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Clin Cancer Res. 2012 May 15;18(10):2838-49. doi: 10.1158/1078-0432.CCR-11-2759. Epub 2012 Mar 29.

Molecular profiling of pancreatic neuroendocrine tumors in sporadic and Von Hippel-Lindau patients.

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  • 1Service d'Anatomie Pathologique, Service de Gastroentérologie-Pancréatologie, Service de Chirurgie Hépatique et Pancréatique, AP-HP, Hôpital Beaujon, Clichy, France.

Abstract

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.

©2012 AACR.

PMID:
22461457
[PubMed - indexed for MEDLINE]
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