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Published in: Medical Oncology 4/2011

01-12-2011 | Original Paper

p14ARF promoter region methylation as a marker for gliomas diagnosis

Authors: Jie He, Jian-bing Qiao, Haiqing Zhu

Published in: Medical Oncology | Issue 4/2011

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Abstract

Methylation in the promoter region is one of the mechanisms through which tumor suppressors are inactivated, resulting in tumorigenesis and/or tumor progression. Herein, we studied the methylation status in the promoter region of the p14ARF tumor suppressor gene in 33 brain tissues isolated from glioma patients (astrocytomas) and compared to 12 brain tissues isolated from autopsy donors using methylation-specific polymerase chain reaction (MSP). The correlation between the expression of P14 and P53 was investigated using immunohistochemistry (IHC). The average percentage of methylation in the promoter region of p14ARF gene in brain samples from glioma patients is 39.4%, while 0 from autopsy donors. No difference in the methylation level between low-grade and high-grade gliomas was detected. The methylation status has no correlation with the prognosis in glioma patients. A significant correlation between the expression of mutant form of TP53 and the grade of the glioma was established. Furthermore, there was a negative correlation between methylation of the p14ARF promoter and the expression of the mutant form of TP53. Therefore, our data suggest that methylation in the promoter region of the p14ARF gene may be used as a biomarker for the diagnosis of gliomas.
Literature
1.
go back to reference Loew S, Schmidt U, Unterberg A, Halatsch ME. The epidermal growth factor receptor as a therapeutic target in glioblastoma multiforme and other malignant neoplasms. Anticancer Agents Med Chem. 2009;9:703–15.PubMed Loew S, Schmidt U, Unterberg A, Halatsch ME. The epidermal growth factor receptor as a therapeutic target in glioblastoma multiforme and other malignant neoplasms. Anticancer Agents Med Chem. 2009;9:703–15.PubMed
2.
go back to reference Ayuso-Sacido A, Moliterno JA, Kratovac S, Kapoor GS, O’Rourke DM, Holland EC, García-Verdugo JM, Roy NS, Boockvar JA. Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells. J Neurooncol. 2010;97:323–37.PubMedCrossRef Ayuso-Sacido A, Moliterno JA, Kratovac S, Kapoor GS, O’Rourke DM, Holland EC, García-Verdugo JM, Roy NS, Boockvar JA. Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells. J Neurooncol. 2010;97:323–37.PubMedCrossRef
3.
go back to reference Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S, Ohgaki H. Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol. 2006;65:846–54.PubMedCrossRef Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S, Ohgaki H. Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol. 2006;65:846–54.PubMedCrossRef
4.
go back to reference Ohgaki H, Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.PubMedCrossRef Ohgaki H, Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004;64:6892–9.PubMedCrossRef
6.
go back to reference Marko NF, Prayson RA, Barnett GH, Weil RJ. Integrated molecular analysis suggests a three-class model for low-grade gliomas: a proof-of-concept study. Genomics. 2010;95:16–24.PubMedCrossRef Marko NF, Prayson RA, Barnett GH, Weil RJ. Integrated molecular analysis suggests a three-class model for low-grade gliomas: a proof-of-concept study. Genomics. 2010;95:16–24.PubMedCrossRef
7.
