High Incidence of MGMT and RARbeta Promoter Methylation in Primary Glioblastomas: Association with Histopathological Characteristics, Inflammatory Mediators and Clinical Outcome

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2009 Oct 8

PMID 19809523

Citations 23

Authors

Christina Piperi

Marios S Themistocleous

George A Papavassiliou

Elena Farmaki

Georgia Levidou

Penelope Korkolopoulou

Christos Adamopoulos

Athanasios G Papavassiliou

Affiliations

Soon will be listed here.

Abstract

Glioblastomas, the most frequent primary brain tumors in adults, are characterized by a highly aggressive, inflammatory and angiogenic phenotype. Methylation of CpG islands in cancer-related genes may serve as an epigenetic biomarker for glioblastoma diagnosis and prognosis. The aim of this study was to analyze the methylation status of four critical tumor-associated genes (MGMT, RARbeta, RASSF1A, CDH13), and investigate possible links with inflammatory (interleukin [IL]-6, IL-8) and angiogenic mediators (vascular endothelial growth factor [VEGF], cyclooxygenase [COX]-2) and clinical outcome in 23 glioma samples (6 grade II astrocytomas, 17 grade IV glioblastomas). RARbeta and MGMT genes were more frequently methylated in 70.58% and 58.8% of glioblastomas, respectively. RASSF1A and CDH13 displayed a similar methylation frequency (23.52%) in glioblastomas. No gene methylation was observed in grade II astrocytomas. Tumor grade correlated positively with MGMT and RARbeta methylation (P = 0.005 and P = 0.019, respectively) and the extent of necrosis (P = 0.001 and P = 0.003). Interestingly, the marker of chronic inflammation, IL-6, was positively associated with methylation of MGMT (P = 0.004), RARbeta (P = 0.002), and RASSF1A (P = 0.0081) as well as the total number of methylated genes (P < 0.0001), indicating the important role of IL-6 in maintaining promoter methylation of these genes. VEGF expression correlated positively with MGMT and RARbeta methylation although these relationships were of marginal significance (P = 0.0679 and P = 0.0757). Kaplan-Meier univariate survival analysis indicated an unfavorable survival period in patients with MGMT methylation compared with those without methylation (P = 0.0474). Our study highlights the implication of MGMT and RARbeta methylation in the aggressive phenotype of primary glioblastomas. The association of MGMT methylation with clinical outcome indicates its potential prognostic value.

Citing Articles

RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells.

Dabrock A, Ernesti N, Will F, Rana M, Leinung N, Ehrich P Int J Mol Sci. 2023; 24(22).

PMID: 38003656 PMC: 10671216. DOI: 10.3390/ijms242216466.

Current Opportunities for Targeting Dysregulated Neurodevelopmental Signaling Pathways in Glioblastoma.

Drakulic D, Schwirtlich M, Petrovic I, Mojsin M, Milivojevic M, Kovacevic-Grujicic N Cells. 2022; 11(16).

PMID: 36010607 PMC: 9406959. DOI: 10.3390/cells11162530.

Epigenetic Underpinnings of Inflammation: A Key to Unlock the Tumor Microenvironment in Glioblastoma.

Chen N, Peng C, Li D Front Immunol. 2022; 13:869307.

PMID: 35572545 PMC: 9100418. DOI: 10.3389/fimmu.2022.869307.

RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis-an updated review.

Dubois F, Bergot E, Zalcman G, Levallet G Cell Death Dis. 2019; 10(12):928.

PMID: 31804463 PMC: 6895193. DOI: 10.1038/s41419-019-2169-x.

Epigenetics and Inflammatory Markers: A Systematic Review of the Current Evidence.

Gonzalez-Jaramillo V, Portilla-Fernandez E, Glisic M, Voortman T, Ghanbari M, Bramer W Int J Inflam. 2019; 2019:6273680.

PMID: 31205673 PMC: 6530203. DOI: 10.1155/2019/6273680.

