Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors
- 25 November 2002
- journal article
- oncogenomics
- Published by Springer Nature in Oncogene
- Vol. 21 (54) , 8372-8378
- https://doi.org/10.1038/sj.onc.1206031
Abstract
Methylation status of the p15INK4B, p16INK4A, p14ARF and retinoblastoma (RB) genes was studied using methylation specific polymerase chain reaction (MSP) in 85 human brain tumors of various subtypes and four normal brain samples. These genes play an important role in the control of the cell cycle. Twenty-four out of 85 cases (28%) had at least one of these genes methylated. The frequency of p14ARF methylation was 15 out of 85 (18%) cases, and the expression of p14ARF in methylated gliomas was significantly lower than in unmethylated gliomas. The incidence of methylation of p15INK4B, p16INK4A and RB gene was 4%, 7%, and 4%, respectively. Samples with p14ARF methylation did not have p16INK4A methylation even though both genes physically overlap. None of the target genes was methylated in the normal brain samples. In addition, the p53 gene was mutated in 19 out of 85 (22%) samples as determined by single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Thirty out of 85 (35%) brain tumors had either a p53 mutation or methylation of p14ARF. Also, the p14ARF expression in p53 wild-type gliomas was lower than levels in p53 mutated gliomas. This finding is consistent with wild-type p53 being able to autoregulate its levels by down-regulating expression of p14ARF. In summary, inactivation of the apoptosis pathway that included the p14ARF and p53 genes by hypermethylation and mutation, respectively, occurred frequently in human brain tumors. Down-regulation of p14ARF in gliomas was associated with hypermethylation of its promoter and the presence of a wild-type p53 in these samples.Keywords
This publication has 35 references indexed in Scilit:
- PTEN mutations in gliomas and glioneuronal tumorsOncogene, 1998
- Cancer Cell CyclesScience, 1996
- Frequent mutations of CDKN2 in primary pancreatic adenocarcinomasGenes, Chromosomes and Cancer, 1995
- Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibitionNature, 1995
- Mutations associated with familial melanoma impair p16INK4 functionNature Genetics, 1995
- Highly Frequent Homozygous Deletion of the p16 Gene in Esophageal Cancer Cell LinesBiochemical and Biophysical Research Communications, 1994
- Rates of p16 ( MTS1 ) Mutations in Primary Tumors with 9p LossScience, 1994
- A Cell Cycle Regulator Potentially Involved in Genesis of Many Tumor TypesScience, 1994
- Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancersNature, 1994
- A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4Nature, 1993