title: Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas.
abstract: The molecular pathogenesis of pleomorphic xanthoastrocytoma (PXA), a rare astrocytic brain tumor with a relatively favorable prognosis, is still poorly understood. We characterized 50 PXAs by comparative genomic hybridization (CGH) and found the most common imbalance to be loss on chromosome 9 in 50% of tumors. Other recurrent losses affected chromosomes 17 (10%), 8, 18, 22 (4% each). Recurrent gains were identified on chromosomes X (16%), 7, 9q, 20 (8% each), 4, 5, 19 (4% each). Two tumors demonstrated amplifications mapping to 2p23-p25, 4p15, 12q13, 12q21, 21q21 and 21q22. Analysis of 10 PXAs with available high molecular weight DNA by high-resolution array-based CGH indicated homozygous 9p21.3 deletions involving the CDKN2A/p14(ARF)/CDKN2B loci in six tumors (60%). Interphase fluorescence in situ hybridization to tissue sections confirmed the presence of tumor cells with homozygous 9p21.3 deletions. Mutational analysis of candidate genes on 9q, PTCH and TSC1, revealed no mutations in PXAs with 9q loss and no evidence of TSC1 promoter methylation. However, PXAs consistently showed low TSC1 transcript levels. Taken together, our study identifies loss of chromosome 9 as the most common chromosomal imbalance in PXAs and suggests important roles for homozygous CDKN2A/p14(ARF)/CDKN2B deletion as well as low TSC1 mRNA expression in these tumors.
authors.affiliation: Department of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany. ruthild.weber@ukb.uni-bonn.de
authors.forename: R G
authors.initials: RG
authors.lastname: Weber
authors.forename: A
authors.initials: A
authors.lastname: Hoischen
authors.forename: M
authors.initials: M
authors.lastname: Ehrler
authors.forename: P
authors.initials: P
authors.lastname: Zipper
authors.forename: K
authors.initials: K
authors.lastname: Kaulich
authors.forename: B
authors.initials: B
authors.lastname: Blaschke
authors.forename: A J
authors.initials: AJ
authors.lastname: Becker
authors.forename: S
authors.initials: S
authors.lastname: Weber-Mangal
authors.forename: A
authors.initials: A
authors.lastname: Jauch
authors.forename: B
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: J
authors.initials: J
authors.lastname: Schramm
authors.forename: O D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: P
authors.initials: P
authors.lastname: Lichter
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000172:deficiency / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis; D000077004:Tuberous Sclerosis Complex 1 Protein; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins