Open AccessOligodendroglial Tumors Frequently Demonstrate Hypermethylation of theCDKN2A(MTS1, p16INK4a),p14ARF, andCDKN2B(MTS2,p15INK4b) Tumor Suppressor Genes
Author(s) -
Marietta Wolter,
Julia Reifenberger,
Britta Blaschke,
Koichi Ichimura,
Esther Schmidt,
V. Peter Collins,
Guido Reifenberger
Publication year - 2001
Publication title -
journal of neuropathology and experimental neurology
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 1.441
H-Index - 164
eISSN - 1554-6578
pISSN - 0022-3069
DOI - 10.1093/jnen/60.12.1170
Subject(s) - p14arf , cdkn2a , cdkn2b , dna methylation , cpg site , biology , cancer research , methylation , microbiology and biotechnology , gene , tumor suppressor gene , gene expression , carcinogenesis , genetics
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.