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  • Oncogenomics
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Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors

Oncogene volume 21, pages 8372–8378 (2002)Cite this article

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.

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Acknowledgements

This work was supported in part by National Institutes of Health, George Harrison Fund and Parker Hughes Trust, and a grant from the Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center. HP Koeffler is a member of the Jonsson Comprehensive Cancer Center and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, 90048, California, CA, USA

    Dong Yin, Dong Xie, Wolf-Karsten Hofmann, Carl W Miller & H Phillip Koeffler

  2. Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, 90048, California, CA, USA

    Keith L Black

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Correspondence to Dong Yin.

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Yin, D., Xie, D., Hofmann, WK. et al. Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors. Oncogene 21, 8372–8378 (2002). https://doi.org/10.1038/sj.onc.1206031

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