Serum markers of angiogenesis in patients with von Hippel-Lindau Disease

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1033 Background: Von Hippel-Lindau disease is an autosomal dominant genetic cancer predisposition syndrome characterized by hemangioblastomas of the retina and cerebellum, renal cell carcinoma, and other tumors. The disease results from a mutation in the 3p25–26 region and this gene conforms to Knudson's two-hit hypothesis of carcinogenesis. The protein product of the VHL gene participates in ubiquitin-mediated proteolysis of hypoxia inducible factors 1 and 2, which upregulate the expression of a variety of proteins. Mutations in the VHL gene lead to decreased proteolysis of HIF, in turn leading to upregulation of downstream products, including VEGF. The tumors associated with this syndrome are often not detected until the second decade of life or later; by this time, damage to organs has already occurred and the only treatment available is surgical. The development of pre-clinical serum markers would be of important clinical utility in detecting at-risk individuals. Methods: This study examines the use of the angiogenic factor VEGF and its soluble receptor sVEGFR1 as serum markers in Von Hippel-Lindau disease in patients with mutations of the VHL gene with varying levels of active disease, compared with the same number of mutation negative family controls. Results: In our preliminary analysis, data has been collected from a total of 27 subjects. 18 (66.7%) of them are affected with VHL, 9 (33.3%) non-affected. The mean concentration of VEGF is 213.7 (SD 148.1) pg/ml in VHL affected subjects, and 88.3 (SD 87.4) pg/ml in non-affected subjects. The difference in VEGF levels in mutation positive and mutation negative individuals was highly significant (p=0.008) A trend was observed towards increasing VEGF levels and number of disease sites involved. Levels of sVEGFR1 did not differ between the two groups. Conclusion: The results suggest preliminarily that subjects affected with VHL disease have significantly higher concentrations of VEGF, as compared to those non-affected with VHL disease (Mean of 213.7 +/− 148.1 vs. 88.3 +/− 87.4; p = 0.008). No significant financial relationships to disclose.

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