title: Mutations in SUFU predispose to medulloblastoma.
abstract: The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.
authors.affiliation: Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Corey
authors.initials: C
authors.lastname: Raffel
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Todd G
authors.initials: TG
authors.lastname: Mainprize
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Ron
authors.initials: R
authors.lastname: Agatep
authors.forename: Sharon
authors.initials: S
authors.lastname: Chiappa
authors.forename: Luzhang
authors.initials: L
authors.lastname: Gao
authors.forename: Anja
authors.initials: A
authors.lastname: Lowrance
authors.forename: Aihau
authors.initials: A
authors.lastname: Hao
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Theodora
authors.initials: T
authors.lastname: Stavrou
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Wieslaw T
authors.initials: WT
authors.lastname: Dura
authors.forename: Brandon
authors.initials: B
authors.lastname: Wainwright
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: David
authors.initials: D
authors.lastname: Hogg
mesh_terms: D001483:Base Sequence; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D016384:Consensus Sequence; D015972:Gene Expression Regulation, Neoplastic; D016153:Genes, Suppressor; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D016142:Holoprosencephaly / Q000209:etiology; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics
chemical_list: D008565:Membrane Proteins