title: Uveal Melanomas with SF3B1 Mutations: A Distinct Subclass Associated with Late-Onset Metastases.
abstract: To investigate the prevalence and prognostic value of SF3B1 and EIF1AX mutations in uveal melanoma (UM) patients.
  
  
  
  Case series.
  
  
  
  Cohort of 151 patients diagnosed with and treated for UM.
  
  
  
  SF3B1 and EIF1AX mutations in primary tumors were investigated using whole-exome sequencing (n = 25) and Sanger sequencing (n = 151). For the detection of BAP1 mutations, a previously reported cohort of 90 patients was extended using BAP1 sequencing or immunohistochemistry.
  
  
  
  The status of SF3B1, EIF1AX, and BAP1 in tumors of patients were correlated to clinical, histopathologic, and genetic parameters. Survival analyses were performed for patients whose tumors had SF3B1, EIF1AX, and BAP1 mutations.
  
  
  
  Patients with tumors harboring EIF1AX mutations rarely demonstrated metastases (2 of 28 patients) and overall had a longer disease-free survival (DFS; 190.1 vs. 100.2 months; P < 0.001). Within the patient group with disomy 3, UM patients with an SF3B1 mutation had an increased metastatic risk compared with those without an SF3B1 mutation (DFS, 132.8 vs. 174.4 months; P = 0.008). Patients with such a mutation were more prone to demonstrate late metastases (median, 8.2 years; range, 23-145 months). Patients with UM and loss of BAP1 expression had a significantly decreased survival (DFS, 69.0 vs. 147.9 months; P < 0.001).
  
  
  
  According to our data, patients with UM can be classified into 3 groups, of which EIF1AX-mutated tumors and tumors without BAP1, SF3B1, or EIF1AX mutations are associated with prolonged survival and low metastatic risk, SF3B1-mutated tumors are associated with late metastasis, and tumors with an aberrant BAP1 are associated with an early metastatic risk and rapid decline in patient DFS.
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Serdar
authors.initials: S
authors.lastname: Yavuzyigitoglu
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Koopmans
authors.affiliation: Department of Pathology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Verdijk
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Vaarwater
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Eussen
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Alice
authors.initials: A
authors.lastname: van Bodegom
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors.forename: Dion
authors.initials: D
authors.lastname: Paridaens
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Emine
authors.initials: E
authors.lastname: Kiliç
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands. Electronic address: a.deklein@erasmusmc.nl.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008545:Melanoma / Q000145:classification* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors / Q000235:genetics*; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D014604:Uveal Neoplasms / Q000145:classification* / Q000235:genetics*; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D015977:Eukaryotic Initiation Factor-1; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; D025521:Tumor Suppressor Proteins; C026022:eukaryotic peptide initiation factor-1A; D043222:Ubiquitin Thiolesterase