Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes

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, p16(INK4a)), p14(ARF), and CDKN2B (MTS2, p15(INK4b)) 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-modi fled DNA, however, revealed frequent hypermethylation of the 5'-CpG islands in CDKN2A, p14(ARF), 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 p14(ARF) gene and the CDKN2B gene. Most tumors with CDKN2A, p14(ARF), 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 allelie losses on chromosomal arms 1p and 19q. In addition, p14(ARF) hypermethylation was predominantly found in tumors without a demonstrated TP53 mutation. Taken together, our results indicate that hypermethylation of CDKN2A, p14(ARF), and CDKN2B is an important epigenetic mechanism by which oligodendroglial tumors may escape from p53- and pRb-dependent growth control.