title: Prognostic parameters in uveal melanoma and their association with BAP1 expression.
abstract: OBJECTIVE
  To determine whether BAP1 gene and protein expression associates with different prognostic parameters in uveal melanoma and whether BAP1 expression correctly identifies patients as being at risk for metastases, following enucleation of the primary tumour.
  
  
  METHODS
  Thirty cases of uveal melanoma obtained by enucleation between 1999 and 2004 were analysed for a variety of prognostic markers, including histological characteristics, chromosome aberrations obtained by fluorescence in situ hybridisation (FISH) and single nucleotide polymorphism (SNP) analysis and gene expression profiling. These parameters were compared with BAP1 gene expression and BAP1 immunostaining.
  
  
  RESULTS
  The presence of monosomy of chromosome 3 as identified by the different chromosome 3 tests showed significantly increased HRs (FISH on isolated nuclei cut-off 30%: HR 11.6, p=0.002; SNP analysis: HR 20.3, p=0.004) for death due to metastasis. The gene expression profile class 2, based on the 15-gene expression profile, similarly provided a significantly increased HR for a poor outcome (HR 8.5, p=0.005). Lower BAP1 gene expression and negative BAP1 immunostaining (50% of 28 tumours were immunonegative) were both associated with these markers for prognostication: FISH cut-off 30% monosomy 3 (BAP1 gene expression: p=0.037; BAP1 immunostaining: p=0.001), SNP-monosomy 3 (BAP1 gene expression: p=0.008; BAP1 immunostaining: p=0.002) and class 2 profile (BAP1 gene expression: p<0.001; BAP1 immunostaining: p=0.001) and were themselves associated with an increased risk of death due to metastasis (BAP1 gene expression dichotomised: HR 8.7, p=0.006; BAP1 immunostaining: HR 4.0, p=0.010).
  
  
  CONCLUSIONS
  Loss of BAP1 expression associated well with all of the methods currently used for prognostication and was itself predictive of death due to metastasis in uveal melanoma after enucleation, thereby emphasising the importance of further research on the role of BAP1 in uveal melanoma.
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: T Huibertus
authors.initials: TH
authors.lastname: van Essen
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Sake I
authors.initials: SI
authors.lastname: van Pelt
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Inge H G
authors.initials: IH
authors.lastname: Bronkhorst
authors.affiliation: Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: van Duinen
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: Marinkovic
authors.affiliation: Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Wilma G M
authors.initials: WG
authors.lastname: Kroes
authors.affiliation: Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.affiliation: Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Shruti
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Human Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.affiliation: Department of Human Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Emine
authors.initials: E
authors.lastname: Kiliç
authors.affiliation: Ocular Oncology Service, Bascom Palmer Eye Institute, Miami, Florida, USA.
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Gregorius P M
authors.initials: GP
authors.lastname: Luyten
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Rob M
authors.initials: RM
authors.lastname: Verdijk
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D015353:Eye Enucleation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009006:Monosomy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: Choroid; Diagnostic tests/Investigation; Genetics; Neoplasia; Pathology