel type of cell death that may mediate tumor-infiltrating immune cells to influence anticancer immunity. In this study, we first selected 11 ferroptosis regulators in UVM samples from the training set (TCGA and GSE84976 databases) by Cox analysis. We then divided these molecules into modules A and B based on the STRING database and used consensus clustering analysis to classify genes in both modules. According to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the results revealed that the clusters in module A were remarkably related to immune-related pathways. Next, we applied the ESTIMATE and CIBERSORT algorithms and found that these ferroptosis-related patterns may affect a proportion of TME infiltrating cells, thereby mediating the tumor immune environment. Additionally, to further develop the prognostic signatures based on the immune landscape, we established a six-gene-regulator prognostic model in the training set and successfully verified it in the validation set (GSE44295 and GSE27831). Subsequently, we identified the key molecules, including ABCC1, CHAC1, and GSS, which were associated with poor overall survival, progression-free survival, disease-specific survival, and progression-free interval. We constructed a competing endogenous RNA network to further elucidate the mechanisms, which consisted of 29 lncRNAs, 12 miRNAs, and 25 ferroptosis-related mRNAs. Our findings indicate that the ferroptosis-related genes may be suitable potential biomarkers to provide novel insights into UVM prognosis and decipher the underlying mechanisms in tumor microenvironment characterization.
Highlights
Uveal melanoma (UVM), which represents 85% of ocular melanomas, is the most common primary intraocular malignancy in adults and arises from melanocytes of the iris (3–5%), ciliary body (5–8%), or choroid (∼85%) (Chang et al, 1998; McLaughlin et al, 2005)
To further verify the biologically plausible hypothesis, UVM cells can communicate with immune cells through a set of ferroptosis-related signals; when clustering by using a consensus clustering analysis according to the expression of genes, the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses were implemented to evaluate the function of clusters in two modules; the results revealed that the function of module A was enriched in the primary immunodeficiency, Th1, Th2, and Th17 cell differentiation, which is remarkably related to the immune landscape
This study is the first to comprehensively explore the role of ferroptosis-related genes in UVM and extensively profile the immune landscape based on ferroptosis pathways
Summary
Uveal melanoma (UVM), which represents 85% of ocular melanomas, is the most common primary intraocular malignancy in adults and arises from melanocytes of the iris (3–5%), ciliary body (5–8%), or choroid (∼85%) (Chang et al, 1998; McLaughlin et al, 2005). The management of surgical options mainly depends on tumor location, extent, and size, adverse effects, and systemic status, including partial iridectomy, iridotrabeculectomy of the iris, and iridocyclectomy (Henderson and Margo, 2008). Approximately 50% of patients develop metastatic disease, predominantly in the liver, which is refractory to traditional treatments such as chemotherapy and surgical metastasectomy (Achberger et al, 2014). Due to the lack of standard therapies to significantly improve survival, newer fields of targeted treatments and immunotherapies have rapidly emerged and yielded impressive results by targeting specific regulators or immune system checkpoints (Chang et al, 1998; de Vries et al, 1998; Chen et al, 2017). Unraveling genomic properties is crucial for the development of effective treatments and prediction of individual survival
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
