title: Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes.
abstract: We investigated 34 oligodendroglial tumors (7 oligodendrogliomas, 11 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas) for deletion, mutation, hypermethylation, and expression of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes at 9p21. One anaplastic oligoastrocytoma carried a homozygous deletion including all 3 genes. None of the tumors demonstrated point mutations in any of the genes. Methylation-specific polymerase chain reaction (MSP) analysis and sequencing of bisulfite-modified DNA, however, revealed frequent hypermethylation of the 5'-CpG islands in CDKN2A, p14ARF, and CDKN2B. Partial or complete methylation of the majority of CpG sites analyzed from each gene was detected in 32% of the tumors at the CDKN2A gene and at a similar percentage (41%) of the tumors at the p14ARF gene and the CDKN2B gene. Most tumors with CDKN2A, p14ARF, and/or CDKN2B hypermethylation either lacked detectable transcripts from these genes or had lower mRNA levels than those determined for non-neoplastic brain tissue. There was a significant correlation between hypermethylation of these genes and the presence of allelic losses on chromosomal arms 1p and 19q. In addition, p14ARF hypermethylation was predominantly found in tumors without a demonstrated TP53 mutation. Taken together, our results indicate that hypermethylation of CDKN2A, p14ARF, and CDKN2B is an important epigenetic mechanism by which oligodendroglial tumors may escape from p53- and pRb-dependent growth control.
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wolter
authors.forename: J
authors.initials: J
authors.lastname: Reifenberger
authors.forename: B
authors.initials: B
authors.lastname: Blaschke
authors.forename: K
authors.initials: K
authors.lastname: Ichimura
authors.forename: E E
authors.initials: EE
authors.lastname: Schmidt
authors.forename: V P
authors.initials: VP
authors.lastname: Collins
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D029968:Escherichia coli Proteins; D005260:Female; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D029968:Escherichia coli Proteins; D016601:RNA-Binding Proteins; C092748:RbfA protein, E coli; D012269:Ribosomal Proteins; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins