Abstract
BackgroundWe 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.ResultsAmong 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.MATERIALS AND METHODSAnalyses 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.ConclusionsPRAME 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.
Highlights
Uveal melanoma is the most common primary cancer of the eye and the second most common form of melanoma
To evaluate the spectrum of Preferentially Expressed Antigen in Melanoma (PRAME) mRNA expression and to establish a threshold for positive PRAME expression in primary uveal melanoma, we analyzed qPCR data from 678 tumor samples, including 123 of our samples and 555 de-identified samples submitted from a large number of ocular oncology centers to Castle Biosciences
We previously showed that any PRAME expression above baseline was associated with increased metastasis in Class 1 tumors and defined any expression above baseline as positive PRAME expression (PRAME+) [6]
Summary
Uveal melanoma is the most common primary cancer of the eye and the second most common form of melanoma. Due to a high rate of metastasis, much research has focused on the development of biomarkers to predict metastatic risk. We described a gene expression profile that could be performed on a fine needle biopsy of the primary tumor that accurately predicted metastasis [1]. A 15 gene array (12 discriminating genes and 3 control genes) was developed and prospectively validated [2, 3]. This assay www.impactjournals.com/oncotarget is available commercially as the DecisionDx-UMTM test (Castle Biosciences), which has been independently validated [4] and is widely used to stratify patients for metastatic surveillance and to identify high risk patients for adjuvant therapy trials [5]. We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas. 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
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