title: Differences in genetic and epigenetic alterations between von Hippel-Lindau disease-related and sporadic hemangioblastomas of the central nervous system.
abstract: Although inactivation of the von Hippel-Lindau gene (VHL), located on chromosome 3p25, is considered to be a major cause of hemangioblastomas (HBs), the incidence of biallelic inactivation of VHL is reportedly low. The aim of this study was to determine the prevalence of VHL alterations in HBs, as well as to identify additional molecular aberrations.
  
  
  
  Genetic and epigenetic alterations were comprehensively and comparatively analyzed in 11 VHL-related and 21 sporadic HBs.
  
  
  
  VHL alterations detected by sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis were more frequent in VHL-related HBs than in sporadic HBs (100% vs 62%; P = 0.029). VHL alterations were found only in 4 sporadic HBs by direct sequencing; however, targeted deep sequencing detected 9 additional alterations. Loss of heterozygosity (LOH) on chromosome 3 was found in 64% and 57% of VHL-related and sporadic HBs, respectively, by single nucleotide polymorphism (SNP) array analysis. Among 19 tumors with chromosome 3 LOH, 5 were classified as copy-neutral LOH. VHL promoter hypermethylation was detected only in sporadic HBs (33%), indicating that epigenetic suppression of VHL is a common mechanism in sporadic HBs. The rate of biallelic VHL inactivation among VHL-related and sporadic HBs was 64% and 52%, respectively. LOH on either chromosome 6 or 10 was detected only in sporadic HBs (43%).
  
  
  
  Although biallelic inactivation of VHL is a dominant mechanistic cause of the pathogenesis of HB, other unknown mechanisms may also be involved, and such mechanisms may be different between VHL-related and sporadic HB.
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Takayanagi
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Akitake
authors.initials: A
authors.lastname: Mukasa
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Omata
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yanagisawa
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakatomi
authors.affiliation: Department of Neurosurgery, Dokkyo Medical University, Mibu, Tochigi,Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
mesh_terms: D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D018325:Hemangioblastoma / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000150:complications* / Q000235:genetics
keywords: DNA methylation; hemangioblastoma; loss of heterozygosity; mutation; von Hippel-Lindau disease