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.
  
  
  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.
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Field
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Durante
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Decatur
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Bercin
authors.initials: B
authors.lastname: Tarlan
authors.affiliation: Castle Biosciences, Inc., Friendswood, TX, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Oelschlager
authors.affiliation: Castle Biosciences, Inc., Friendswood, TX, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Stone
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Jeffim
authors.initials: J
authors.lastname: Kuznetsov
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kurtenbach
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D002465:Cell Movement; D065150:Cellular Reprogramming; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D009362:Neoplasm Metastasis; D011379:Prognosis; D012306:Risk; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000098943:Uveal Melanoma
chemical_list: D000951:Antigens, Neoplasm; C404944:PRAME protein, human
keywords: DNA methylation; PRAME; chromosomal instability; preferentially expressed antigen in melanoma; uveal melanoma