title: Loss of SUFU function in familial multiple meningioma.
abstract: Meningiomas are the most common primary tumors of the CNS and account for up to 30% of all CNS tumors. An increased risk of meningiomas has been associated with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified. Here, we report on a family of five meningioma-affected siblings, four of whom have multiple tumors. No NF2 mutations were identified in the germline or tumors. We combined genome-wide linkage analysis and exome sequencing, and we identified in suppressor of fused homolog (Drosophila), SUFU, a c.367C>T (p.Arg123Cys) mutation segregating with the meningiomas in the family. The variation was not present in healthy controls, and all seven meningiomas analyzed displayed loss of the wild-type allele according to the classic two-hit model for tumor-suppressor genes. In silico modeling predicted the variant to affect the tertiary structure of the protein, and functional analyses showed that the activity of the altered SUFU was significantly reduced and therefore led to dysregulated hedgehog (Hh) signaling. SUFU is a known tumor-suppressor gene previously associated with childhood medulloblastoma predisposition. Our genetic and functional analyses indicate that germline mutations in SUFU also predispose to meningiomas, particularly to multiple meningiomas. It is possible that other genic mutations resulting in aberrant activation of the Hh pathway might underlie meningioma predisposition in families with an unknown etiology.
authors.affiliation: Genome-Scale Biology Research Program, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Aavikko
authors.forename: Song-Ping
authors.initials: SP
authors.lastname: Li
authors.forename: Silva
authors.initials: S
authors.lastname: Saarinen
authors.forename: Pia
authors.initials: P
authors.lastname: Alhopuro
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Morgunova
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.forename: Kari
authors.initials: K
authors.lastname: Vesanen
authors.forename: Miriam J
authors.initials: MJ
authors.lastname: Smith
authors.forename: D Gareth R
authors.initials: DG
authors.lastname: Evans
authors.forename: Minna
authors.initials: M
authors.lastname: Pöyhönen
authors.forename: Anne
authors.initials: A
authors.lastname: Kiuru
authors.forename: Anssi
authors.initials: A
authors.lastname: Auvinen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D016515:Genes, Neurofibromatosis 2; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics; D008579:Meningioma / Q000235:genetics; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C490764:SUFU protein, human