Abstract
Uveal melanoma (UM) is a subtype of melanoma with poor prognosis. This study aimed to construct a new prognostic gene signature that can be used for survival prediction and risk stratification of UM patients. In this work, transcriptome data from the Molecular Signatures Database were used to identify the cancer hallmarks most relevant to the prognosis of UM patients. Weighted gene co-expression network, univariate least absolute contraction and selection operator (LASSO), and multivariate Cox regression analyses were used to construct the prognostic gene characteristics. Kaplan–Meier and receiver operating characteristic (ROC) curves were used to evaluate the survival predictive ability of the gene signature. The results showed that glycolysis and immune response were the main risk factors for overall survival (OS) in UM patients. Using univariate Cox regression analysis, 238 candidates related to the prognosis of UM patients were identified (p < 0.05). Using LASSO and multivariate Cox regression analyses, a six-gene signature including ARPC1B, BTBD6, GUSB, KRTCAP2, RHBDD3, and SLC39A4 was constructed. Kaplan–Meier analysis of the UM cohort in the training set showed that patients with higher risk scores had worse OS (HR = 2.61, p < 0.001). The time-dependent ROC (t-ROC) curve showed that the risk score had good predictive efficiency for UM patients in the training set (AUC > 0.9). Besides, t-ROC analysis showed that the predictive ability of risk scores was significantly higher than that of other clinicopathological characteristics. Univariate and multivariate Cox regression analyses showed that risk score was an independent risk factor for OS in UM patients. The prognostic value of risk scores was further verified in two external UM cohorts (GSE22138 and GSE84976). Two-factor survival analysis showed that UM patients with high hypoxia or immune response scores and high risk scores had the worst prognosis. Moreover, a nomogram based on the six-gene signature was established for clinical practice. In addition, risk scores were related to the immune infiltration profiles. Taken together, this study identified a new prognostic six-gene signature related to glycolysis and immune response. This six-gene signature can not only be used for survival prediction and risk stratification but also may be a potential therapeutic target for UM patients.
Highlights
Uveal melanoma (UM) is a rare and aggressive intraocular malignant tumor, and about 50% of patients are prone to liver metastases
Using the transcriptome profiling data and hallmark gene sets from the Molecular Signatures Database (MSigDB) and the single-sample gene set enrichment analysis (R package “gsva”), the performance of the cancer hallmarks in the training set was quantified for univariate Cox proportional hazards (Cox-PH) regression analysis to evaluate the significance of various cancer hallmarks in UM (R package “survival”) [19, 20]
Glycolysis and immune response are identified as the primary cancer hallmarks for survival in UM
Summary
Uveal melanoma (UM) is a rare and aggressive intraocular malignant tumor, and about 50% of patients are prone to liver metastases. The prognosis of metastatic UM is poor, and there is a lack of effective treatments. The clinicopathological characteristics (such as the diameter of the basal tumor, ciliary body involvement, and scleral expansion), non-random chromosomal aberrations, gene mutations (such as BAP1 and SF3B1 mutations) are considered to be related to the prognosis of patients with UM [3,4,5]. Early surgical treatment of UM liver metastases may help improve the progression-free survival (PFS) and overall survival (OS) in UM patients with liver metastases [7,8,9,10,11]. Early diagnosis and surgical treatment are essential to improve the prognosis of patients with UM [12, 13]
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