title: Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma.
abstract: PTCH1 and SUFU are both regulators of the sonic hedgehog signalling pathway. Germline inactivating mutations in both genes are associated with multisystem phenotypes including medulloblastoma. Somatic inactivating mutations in PTCH1 and SUFU each occur in approximately 10% of medulloblastomas. Recently, SUFU mutations were reported in familial medulloblastoma pedigrees without additional phenotypic features. We sought to further investigate the contribution of germline PTCH1 and SUFU mutations to familial and sporadic medulloblastoma. We performed full-gene mutational analysis of both PTCH1 and SUFU in three familial medulloblastoma pedigrees and 83 individuals with sporadic non-familial medulloblastoma. We identified no mutations in PTCH1 or SUFU in the three familial medulloblastoma pedigrees. We identified no PTCH1 mutations and two SUFU mutations that cause premature protein truncating in the series of sporadic non-familial medulloblastomas. The SUFU mutations were identified in two of the 16 individuals with desmoplastic medulloblastomas. These data indicate that familial medulloblastoma is a genetically heterogeneous disorder with at least one further susceptibility gene to be discovered. Furthermore, although both PTCH1 and SUFU play a key role in the sonic hedgehog signalling pathway, PTCH1 does not make an appreciable contribution to non-familial sporadic medulloblastoma, whereas inactivating germline mutations of SUFU cause ~2-3% of sporadic medulloblastomas and > 10% of desmoplastic medulloblastomas.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research and Royal Marsden Hospital, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Slade
authors.forename: Anne
authors.initials: A
authors.lastname: Murray
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanks
authors.forename: Ajith
authors.initials: A
authors.lastname: Kumar
authors.forename: Lisa
authors.initials: L
authors.lastname: Walker
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
authors.forename: Jenny
authors.initials: J
authors.lastname: Douglas
authors.forename: Charles
authors.initials: C
authors.lastname: Stiller
authors.forename: Louise
authors.initials: L
authors.lastname: Izatt
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D000328:Adult; D000368:Aged; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics*; D008875:Middle Aged; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C490764:SUFU protein, human