title: Comparing the Prognostic Value of BAP1 Mutation Pattern, Chromosome 3 Status, and BAP1 Immunohistochemistry in Uveal Melanoma.
abstract: Uveal melanoma (UM), a tumor of the eye, can be divided into 2 major classes correlating with patients' prognosis. Gene expression profiles and chromosome 3 status are correlated with tumor classification and prognosis. Somatic BAP1 mutations are another feature largely restricted to metastatic UM. Here we performed thorough BAP1 mutation analysis including sequencing and gene dosage analysis of all BAP1 coding exons as well as methylation analysis of the promoter CpG island in a set of 66 UMs. The results were compared with the BAP1 protein expression as determined by immunohistochemistry and the tumor-related survival of the patients. BAP1 sequencing and gene dosage analysis of BAP1 exons by multiplex ligation-dependent probe amplification revealed a mutation in 33 (89%) of 37 tumors with monosomy 3 (M3) or isodisomy 3. BAP1 mutations were not detected in any of the 28 tumors with disomy 3 or partial monosomy 3 (partM3). Most of the sequence mutations (21 of 28) were frame-shift, splice-site, or nonsense mutations leading to a premature termination codon. BAP1 protein as determined by immunohistochemistry was absent in all samples with a BAP1 mutation irrespective of the functional type of mutation. Kaplan-Meier analysis revealed a highly significant association between BAP1 protein staining and patients' survival (P=0.0004). The association between BAP1 mutation status and tumor-related survival was less pronounced but still significant (P=0.0023). We conclude that BAP1 protein staining is favorable over BAP1 mutation screening by Sanger sequencing for prognostic testing of UM patients.
authors.affiliation: *Institute of Neuropathology †Institute of Human Genetics §Department of Opthalmology ∥Institute of Pathology ‡Center for Medical Biotechnology, Microbiology II, University Duisburg-Essen, Essen, Germany.
authors.forename: Johannes A P
authors.initials: JA
authors.lastname: van de Nes
authors.forename: Jasmin
authors.initials: J
authors.lastname: Nelles
authors.forename: Stefan
authors.initials: S
authors.lastname: Kreis
authors.forename: Claudia H D
authors.initials: CH
authors.lastname: Metz
authors.forename: Thomas
authors.initials: T
authors.lastname: Hager
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
authors.forename: Michael
authors.initials: M
authors.lastname: Zeschnigk
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics* / Q000401:mortality; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase