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Prognostic parameters in uveal melanoma and their association with BAP1 expression
  1. T Huibertus van Essen1,
  2. Sake I van Pelt1,
  3. Mieke Versluis1,
  4. Inge HG Bronkhorst1,
  5. Sjoerd G van Duinen2,
  6. Marina Marinkovic1,
  7. Wilma GM Kroes3,
  8. Claudia AL Ruivenkamp3,
  9. Shruti Shukla3,
  10. Annelies de Klein4,
  11. Emine Kiliç4,
  12. J William Harbour5,
  13. Gregorius PM Luyten1,
  14. Pieter A van der Velden1,
  15. Rob M Verdijk6,
  16. Martine J Jager1
  1. 1Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
  2. 2Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
  3. 3Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands
  4. 4Department of Human Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  5. 5Ocular Oncology Service, Bascom Palmer Eye Institute, Miami, Florida, USA
  6. 6Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
  1. Correspondence to Dr Martine J Jager, Deptartment of Ophthalmology, LUMC, PO Box 9600, Leiden 2300 RC, the Netherlands; m.j.jager{at}lumc.nl

Abstract

Aim 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.

  • Neoplasia
  • Pathology
  • Diagnostic tests/Investigation
  • Genetics
  • Choroid

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