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, J. William Harbour

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)59209-59219
Number of pages11
JournalOncotarget
Volume7
Issue number37
DOIs
StatePublished - 2016

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Epigenomics
Mutation
Neoplasms
Biomarkers
DNA Methylation
Immunotherapy
Melanoma
Neoplasm Metastasis
Messenger RNA
Mortality
Uveal melanoma

Keywords

  • Chromosomal instability
  • DNA methylation
  • PRAME
  • Preferentially expressed antigen in melanoma
  • Uveal melanoma

ASJC Scopus subject areas

  • Oncology

Cite this

Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas. / Field, Matthew G.; Durante, Michael A.; Decatur, Christina L.; Tarlan, Bercin; Oelschlager, Kristen M.; Stone, John F.; Kuznetsov, Jeffim; Bowcock, Anne M.; Kurtenbach, Stefan; William Harbour, J.

In: Oncotarget, Vol. 7, No. 37, 2016, p. 59209-59219.

Research output: Contribution to journalArticle

Field, MG, Durante, MA, Decatur, CL, Tarlan, B, Oelschlager, KM, Stone, JF, Kuznetsov, J, Bowcock, AM, Kurtenbach, S & William Harbour, J 2016, 'Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas', Oncotarget, vol. 7, no. 37, pp. 59209-59219. https://doi.org/10.18632/oncotarget.10962
Field, Matthew G. ; Durante, Michael A. ; Decatur, Christina L. ; Tarlan, Bercin ; Oelschlager, Kristen M. ; Stone, John F. ; Kuznetsov, Jeffim ; Bowcock, Anne M. ; Kurtenbach, Stefan ; William Harbour, J. / Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas. In: Oncotarget. 2016 ; Vol. 7, No. 37. pp. 59209-59219.
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title = "Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas",
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.",
keywords = "Chromosomal instability, DNA methylation, PRAME, Preferentially expressed antigen in melanoma, Uveal melanoma",
author = "Field, {Matthew G.} and Durante, {Michael A.} and Decatur, {Christina L.} and Bercin Tarlan and Oelschlager, {Kristen M.} and Stone, {John F.} and Jeffim Kuznetsov and Bowcock, {Anne M.} and Stefan Kurtenbach and {William Harbour}, J.",
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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 - William Harbour, J.

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

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