TP53 promoter methylation in human gliomas
Methylation of the promoter region of tumor suppressor genes may be associated with transcriptional silencing and tumor progression. The 5′ region of the TP53 gene does not contain a CpG island, but a basal promoter region of 85 bp is essential for its full promoter activity. In the present study, we assessed whether TP53 promoter methylation is present in malignant glioma cells and whether this is associated with reduced TP53 expression. Methylation-specific PCR revealed TP53 promoter methylation in three (U87MG, LNT-229, T98G) out of six malignant glioma cell lines studied. Treatment with 5-aza-2’-deoxycytidine (5-aza-dC) led to up-regulated expression of TP53 mRNA and protein in U87MG and T98G cells, suggesting that promoter methylation is associated with reduced expression in some malignant glioma cells. We then assessed TP53 promoter methylation in primary tissue of low-grade gliomas, and observed TP53 promoter methylation in 29/48 (60%) low-grade astrocytomas, 11/18 (61%) oligoastrocytomas, and 31/42 (74%) oligodendrogliomas. Promoter methylation of the p14 ARF gene, another gene involved in the TP53 pathway, was detected by methylation-specific PCR in 5/49 (10%) low-grade astrocytomas, 7/18 (39%) oligoastrocytomas, and 15/41 (37%) oligodendrogliomas. Our previous and present data show alterations of at least one of TP53 promoter methylation, p14 ARF promoter methylation, and TP53 mutations in 43/49 (88%) of low-grade astrocytomas, 15/18 (83%) of oligoastrocytomas, and 35/42 (83%) oligodendrogliomas, suggesting that disruption of the TP53/p14 ARF pathway is frequent in all histological types of low-grade glioma.
KeywordsTP53 mutation TP53 methylation p14ARF methylation Low-grade astrocytoma Oligodendrogliomas
This study was supported by the Jaqueline Seroussi Memorial Foundation for Cancer Research (MW) and the Foundation for Promotion of Cancer Research, Japan.
- 1.Agirre X, Vizmanos JL, Calasanz MJ, Garcia-Delgado M, Larrayoz MJ, Novo FJ (2003) Methylation of CpG dinucleotides and/or CCWGG motifs at the promoter of TP53 correlates with decreased gene expression in a subset of acute lymphoblastic leukemia patients. Oncogene 22:1070–1072CrossRefPubMedGoogle Scholar
- 6.Fruhwald MC, O’Dorisio MS, Dai Z, Tanner SM, Balster DA, Gao X, Wright FA, Plass C (2001) Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas—implications for tumor biology and potential clinical utility. Oncogene 20:5033–5042CrossRefPubMedGoogle Scholar
- 13.Kang JH, Kim SJ, Noh DY, Park IA, Choe KJ, Yoo OJ, Kang HS (2001) Methylation in the p53 promoter is a supplementary route to breast carcinogenesis: correlation between CpG methylation in the p53 promoter and the mutation of the p53 gene in the progression from ductal carcinoma in situ to invasive ductal carcinoma. Lab Invest 81:573–579PubMedGoogle Scholar
- 15.Kleihues P, Cavenee WK (2000) WHO Classification of tumours: pathology and genetics of tumours of the nervous system. IARCPress, LyonGoogle Scholar
- 16.Kleihues P, Davis RL, Ohgaki H, Burger PC, Westphal MM, Cavenee WK (2000) Diffuse astrocytoma. In: Kleihues P, Cavenee WK (eds) WHO classification of tumours: pathology and genetics of tumours of the nervous system. IARC Press, Lyon, pp 22–26Google Scholar
- 20.Naumann U, Kugler S, Wolburg H, Wick W, Rascher G, Schulz JB, Conseiller E, Bahr M, Weller M (2001) Chimeric tumor suppressor 1, a p53-derived chimeric tumor suppressor gene, kills p53 mutant and p53 wild-type glioma cells in synergy with irradiation and CD95 ligand. Cancer Res 61:5833–5842PubMedGoogle Scholar
- 23.Okamoto Y, Di Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M, Schuler D, Probst-Hensch NM, Yasargil MG, Yonekawa Y, Lutolf U, Kleihues P, Ohgaki H (2004) Population-based study on incidence, survival rates, and genetic alterations of low-grade astrocytomas and oligodendrogliomas. Acta Neuropathol 108:49–56CrossRefPubMedGoogle Scholar
- 30.Ueki K, Nishikawa R, Nakazato Y, Hirose T, Hirato J, Funada N, Fujimaki T, Hojo S, Kubo O, Ide T, Usui M, Ochiai C, Ito S, Takahashi H, Mukasa A, Asai A, Kirino T (2002) Correlation of histology and molecular genetic analysis of 1p, 19q, 10q, TP53, EGFR, CDK4, and CDKN2A in 91 astrocytic and oligodendroglial tumors. Clin Cancer Res 8:196–201PubMedGoogle Scholar
- 38.Wolter M, Reifenberger J, Blaschke B, Ichimura K, Schmidt EE, Collins VP, Reifenberger G (2001) Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes. J Neuropathol Exp Neurol 60:1170–1180PubMedGoogle Scholar