go back to reference Jeon YK, Park K, Park CK, Paek SH, Jung HW, Park SH. Chromosome 1p and 19q status and p53 and p16 expression patterns as prognostic indicators of oligodendroglial tumors: a clinicopathological study using fluorescence in situ hybridization. Neuropathology. 2007;27:10–20.PubMedCrossRef Jeon YK, Park K, Park CK, Paek SH, Jung HW, Park SH. Chromosome 1p and 19q status and p53 and p16 expression patterns as prognostic indicators of oligodendroglial tumors: a clinicopathological study using fluorescence in situ hybridization. Neuropathology. 2007;27:10–20.PubMedCrossRef
8.
go back to reference Aldape K, Burger PC, Perry A. Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med. 2007;131:242–51.PubMed Aldape K, Burger PC, Perry A. Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch Pathol Lab Med. 2007;131:242–51.PubMed
9.
go back to reference Fontaine D, Vandenbos F, Lebrun C, Paquis V, Frenay M. Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas: critical review of the literature and implications in daily clinical practice. Rev Neurol (Paris). 2008;164:595–604.CrossRef Fontaine D, Vandenbos F, Lebrun C, Paquis V, Frenay M. Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas: critical review of the literature and implications in daily clinical practice. Rev Neurol (Paris). 2008;164:595–604.CrossRef
10.
go back to reference Elias A, Siegelin MD, Steinmüller A, von Deimling A, Lass U, Korn B, Mueller W. Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas. Clin Cancer Res. 2009;15:5457–65.PubMedCrossRef Elias A, Siegelin MD, Steinmüller A, von Deimling A, Lass U, Korn B, Mueller W. Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas. Clin Cancer Res. 2009;15:5457–65.PubMedCrossRef
11.
go back to reference Nagarajan RP, Costello JF. Molecular epigenetics and genetics in neuro-oncology. Neurotherapeutics. 2009;6:436–46.PubMedCrossRef Nagarajan RP, Costello JF. Molecular epigenetics and genetics in neuro-oncology. Neurotherapeutics. 2009;6:436–46.PubMedCrossRef
12.
go back to reference Chin L, Pomerantz J, DePinho RA. The INK4a/ARF tumor suppressor: one gene—two products—two pathways. Trends Biochem Sci. 1998;23:291–6.PubMedCrossRef Chin L, Pomerantz J, DePinho RA. The INK4a/ARF tumor suppressor: one gene—two products—two pathways. Trends Biochem Sci. 1998;23:291–6.PubMedCrossRef
13.
go back to reference Watanabe T, Katayama Y, Yoshino A, Yachi K, Ohta T, Ogino A, Komine C, Fukushima T. Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol. 2007;17:5–10.PubMedCrossRef Watanabe T, Katayama Y, Yoshino A, Yachi K, Ohta T, Ogino A, Komine C, Fukushima T. Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol. 2007;17:5–10.PubMedCrossRef
14.
go back to reference Carr J, Bell E, Pearson AD, Kees UR, Beris H, Lunec J, Tweddle DA. Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer Res. 2006;66:2138–45.PubMedCrossRef Carr J, Bell E, Pearson AD, Kees UR, Beris H, Lunec J, Tweddle DA. Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer Res. 2006;66:2138–45.PubMedCrossRef
15.
go back to reference Brooks CL, Gu W. Dynamics in the p53-Mdm2 ubiquitination pathway. Cell Cycle. 2004;3:895–9.PubMed Brooks CL, Gu W. Dynamics in the p53-Mdm2 ubiquitination pathway. Cell Cycle. 2004;3:895–9.PubMed
16.
go back to reference Ohta S, Uemura H, Matsui Y, Ishiguro H, Fujinami K, Kondo K, Miyamoto H, Yazawa T, Danenberg K, Danenberg PV, Tohnai I, Kubota Y. Alterations of p16 and p14ARF genes and their 9p21 locus in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:81–91.PubMedCrossRef Ohta S, Uemura H, Matsui Y, Ishiguro H, Fujinami K, Kondo K, Miyamoto H, Yazawa T, Danenberg K, Danenberg PV, Tohnai I, Kubota Y. Alterations of p16 and p14ARF genes and their 9p21 locus in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:81–91.PubMedCrossRef
