Journal
ONCOTARGET
Volume 7, Issue 37, Pages 59209-59219Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10962
Keywords
PRAME; preferentially expressed antigen in melanoma; uveal melanoma; DNA methylation; chromosomal instability
Categories
Funding
- National Cancer Institute [R01 CA125970, R01 CA161870, F30 CA206430]
- Research to Prevent Blindness, Inc.
- Melanoma Research Foundation
- Melanoma Research Alliance
- Ocular Melanoma Foundation
- RRF/Kayser Global Pan-American Award
- Sylvester Comprehensive Cancer Center
- University of Miami Sheila and David Fuente Graduate Program in Cancer Biology
- Center for Computational Science Fellowship
- AACR-Ocular Melanoma Foundation
- NIH [P30EY014801]
- Department of Defense [W81XWH-13-1-0048]
- Research to Prevent Blindness Unrestricted Grant
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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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