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.