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Hua Yang, Zezhong Li, Qing Zhang, Caroline M Craven, Scott E Woodman, Tara A McCannel, Hans E Grossniklaus; Loss of BAP1 results in high metastatic rate in a mouse ocular melanoma model. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4105.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the relationship between mutated BAP1 gene expression in human uveal melanoma and metastasis in a xenograft mouse model.
Human primary uveal melanoma 92.1 (wild type) or M20-09-196 (which contains a large inframe deletion in the enzymatic domain of the BAP1 gene) cells (1X106) were inoculated into the choroid of right eyes in immunodeficient Foxn1nu mice. Tumor-bearing eyes were enucleated at 2 weeks, and livers were collected at 2 weeks and 10 weeks after inoculation, and then processed for histologic examination. The size of the intraocular melanoma, number , pattern and stage of hepatic metastases were determined by light microscopy and image analysis (Image J). The melanomas and loss of BAP1 expression were confirmed by IHC staining for BAP1 and HMB45 and PAS staining was used to determine vascular density.
The melanomas grew in all eyes and there was no statistically significant difference in their size. IHC showed loss of BAP1 expression in the nuclei of Mel20-01-196 cells. PAS displayed no difference in vascular density in the ocular tumors. At 2 weeks, 100% of mice in both groups developed hepatic metastases, but there was a higher number of metastasis in the BAP1 mutation group (39.83±14.24) than in the wild type group (17.83±6.52, P=0.003). Likewise, at 10 weeks, there were more metastasis in the BAP1 mutation group (34.33±11.30) than the wild type group (16.83±10.94, P=0.01). There was no difference in metatastic stage between the two groups (P=0.13), although there was a higher percentage of periportal than sinusoidal tumors in the BAP1 mutant group (92.96% vs control 60.41%, P=0.019).
Loss of BAP1 caused by BAP1 mutations results in a higher rate but not higher stage of metastasis in a mouse ocular melanoma model, indicating that the BAP1 mutation increases the number of melanoma cells extravasated from the ocular tumor.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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