title: The von Hippel-Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma.
abstract: Deletions of the short arm of chromosome 3 are often observed in a specific subset of aggressive neuroblastomas (NBs) with loss of distal 11q and without MYCN amplification. The critical deleted region encompasses the locus of the von Hippel-Lindau gene (VHL, 3p25). Constitutional loss of function mutations in the VHL gene are responsible for the VHL syndrome, a dominantly inherited familial cancer syndrome predisposing to a variety of neoplasms, including pheochromocytoma. Pheochromocytomas are, like NB, derived from neural crest cells, but, unlike NB, consist of more mature chromaffin cells instead of immature neuroblasts. Further arguments for a putative role of VHL in NB are its function as oxygen sensitizer and the reported relation between hypoxia and dedifferentiation of NB cells, leading to a more aggressive phenotype. To test the possible involvement of VHL in NB, we did mRNA expression analysis and sought evidence for VHL gene inactivation. Although no evidence for a classic tumor suppressor role for VHL in NB could be obtained, a strong correlation was observed between reduced levels of VHL mRNA and low patient survival probability (p=0.013). Furthermore, VHL appears to have predictive power in NTRK1 (TRKA) positive tumor samples with presumed favorable prognosis, which makes it a potentially valuable marker for more accurate risk assessment in this subgroup of patients. The significance of the reduced VHL expression levels in relation to NB tumor biology remains unexplained, as functional analysis demonstrated no clear effect of the reduction in VHL mRNA expression on protein stability of its downstream target hypoxia-inducible factor alpha.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jasmien
authors.initials: J
authors.lastname: Hoebeeck
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Helén
authors.initials: H
authors.lastname: Nilsson
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.forename: Els
authors.initials: E
authors.lastname: De Smet
authors.forename: Nurten
authors.initials: N
authors.lastname: Yigit
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Geneviève
authors.initials: G
authors.lastname: Laureys
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human