Von Hippel-Lindau gene deletion and expression of hypoxia-inducible factor and ubiquitin in optic nerve hemangioma.

PURPOSE Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome expressed in multiple organs caused by germline alterations of the VHL gene. We have shown VHL deletion in the "stromal" cells of retinal angiomas. The VHL protein-associated complex is a primary ubiquitin ligase for the ubiquitination of hypoxia-inducible factor (HIF). This study examines VHL and ubiquitin expression in optic nerve hemangiomas and juxtapapillary angiomas. METHODS Using microdissection and polymerase chain reaction, four optic nerve hemangiomas (one also had juxtapapillary angioma) associated with VHL disease were analyzed for loss of heterozygosity in the VHL gene. In addition, expression of HIF and ubiquitin was evaluated in these tumors by immunohistochemistry. RESULTS All informative optic nerve and juxtapapillary lesions showed loss of heterozygosity in the VHL gene detected in vacuolated "stromal" cells. Both HIF and ubiquitin were highly expressed in the hemangiomas of all four VHL cases. CONCLUSIONS Like retinal angiomas and other VHL tumor lesions, VHL gene deletion is found in optic nerve hemangiomas and juxtapapillary angiomas. These tumor cells also express HIF and ubiquitin, the protein responsible for the negative regulation of HIF that results in the hypervascularization characteristic of VHL disease.