title: High incidence of MGMT and RARbeta promoter methylation in primary glioblastomas: association with histopathological characteristics, inflammatory mediators and clinical outcome.
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.
authors.affiliation: Department of Biological Chemistry, Medical School, University of Athens, 11527 Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.forename: Marios S
authors.initials: MS
authors.lastname: Themistocleous
authors.forename: George A
authors.initials: GA
authors.lastname: Papavassiliou
authors.forename: Elena
authors.initials: E
authors.lastname: Farmaki
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
authors.forename: Christos
authors.initials: C
authors.lastname: Adamopoulos
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
mesh_terms: D000328:Adult; D000368:Aged; D042501:Angiogenic Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D015820:Cadherins; C099972:H-cadherin; D018836:Inflammation Mediators; D007378:Interleukins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes