PURPOSE: Von Hippel-Lindau (VHL) disease is an inherited syndrome caused by 
germline mutations in the VHL tumor suppressor gene, predisposing to a variety 
of neoplasms including pancreatic neuroendocrine tumors (PanNET). In VHL 
disease, PanNET probably progress according to a specific pathway of 
carcinogenesis. Our aim was to characterize by molecular quantitative analysis a 
panel of molecules implicated in the VHL pathway and in tumor progression in the 
PanNET of patients with VHL.
EXPERIMENTAL DESIGN: The expression of 52 genes was studied by quantitative 
reverse transcriptase PCR in 18 patients with VHL operated on for PanNET and 
compared with 16 non-VHL PanNET. The VHL and non-VHL tumors were matched 
according to their size and cell proliferation. For some genes, we looked for 
differences in the protein expression in VHL PanNET (n = 31), microadenomas (n = 
22), and non-VHL PanNET (n = 16), included in tissue microarray blocks.
RESULTS: Nineteen (36%) genes were significantly upregulated and three (6%) 
downregulated in VHL PanNET. The upregulated genes were related to (i) 
hypoxia-inducible factor (HIF) molecules (CA9, HIF2A, and GLUT1), (ii) 
angiogenesis (CDH5, VEGFR1, EDNRA, ANGPT2, CD34, VEGFR2, VEGFA, and ANGPT1), 
(iii) the processes of epithelial-mesenchymal transition (VIM) and/or metastasis 
(LAMA4 and CXCR4), (iv) growth factors and receptors (PDGFB, IRS1, and ERBB1), 
or (v) cell cycle (CCND1 and CDKN2A). The downregulated genes were related to 
(i) EMT (OCLN) and (ii) signaling pathways (RPS6KB1 and GADD45B).
CONCLUSION: This study shows that the progression of PanNET in patients with VHL 
tumors follows a specific pathway and supports that targeting molecules 
specifically involved may be of therapeutic importance.