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Gülçin Gezgin, Inge H.G. Bronkhorst, T Huibertus Van Essen, Sake van Pelt, Robert M. Verdijk, Pieter A. van der Velden, Gregorius P M Luyten, Thorbald van Hall, Sjoerd H van der Burg, Martine J Jager; Loss of BAP1 expression is associated with increased angiogenesis in uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5323.
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© ARVO (1962-2015); The Authors (2016-present)
High risk uveal melanoma (UM) is associated with an inflammatory infiltrate and show an increased amount of vessel growth. UM with monosomy 3 have an increased inflammatory infiltrate in comparison to UM with disomy 3. Although monosomy 3 is associated with loss of BAP1, there are monosomy 3 cases that still have BAP1 expression. We wondered whether loss of BAP1 is associated with higher inflammatory infiltrate and more vessel growth. Therefore, the aim of this study was to analyse the association of BAP1 with inflammatory infiltrate, vessel density and pro-angiogenic factors in uveal melanoma.
Fifty-four eyes with uveal melanoma obtained by enucleation between 2001 and 2007 were included and were analysed for a variety of infiltrating cells, vessel density and pro-angiogenic factors by immunostaining and RNA sequencing with Illumina. These parameters were compared with BAP1 immunohistochemistry staining.
Immunohistochemical staining of BAP1 was negative in 30 tumors, whereas 24 tumors stained BAP1 positive. Negative BAP1 staining showed a significant increase of HCA2, HC10, HLA-DR, CD68, CD163, CD4, FOXP3, CD8 and CD3 compared to BAP1 positive tumors (p=0.003, p=0.000, p=0.035, p=0.000, p=0.000, p=0.003, p=0.000, p=0.003, p=0.002). Also, a significantly increased CD34 staining was observed in tumors with negative BAP1 compared to BAP1 positive tumors (p=0.005), indicating that these tumors contain a higher vessel density. The immunostained BAP1 tumors were also compared with gene expression of infiltrating cells. Again, negative BAP1 tumors showed a significant increased gene expression of CD3, CD4, CD8, HLA-A, HLA-B, CD68 and CD163L1 compared to positive BAP1 tumors (p=0.015, p=0.042, p=0.016, p=0.000, p=0.000, p=0.002 and p=0.001). Gene expression of pro-angiogenic factors, such as HIF1A, PECAM1, CDH1, vWF, PDGFRB, MMP14, MMP25 and MMP9 were significantly increased in BAP1 negative tumors compared to BAP1 positive tumors (p=0.000, p=0.004, p=0.000, p=0.013, p=0.004, p=0.002, p=0.024 and p=0.025). However, some other factors, such as VHL and VEGFB, showed the opposite (p=0.003 and p=0.001).
Loss of BAP1 expression in UM is not only associated with an increased inflammatory infiltrate, but also with an increase in vessel density and pro-angiogenic factors, suggesting that BAP1 associated leukocyte influx may stimulate angiogenesis.
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