title: Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma.
abstract: Uveal melanoma is a lethal cancer with a strong propensity to metastasize. Limited therapeutic options are available once the disease has disseminated. A strong predictor for metastasis is the loss of chromosome 3. Inactivating mutations in BAP1 encoding the BRCA1-associated protein 1 and located on chromosome 3p21.1, have been described in uveal melanoma and other types of cancer. In this study, we determined the prevalence of somatic BAP1 mutations and examined whether these mutations correlate with the functional expression of BAP1 in uveal melanoma tissue and with other clinical, histopathological and chromosomal parameters. We screened a cohort of 74 uveal melanomas for BAP1 mutations, using different deep sequencing methods. The frequency of BAP1 mutations in our study group was 47%. The expression of BAP1 protein was studied using immunohistochemistry. BAP1 staining was absent in 43% of the cases. BAP1 mutation status was strongly associated with BAP1 protein expression (P<0.001), loss of chromosome 3 (P<0.001), and other aggressive prognostic factors. Patients with a BAP1 mutation and absent BAP1 expression had an almost eightfold higher chance of developing metastases compared with those without these changes (P=0.002). We found a strong correlation between the immunohistochemical and sequencing data and therefore propose that, immunohistochemical screening for BAP1 should become routine in the histopathological work-up of uveal melanoma. Furthermore, our analysis indicates that loss of BAP1 may be particularly involved in the progression of uveal melanoma to an aggressive, metastatic phenotype.
authors.affiliation: 1] Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Koopmans
authors.affiliation: Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Verdijk
authors.affiliation: Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Rutger W W
authors.initials: RW
authors.lastname: Brouwer
authors.affiliation: Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Thierry P P
authors.initials: TP
authors.lastname: van den Bosch
authors.affiliation: 1] Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mike M P
authors.initials: MM
authors.lastname: van den Berg
authors.affiliation: 1] Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Vaarwater
authors.affiliation: Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Christel E M
authors.initials: CE
authors.lastname: Kockx
authors.affiliation: Department of Ocular Oncology, The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
authors.forename: Dion
authors.initials: D
authors.lastname: Paridaens
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Naus
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.affiliation: Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.identifier: 0000000204218301
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Emine
authors.initials: E
authors.lastname: Kiliç
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase