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Serum markers of angiogenesis in patients with von Hippel-Lindau Disease
J. Spaulding, R. Brekken, L. Robinson, K. Koeneman, B. Mickey, J. Cadeddu, C.
Croft, A. Sagalowsky, N. Ahmad, G. E. Tomlinson
University of Texas Southwestern Medical Center, Dallas, TX;
Children's Medical Center of Dallas, Dallas, TX
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).
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-001730,00.asp
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