17.
go back to reference Kim M, Yim SH, Cho NS, Kang SH, Ko DH, Oh B, Kim TY, Min HJ, She CJ, Kang HJ, Shin HY, Ahn HS, Yoon SS, Kim BK, Shin HR, Han KS, Cho HI, Lee DS. Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: a comparative deletion and hypermethylation study. Cancer Genet Cytogenet. 2009;195:59–65.PubMedCrossRef Kim M, Yim SH, Cho NS, Kang SH, Ko DH, Oh B, Kim TY, Min HJ, She CJ, Kang HJ, Shin HY, Ahn HS, Yoon SS, Kim BK, Shin HR, Han KS, Cho HI, Lee DS. Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: a comparative deletion and hypermethylation study. Cancer Genet Cytogenet. 2009;195:59–65.PubMedCrossRef
18.
go back to reference Kominami K, Nagasaka T, Cullings HM, Hoshizima N, Sasamoto H, Young J, Leggett BA, Tanaka N, Matsubara N. Methylation in p14(ARF) is frequently observed in colorectal cancer with low-level microsatellite instability. J Int Med Res. 2009;37:1038–45.PubMed Kominami K, Nagasaka T, Cullings HM, Hoshizima N, Sasamoto H, Young J, Leggett BA, Tanaka N, Matsubara N. Methylation in p14(ARF) is frequently observed in colorectal cancer with low-level microsatellite instability. J Int Med Res. 2009;37:1038–45.PubMed
19.
go back to reference Xiong J, Epstein RJ. Growth inhibition of human cancer cells by 5-aza-2′-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status. Mol Cancer Ther. 2009;8:779–85.PubMedCrossRef Xiong J, Epstein RJ. Growth inhibition of human cancer cells by 5-aza-2′-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status. Mol Cancer Ther. 2009;8:779–85.PubMedCrossRef
20.
go back to reference Gonzlaez-Gomez P, Bello MJ, Arjona D, Lomas J, Alonso ME, De Campos JM, Vaquero J, Isla A, Gutierrez M, Rey JA. Promoter hypermethylation of multiple genes in astrocytic gliomas. Int J Oncology. 2003;22:601–8. Gonzlaez-Gomez P, Bello MJ, Arjona D, Lomas J, Alonso ME, De Campos JM, Vaquero J, Isla A, Gutierrez M, Rey JA. Promoter hypermethylation of multiple genes in astrocytic gliomas. Int J Oncology. 2003;22:601–8.
21.
go back to reference Yu J, Zhang H, Gu J, Lin S, Li J, Lu W, Wang Y, Zhu J. Methylation profiles of thirty-four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer. 2004;4:65–79.PubMedCrossRef Yu J, Zhang H, Gu J, Lin S, Li J, Lu W, Wang Y, Zhu J. Methylation profiles of thirty-four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer. 2004;4:65–79.PubMedCrossRef
22.
go back to reference Nosho K, Kawasaki T, Chan AT, Ohnishi M, Suemoto Y, Kirkner GJ, Fuchs CS, Ogino S. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588–98.PubMedCrossRef Nosho K, Kawasaki T, Chan AT, Ohnishi M, Suemoto Y, Kirkner GJ, Fuchs CS, Ogino S. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53:588–98.PubMedCrossRef
23.
go back to reference Ksiaa F, Ziadi S, Amara K, Korbi S, Trimeche M. Biological significance of promoter hypermethylation of tumor-related genes in patients with gastric carcinoma. Clin Chim Acta. 2009;404:128–33.PubMedCrossRef Ksiaa F, Ziadi S, Amara K, Korbi S, Trimeche M. Biological significance of promoter hypermethylation of tumor-related genes in patients with gastric carcinoma. Clin Chim Acta. 2009;404:128–33.PubMedCrossRef
24.
go back to reference De Jong WK, Verpooten GF, Kramer H, Louwagie J, Groen HJ. Promoter methylation primarily occurs in tumor cells of patients with non-small cell lung cancer. Anticancer Res. 2009;29:363–9.PubMed De Jong WK, Verpooten GF, Kramer H, Louwagie J, Groen HJ. Promoter methylation primarily occurs in tumor cells of patients with non-small cell lung cancer. Anticancer Res. 2009;29:363–9.PubMed
