title: Mutational analysis of PDGFR-RAS/MAPK pathway activation in childhood medulloblastoma.
abstract: Aberrant signalling via platelet derived growth factor receptors (PDGFRs) and the RAS/MAPK pathway has been implicated in the development of medulloblastoma, the most common malignant brain tumour in childhood. To determine whether genetic mechanisms play a role in the activation of PDGFR-RAS/MAPK signalling in medulloblastoma, we performed a direct sequence analysis of the established mutational "hotspots" of known targets of activating mutations within the pathway (PDGFRA, NRAS, KRAS, HRAS and BRAF) and PDFRFB, in a cohort of 28 primary tumours. A synonymous sequence variation in PDGFRA (CCG to CCA; PRO 567 PRO) was detected in two cases (approximately 7%), but not in 150 normal chromosomes assessed, suggesting that the PDGFRA locus may be associated with medulloblastoma development in certain cases. No evidence for oncogenic mutations affecting NRAS, KRAS, HRAS, BRAF or PDFRFB was found in any case. These data demonstrate that activating mutations in established mutational hotspots within the PDGFR-RAS/MAPK pathway are rare events in medulloblastoma development, and suggest that alternative mechanisms are responsible for RAS/MAPK pathway activation in this disease.
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, The Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK, and Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Jaqueline A
authors.initials: JA
authors.lastname: Langdon
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollander
authors.forename: Roberto
authors.initials: R
authors.lastname: Hernan
authors.forename: Twala L
authors.initials: TL
authors.lastname: Hogg
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Christine
authors.initials: C
authors.lastname: Fuller
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
mesh_terms: D000293:Adolescent; D000328:Adult; D002528:Cerebellar Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007223:Infant; D020935:MAP Kinase Signaling System; D008297:Male; D008527:Medulloblastoma / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics*
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha; D017479:Receptors, Platelet-Derived Growth Factor; D020928:Mitogen-Activated Protein Kinases