Uveal melanoma (UM) is a severe human malignancy with a high mortality rate that demands continued research into new and alternative forms of prevention and treatment.,The emerging field of epigenetics is beginning to unfold an era of contemporary approaches to reducing the risk and improving the clinical treatment of UM.,Epigenetic changes have a high prevalence rate in cancer, are reversible in nature, and can lead to cancer characteristics even in mutation-free cells.,The information contained in this review highlights and expands on the main mechanisms of epigenetic dysregulation in UM tumorigenesis, progression and metastasis, including microRNA expression, hypermethylation of genes and histone modification.,Epigenetic drugs have been shown to enhance tumor suppressor gene expression and drug sensitivity in many other cancer cell lines and animal models.,An increased understanding of epigenetic mechanisms in UM will be invaluable in the design of more potent epigenetic drugs, which when used in combination with traditional therapies, may permit improved therapeutic outcomes.
We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas.,In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter.,Among 678 samples analyzed by qPCR, 498 (73.5%) were PRAME- and 180 (26.5%) were PRAME+.,Class 1 tumors were more likely to be PRAME-, whereas Class 2 tumors were more likely to be PRAME+ (P < 0.0001).,PRAME expression was associated with shorter time to metastasis and melanoma specific mortality in Class 2 tumors (P = 0.01 and P = 0.02, respectively).,In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004).,PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter.,Analyses included PRAME mRNA expression, Class 1 versus Class 2 status, chromosomal copy number, mutation status of BAP1, EIF1AX, GNA11, GNAQ and SF3B1, and genomic DNA methylation status.,Analyses were performed on 555 de-identified samples from Castle Biosciences, 123 samples from our center, and 80 samples from the TCGA.,PRAME is aberrantly hypomethylated and activated in Class 1 and Class 2 uveal melanomas and is associated with increased metastatic risk in both classes.,Since PRAME has been successfully targeted for immunotherapy, it may prove to be a companion prognostic biomarker.