title: Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components.
abstract: Desmoplastic medulloblastoma (DMB) is a malignant cerebellar tumour composed of two distinct tissue components, pale islands and desmoplastic areas. Previous studies revealed mutations in genes encoding members of the sonic hedgehog pathway, including PTCH, SMOH and SUFUH in DMBs. However, little is known about other genomic aberrations. We performed comparative genomic hybridization (CGH) analysis of 22 sporadic DMBs and identified chromosomal imbalances in 20 tumours (91%; mean, 4.9 imbalances/tumour). Recurrent chromosomal gains were found on chromosomes 3, 9 (six tumours each), 20, 22 (five tumours each), 2, 6, 7, 17 (four tumours each) and 1 (three tumours). Recurrent losses involved chromosomes X (eight tumours), Y (six of eleven tumours from male patients), 9, 12 (four tumours each), as well as 10, 13 and 17 (three tumours each). Four tumours demonstrated high-level amplifications involving sequences from 1p22, 5p15, 9p, 12p13, 13q33-q34 and 17q22-q24, respectively. Further analysis of the 9p and 17q22-q24 amplicons by array-based CGH (matrix-CGH) and candidate gene analyses revealed amplification of JMJD2C at 9p24 in one DMB and amplification of RPS6KB1, APPBP2, PPM1D and BCAS3 from 17q23 in three DMBs. Among the 17q23 genes, RPS6KB1 showed markedly elevated transcript levels as compared to normal cerebellum in five of six DMBs and four of five classic medulloblastomas investigated. Finally, CGH analysis of microdissected pale islands and desmoplastic areas showed common chromosomal imbalances in five of six informative tumours. In summary, we have identified several novel genetic alterations in DMBs and provide genetic evidence for a monoclonal origin of their different tissue components.
authors.affiliation: Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Wilhelmstrasse 31, D-53111 Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ehrbrecht
authors.forename: U
authors.initials: U
authors.lastname: Müller
authors.forename: M
authors.initials: M
authors.lastname: Wolter
authors.forename: A
authors.initials: A
authors.lastname: Hoischen
authors.forename: A
authors.initials: A
authors.lastname: Koch
authors.forename: B
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: B
authors.initials: B
authors.lastname: Actor
authors.forename: A
authors.initials: A
authors.lastname: Mincheva
authors.forename: T
authors.initials: T
authors.lastname: Pietsch
authors.forename: P
authors.initials: P
authors.lastname: Lichter
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
authors.forename: R G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D001483:Base Sequence; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics
chemical_list: D005819:Genetic Markers; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1