Abstract
ObjectivesUveal melanoma (UM) is the most common primary intraocular malignancy in adults, and immune infiltration plays a crucial role in the prognosis of UM. This study aimed to generate an immunological marker-based predictive signature for the overall survival (OS) of UM patients.MethodsSingle-sample gene-set enrichment analysis (ssGSEA) was used to profile immune cell infiltration in 79 patients with UM from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate least absolute shrinkage and selection operator (LASSO) Cox regressions were used to determine the prognostic factors for UM and construct the predictive immunosignature. Receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were performed to evaluate the clinical ability and accuracy of the model. In addition, the predictive accuracy was compared between the immunosignature and the Tumor, Node, Metastasis (TNM) staging system of American Joint Committee on Cancer (AJCC). We further analyzed the differences in clinical characteristics, immune infiltrates, immune checkpoints, and therapy sensitivity between high- and low-risk groups characterized by the prognostic model.ResultsHigher levels of immune cell infiltration in UM were related to a lower survival rate. Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy. The immunosignature was developed with a concordance index (C-index) of 0.881, which is significantly better than that of the TNM staging system (p < 0.001). We further identified 1,762 genes with upregulated expression and 798 genes with downregulated expression in the high-risk group, and the differences between the high- and low-risk groups were mainly in immune-related processes. In addition, the expression of most of the immune checkpoint-relevant and immune activity-relevant genes was significantly higher in the high-risk group, which was more sensitive to therapy.ConclusionWe developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the OS of UM.
Highlights
Uveal melanoma (UM), arising from melanocytes in the uvea, is the most common primary intraocular malignancy in adults (Li et al, 2020)
Matrix metallopeptidase 12 (MMP12), TCDD inducible poly (ADP-ribose) polymerase (TIPARP), and leucine rich repeat neuronal 3 (LRRN3) were identified as prognostic signatures, and an immunological marker-based prognostic signature was constructed with good clinical ability and accuracy
We developed a novel immunosignature constructed by MMP12, TIPARP, and LRRN3 that could effectively predict the overall survival (OS) of UM
Summary
Uveal melanoma (UM), arising from melanocytes in the uvea, is the most common primary intraocular malignancy in adults (Li et al, 2020). More than 90% of UM cases have choroidal involvement, and the remaining 10% are confined to the ciliary body or the iris (Shields et al, 2012). Genetic mutations in G protein subunit alpha q (GNAQ) and G protein subunit alpha 11 (GNA11) are suspected to be the initiating event in UM (Vader et al, 2017). Despite the advancements in diagnostics and therapies for UM, the prognosis of patients with UM remains unsatisfactory (Kashyap et al, 2016; Rantala et al, 2019). Identifying high-risk patients at the initial diagnosis is of great importance and may guide clinicians in their therapeutic decisions
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