title: Molecular profiling of pancreatic neuroendocrine tumors in sporadic and Von Hippel-Lindau patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service d'Anatomie Pathologique, Service de Gastroentérologie-Pancréatologie, Service de Chirurgie Hépatique et Pancréatique, AP-HP, Hôpital Beaujon, Clichy, France.
authors.forename: Daniela
authors.initials: D
authors.lastname: Speisky
authors.forename: Aurélie
authors.initials: A
authors.lastname: Duces
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Vinciane
authors.initials: V
authors.lastname: Rebours
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Alain
authors.initials: A
authors.lastname: Sauvanet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Murat
authors.forename: Patricia
authors.initials: P
authors.lastname: Niccoli
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
mesh_terms: D000328:Adult; D000368:Aged; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human