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Helen Kalirai, Andrew Dodson, Sohaib Faqir, Bertil E. Damato, Sarah E. Coupland; BAP1 Protein Expression In UM; High Throughput Analysis Using Tissue Microarrays Of Primary Uveal Melanoma And Liver Metastases. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5251.
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Uveal melanoma (UM) with monosomy 3 (M3) have a high risk of metastasis, possibly due to the presence of mutations on the remaining copy of chromosome 3 that contribute to tumor progression and spread. One such inactivating mutation of BRCA1 associated protein 1 (BAP1; chromosome 3p21.1) occurs in 84% of UM with a class 2 gene expression profile, which is associated with poor prognosis. BAP1 is a de-ubiquitylating enzyme involved in the assembly of transcription factor complexes regulating cell proliferation and migration. In this study we correlated BAP1 protein expression in tissue microarrays of primary and metastatic UM (PUM-TMA1 & MUM-TMA2 respectively) with histological and clinical data and with survival.
BAP1 protein expression was assessed by immunohistochemistry using a mouse anti-human BAP1 antibody (SantaCruz sc28383). TMA1 contained triplicate cores from 70 PUM of consenting patients treated by enucleation or local resection between 1996-2009. The patients (41 F, 24 M) had a mean age of 62 years (range 31-89). Tumors had a mean largest basal diameter of 16.4mm (range 4-21.5) with: M3 in 45; closed-loops in 40; epithelioid cells in 47; averaging 7.9 mitoses per 40-HPFs (range 1-23). TMA2 contained duplicate or triplicate cores from 19 MUM matched with a proportion of cases on TMA1. The percentage of tumor cell nuclei staining positively was scored blind by three independent assessors. Correlations were measured with the Spearman’s and Pearson’s tests, using SPSS.
In assessable specimens on TMA1 and TMA2, BAP1 protein was either completely absent or present in >75% tumour cell nuclei. In TMA1, absence of BAP1 protein correlated significantly with: ciliary body involvement (p=0.009); presence of closed loops (p=0.013); epithelioid cells (p=0.054); and M3 (p=0.013). Despite the latter correlation, BAP1 protein was absent in 30% of disomy 3 tumors and present in 35% of M3 tumors. BAP1 protein was absent in 11/13 MUM lesions on TMA2. Expression was 100% concordant in 13 paired primary and metastatic tumors from the same patients. Patients were more likely to die from metastatic melanoma if BAP1 protein was absent (p=0.012).
We confirm that absence of the tumour suppressor BAP1 correlates with metastasis of UM; however, metastasis can occur despite BAP1 expression.
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