Analysis of von hippel-lindau mutations with comparative genomic hybridization in sporadic and hereditary hemangioblastomas: possible genetic heterogeneity.
OBJECTIVE
Hemangioblastomas (HBs) occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. In the majority of VHL-related HBs, inactivation of the VHL tumor suppressor gene (TSG), which is located on chromosome 3p25-26, is found. The VHL gene is assumed to be involved also in the development of sporadic HBs. In a previous study of chromosomal aberrations of sporadic HBs, multiple chromosomal imbalances were found in the majority of tumors. The aim of this study was to analyze further both sporadic HBs and VHL-related HBs to determine if these histopathologically identical tumors have a different genetic background.


METHODS
Sixteen sporadic HBs and seven VHL-related HBs were identified by clinical criteria and analyzed. Comparative genomic hybridization was used to screen for chromosomal imbalances throughout the entire HB genome. Additionally, mutation analysis of the VHL gene was performed using direct sequencing. Loss of chromosome 3 and multiple other chromosomal imbalances were found in the sporadic HBs, although only one imbalance, a loss of chromosome 3, was detected in the seven VHL-related HBs. Somatic VHL gene mutations were found in one third of sporadic HBs, whereas a mutation of the VHL gene was detected in all VHL-related HBs.


CONCLUSIONS
These results indicate that the molecular mechanisms underlying sporadic HBs and VHL-related HBs are different. Inactivation of the VHL gene is probably not the most important event in the tumorigenesis of sporadic HBs. Other mechanisms of inhibition of VHL protein function, or inactivation of other TSGs, on chromosome 3p or on other chromosomes, might be important in the development of sporadic HBs.
Gijtenbeek
Johanna M M
JM
Department of Neurology, University Medical Center Nijmegen, The Netherlands. j.gijtenbeek@czzoneu.azn.nl
Jacobs
Bram
B
Sprenger
Sandra H E
SH
Eleveld
Marc J
MJ
van Kessel
Ad Geurts
AG
Kros
Johan M
JM
Sciot
Raf
R
van Calenbergh
Frank
F
Wesseling
Pieter
P
Jeuken
Judith W M
JW
D000328:Adult; D000368:Aged; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D018740:Genetic Heterogeneity; D018325:Hemangioblastoma / Q000235:genetics*; D006801:Humans; D008025:Ligases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009693:Nucleic Acid Hybridization; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics*
D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human