title: Sporadic hemangioblastomas are characterized by cryptic VHL inactivation.
abstract: Hemangioblastomas consist of 10-20% neoplastic "stromal" cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.
authors.forename: Ganesh M
authors.initials: GM
authors.lastname: Shankar
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.forename: Nina
authors.initials: N
authors.lastname: Lelic
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jones
authors.forename: James C
authors.initials: JC
authors.lastname: Kim
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.forename: Malak
authors.initials: M
authors.lastname: Abedalthagafi
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Borges
authors.forename: Jean-Valery
authors.initials: JV
authors.lastname: Coumans
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.forename: Brian V
authors.initials: BV
authors.lastname: Nahed
authors.forename: John H
authors.initials: JH
authors.lastname: Shin
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Paek
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Park
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Fred G
authors.initials: FG
authors.lastname: Barker
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Departments of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA. pbrastianos@mgh.harvard.edu.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
mesh_terms: D000328:Adult; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D005260:Female; D020868:Gene Silencing; D018325:Hemangioblastoma / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA; D013120:Spinal Cord Neoplasms / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human