title: PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma.
abstract: OBJECTIVE
  Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1. Nevertheless, a small percentage of Class 1 tumors give rise to metastatic disease. The purpose of this study was to identify biomarkers of metastasis in Class 1 tumors.
  
  
  METHODS
  A total of 389 consecutive patients with UM were assigned to Class 1 or Class 2 using a prospectively validated 12-gene prognostic classifier. Selected tumors were further analyzed using global GEP and single nucleotide polymorphism microarrays. PRAME (preferentially expressed antigen in melanoma) mRNA expression was analyzed in 64 Class 1 tumors by qPCR.
  
  
  RESULTS
  Among Class 1 UMs, the most significant predictor of metastasis was PRAME mRNA expression (P = 0.0006). The 5-year actuarial rate of metastasis was 0% for Class1(PRAME-), 38% for Class1(PRAME+), and 71% for Class 2 tumors. Median metastasis-free survival for Class1(PRAME+) patients was 88 months, compared to 32 months for Class 2 patients. Findings were validated using three independent datasets, including one using disomy 3 to identify low-risk UM. Chromosome copy number changes associated with Class1(PRAME+) tumors included gain of 1q, 6p, 8q, and 9q and loss of 6q and 11q. PRAME expression was associated with larger tumor diameter (P = 0.05) and SF3B1 mutations (P = 0.003).
  
  
  CONCLUSIONS
  PRAME is an independent prognostic biomarker in UM, which identifies increased metastatic risk in patients with Class 1 or disomy 3 tumors. This finding may further enhance the accuracy of prognostic testing and precision medicine for UM.
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
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, Florida.
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, Florida.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kurtenbach
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Gülçin
authors.initials: G
authors.lastname: Gezgin
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Kaleigh N
authors.initials: KN
authors.lastname: Kozak
authors.affiliation: Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida. harbour@miami.edu.
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D044963:Biopsy, Fine-Needle; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics; D000072260:RNA Splicing Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D014604:Uveal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: D000951:Antigens, Neoplasm; C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; C404944:PRAME protein, human; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase