Molecular profiling of pancreatic neuroendocrine tumors in sporadic and von Hippel-Lindau patients
Menée sur 34 patients atteints d'une tumeur neuroendocrine du pancréas (18 patients porteurs d'une mutation germinale du gène VHL et 16 patients non porteurs), cette étude identifie un ensemble de gènes dont l'expression est spécifiquement associée à la forme héréditaire de la maladie
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 VHL patients. Experimental Design:The expression of 52 genes was studied by qRT-PCR in 18 VHL patients 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 (TMA) blocks. Results:19 (36%) genes were significantly upregulated and 3 (6%) downregulated in VHL PanNET. The upregulated genes were related to 1/HIF molecules (CA9, HIF2A, GLUT1), 2/angiogenesis (CDH5, VEGFR1, EDNRA, ANGPT2, CD34, VEGFR2, VEGFA, ANGPT1), 3/the processes of epithelial-mesenchymal transition (VIM) and/or metastasis (LAMA4, CXCR4), 4/growth factors and receptors (PDGFB, IRS1,ERBB1) or 5/cell cycle (CCND1, CDKN2A). The downregulated genes were related to 1/epithelial-mesenchymal transition (OCLN) and 2/signaling pathways (RPS6KB1, GADD45B). Conclusions:This study shows that the progression of PanNET in VHL patients tumors follows a specific pathway and supports that targeting molecules specifically involved may be of therapeutic importance.
Clinical Cancer Research , résumé, 2012