BAP1 correlates with metastasis in polyploid uveal melanoma

Purpose Most of the Uvea melanoma (UM) display a near-diploid karyotype with only a few chromosomal changes. In contrast to these simple aberrations 10% of the UM samples show a polyploid character (> 58 chromosomes) and were associated with unfavorable prognosis. This study attempts to gain insight in polyploidy in UM and supplement the old data with the current knowledge on mutations in UM specific genes. Methods Fluorescence-In-Situ-Hybridization (FISH) and/or Single-Nucleotide-Polymorphism (SNP) array was used to determine the ploidy status. Tumors showing signs of polyploidy (range tri- tetraploidy) were further investigated. Immune-histochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) or the hotspots for the GNAQ, GNA11, SF3B1 and EIF1AX genes was carried out using Sanger Sequencing . Results Polyploidy was seen in 23 tumor samples. Fourteen of the UM patients developed metastases with a median follow-up of 35 months. Thirteen tumors showed loss of BAP1 expression and all genetically tested polyploid tumors harbored a GNAQ or GNA11 mutation. SF3B1 mutations were found in three UM specimens and one of the tumors harbored an EIF1AX mutation. Univariate analyses showed a significant association with decreased survival for chromosome 1, 3 and 8 aberrations, SF3B1 wild type and a loss of BAP1 expression. In the multivariate analyses, BAP1 expression was the only independent prognostic marker within the polyploid tumors (HR 10.1; p = 0.008). Conclusions Also for the tumors displaying polyploidy loss of BAP1 expression is associated with an increased risk of metastatic disease.