TY - JOUR
T1 - Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas
AU - Field, Matthew G.
AU - Durante, Michael A.
AU - Decatur, Christina L.
AU - Tarlan, Bercin
AU - Oelschlager, Kristen M.
AU - Stone, John F.
AU - Kuznetsov, Jeffim
AU - Bowcock, Anne M.
AU - Kurtenbach, Stefan
AU - Harbour, J. William
N1 - Funding Information:
The authors acknowledge the support of the Oncogenomics Core and the Biostatistics and Bioinformatics Core at the Sylvester Comprehensive Cancer Center, and the Center for Computational Science at the University of Miami for help and support with the data management and analytics. This work was supported by National Cancer Institute grants R01 CA125970 (J.W.H.), R01 CA161870 (J.W.H. and A.M.B.) and F30 CA206430 (M.G.F.), Research to Prevent Blindness, Inc. Senior Scientific Investigator Award (J.W.H.), Melanoma Research Foundation (J.W.H., M.G.F.), Melanoma Research Alliance (J.W.H.), Ocular Melanoma Foundation (J.W.H.), the 2015 RRF/Kayser Global Pan-American Award (J.W.H.), the Sylvester Comprehensive Cancer Center, the University of Miami Sheila and David Fuente Graduate Program in Cancer Biology (M.G.F., M.A.D.), the Center for Computational Science Fellowship (M.G.F.), and the AACR-Ocular Melanoma Foundation Fellowship in honor of Robert C. Allen, MD (S.K.). The Bascom Palmer Eye Institute also received funding from NIH Core Grant P30EY014801, Department of Defense Grant #W81XWH-13-1-0048, and a Research to Prevent Blindness Unrestricted Grant.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Chromosomal instability
KW - DNA methylation
KW - PRAME
KW - Preferentially expressed antigen in melanoma
KW - Uveal melanoma
UR - http://www.scopus.com/inward/record.url?scp=84991289721&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10962
DO - 10.18632/oncotarget.10962
M3 - Article
C2 - 27486988
AN - SCOPUS:84991289721
SN - 1949-2553
VL - 7
SP - 59209
EP - 59219
JO - Oncotarget
JF - Oncotarget
IS - 37
ER -