Research Papers:

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

Matthew G. Field, Michael A. Durante, Christina L. Decatur, Bercin Tarlan, Kristen M. Oelschlager, John F. Stone, Jeffim Kuznetsov, Anne M. Bowcock, Stefan Kurtenbach and J. William Harbour _

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Oncotarget. 2016; 7:59209-59219. https://doi.org/10.18632/oncotarget.10962

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Matthew G. Field1, Michael A. Durante1, Christina L. Decatur1, Bercin Tarlan1, Kristen M. Oelschlager2, John F. Stone2, Jeffim Kuznetsov1, Anne M. Bowcock3, Stefan Kurtenbach1, J. William Harbour1

1Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA

2Castle Biosciences, Inc., Friendswood, TX, USA

3National Heart and Lung Institute, Imperial College London, London, UK

Correspondence to:

J. William Harbour, email: [email protected]

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


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.

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