References

Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M . Long-term survival with glioblastoma multiforme. Brain. 2007; 130(Pt 10):2596-606. DOI: 10.1093/brain/awm204. View

Yu J, Zhang H, Gu J, Lin S, Li J, Lu W . 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. PMC: 520749. DOI: 10.1186/1471-2407-4-65. View

Gorlia T, van den Bent M, Hegi M, Mirimanoff R, Weller M, Cairncross J . Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol. 2007; 9(1):29-38. DOI: 10.1016/S1470-2045(07)70384-4. View

van Meir E, Ceska M, Effenberger F, Walz A, Grouzmann E, Desbaillets I . Interleukin-8 is produced in neoplastic and infectious diseases of the human central nervous system. Cancer Res. 1992; 52(16):4297-305. View

Agathanggelou A, Honorio S, Macartney D, Martinez A, Dallol A, Rader J . Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene. 2001; 20(12):1509-18. DOI: 10.1038/sj.onc.1204175. View

Louis D, Ohgaki H, Wiestler O, Cavenee W, Burger P, Jouvet A . The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007; 114(2):97-109. PMC: 1929165. DOI: 10.1007/s00401-007-0243-4. View

Hsieh J, Lesniak M . Surgical management of high-grade gliomas. Expert Rev Neurother. 2005; 5(6 Suppl):S33-9. DOI: 10.1586/14737175.5.6.S33. View

Azarschab P, Stembalska A, Baus Loncar M, Pfister M, Sasiadek M, Blin N . Epigenetic control of E-cadherin (CDH1) by CpG methylation in metastasising laryngeal cancer. Oncol Rep. 2003; 10(2):501-3. View

Toyooka K, Toyooka S, Virmani A, Sathyanarayana U, Euhus D, Gilcrease M . Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. Cancer Res. 2001; 61(11):4556-60. View

10.

Michalowski M, De Fraipont F, Michelland S, Entz-Werle N, Grill J, Pasquier B . Methylation of RASSF1A and TRAIL pathway-related genes is frequent in childhood intracranial ependymomas and benign choroid plexus papilloma. Cancer Genet Cytogenet. 2006; 166(1):74-81. DOI: 10.1016/j.cancergencyto.2005.09.004. View

11.

Watanabe T, Katayama Y, Komine C, Yoshino A, Ogino A, Ohta T . O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. Int J Cancer. 2004; 113(4):581-7. DOI: 10.1002/ijc.20625. View

12.

Paz M, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L . CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res. 2004; 10(15):4933-8. DOI: 10.1158/1078-0432.CCR-04-0392. View

13.

Kohya N, Kitajima Y, Kitahara K, Miyazaki K . Mutation analysis of K-ras and beta-catenin genes related to O6-methylguanin-DNA methyltransferase and mismatch repair protein status in human gallbladder carcinoma. Int J Mol Med. 2002; 11(1):65-9. View

14.

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

15.

Lorente A, Mueller W, Urdangarin E, Lazcoz P, Lass U, von Deimling A . RASSF1A, BLU, NORE1A, PTEN and MGMT expression and promoter methylation in gliomas and glioma cell lines and evidence of deregulated expression of de novo DNMTs. Brain Pathol. 2008; 19(2):279-92. PMC: 8094756. DOI: 10.1111/j.1750-3639.2008.00185.x. View

16.

Jesien-Lewandowicz E, Jesionek-Kupnicka D, Zawlik I, Szybka M, Kulczycka-Wojdala D, Rieske P . High incidence of MGMT promoter methylation in primary glioblastomas without correlation with TP53 gene mutations. Cancer Genet Cytogenet. 2008; 188(2):77-82. DOI: 10.1016/j.cancergencyto.2008.09.015. View

17.

Wenger R, Gassmann M . Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem. 1997; 378(7):609-16. View

18.

Yarosh D, Foote R, Mitra S, Day 3rd R . Repair of O6-methylguanine in DNA by demethylation is lacking in Mer- human tumor cell strains. Carcinogenesis. 1983; 4(2):199-205. DOI: 10.1093/carcin/4.2.199. View

19.

Gao Y, Guan M, Su B, Liu W, Xu M, Lu Y . Hypermethylation of the RASSF1A gene in gliomas. Clin Chim Acta. 2004; 349(1-2):173-9. DOI: 10.1016/j.cccn.2004.07.006. View

20.

Hegi M, Diserens A, Godard S, Dietrich P, Regli L, Ostermann S . Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 2004; 10(6):1871-4. DOI: 10.1158/1078-0432.ccr-03-0384. View