Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas

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// Matthew G. Field 1 , Michael A. Durante 1 , Christina L. Decatur 1 , Bercin Tarlan 1 , Kristen M. Oelschlager 2 , John F. Stone 2 , Jeffim Kuznetsov 1 , Anne M. Bowcock 3 , Stefan Kurtenbach 1 , J. William Harbour 1 1 Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA 2 Castle Biosciences, Inc., Friendswood, TX, USA 3 National Heart and Lung Institute, Imperial College London, London, UK Correspondence to: J. William Harbour, email: harbour@miami.edu Keywords: PRAME, preferentially expressed antigen in melanoma, uveal melanoma, DNA methylation, chromosomal instability Received: June 07, 2016 Accepted: July 13, 2016 Published: July 30, 2016 ABSTRACT Background: 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. Results: 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. Materials and methods: 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. Conclusions: 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.