25.
go back to reference Lin HH, Ke HL, Huang SP, Wu WJ, Chen YK, Chang LL. Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine. Urol Oncol. 2009. doi:10.1016/j.urolonc.2008.12.008. Lin HH, Ke HL, Huang SP, Wu WJ, Chen YK, Chang LL. Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine. Urol Oncol. 2009. doi:10.​1016/​j.​urolonc.​2008.​12.​008.
26.
go back to reference Kuo LT, Kuo KT, Lee MJ, Wei CC, Scaravilli F, Tsai JC, Tseng HM, Kuo MF, Tu YK. Correlation among pathology, genetic and epigenetic profiles, and clinical outcome in oligodendroglial tumors. Int J Cancer. 2009;124:2872–9.PubMedCrossRef Kuo LT, Kuo KT, Lee MJ, Wei CC, Scaravilli F, Tsai JC, Tseng HM, Kuo MF, Tu YK. Correlation among pathology, genetic and epigenetic profiles, and clinical outcome in oligodendroglial tumors. Int J Cancer. 2009;124:2872–9.PubMedCrossRef
27.
go back to reference Santos MC, Saito CP, Line SR. Extraction of genomic DNA from paraffin-embedded tissue section of human fetuses fixed and stored in formalin for long periods. Pathol Res Pract. 2008;204:633–6.PubMedCrossRef Santos MC, Saito CP, Line SR. Extraction of genomic DNA from paraffin-embedded tissue section of human fetuses fixed and stored in formalin for long periods. Pathol Res Pract. 2008;204:633–6.PubMedCrossRef
28.
go back to reference Sato M, Horio Y, Sekido Y, Minna JD, Shimokata K, Hasegawa Y. The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines. Oncogene. 2002;21:4822–9.PubMedCrossRef Sato M, Horio Y, Sekido Y, Minna JD, Shimokata K, Hasegawa Y. The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines. Oncogene. 2002;21:4822–9.PubMedCrossRef
29.
go back to reference Hamelin R, Laurent-Puig P, Olschwang S, Jego N, Asselain B, Remvikos Y, Girodet J, Salmon RJ, Thomas G. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology. 1994;106:42–8.PubMed Hamelin R, Laurent-Puig P, Olschwang S, Jego N, Asselain B, Remvikos Y, Girodet J, Salmon RJ, Thomas G. Association of p53 mutations with short survival in colorectal cancer. Gastroenterology. 1994;106:42–8.PubMed
31.
go back to reference Oren M. The p53 cellular tumor antigen: gene structure, expression and protein properties. Biochim Biophys Acta. 1985;823:67–78.PubMed Oren M. The p53 cellular tumor antigen: gene structure, expression and protein properties. Biochim Biophys Acta. 1985;823:67–78.PubMed
33.
go back to reference Kondo I, Iida S, Takagi Y, Sugihara K. MDM2 mRNA expression in the p53 pathway may predict the potential of invasion and liver metastasis in colorectal cancer. Dis Colon Rectum. 2008;51:1395–402.PubMedCrossRef Kondo I, Iida S, Takagi Y, Sugihara K. MDM2 mRNA expression in the p53 pathway may predict the potential of invasion and liver metastasis in colorectal cancer. Dis Colon Rectum. 2008;51:1395–402.PubMedCrossRef
34.
go back to reference Pacifico A, Goldberg LH, Peris K, Chimenti S, Leone G, Ananthaswamy HN. Loss of CDKN2A and p14ARF expression occurs frequently in human monmelanoma skin cancers. Br J Dermatol. 2008;158:291–7.PubMedCrossRef Pacifico A, Goldberg LH, Peris K, Chimenti S, Leone G, Ananthaswamy HN. Loss of CDKN2A and p14ARF expression occurs frequently in human monmelanoma skin cancers. Br J Dermatol. 2008;158:291–7.PubMedCrossRef
Metadata
Title
p14ARF promoter region methylation as a marker for gliomas diagnosis
Authors
Jie He
Jian-bing Qiao
Haiqing Zhu
Publication date
01-12-2011
Publisher
Springer US
Published in
Medical Oncology / Issue 4/2011
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-010-9651-8

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