High incidence of MGMT and RARbeta promoter methylation in primary glioblastomas: association with histopathological characteristics, inflammatory mediators and clinical outcome

Mol Med. Jan-Feb 2010;16(1-2):1-9. doi: 10.2119/molmed.2009.00140. Epub 2009 Oct 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiogenic Proteins / metabolism
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism
  • DNA Methylation*
  • DNA Modification Methylases / genetics*
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • Female
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Humans
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Interleukins / metabolism
  • Male
  • Middle Aged
  • Prognosis
  • Promoter Regions, Genetic
  • Receptors, Retinoic Acid / genetics*
  • Receptors, Retinoic Acid / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Angiogenic Proteins
  • Cadherins
  • H-cadherin
  • Inflammation Mediators
  • Interleukins
  • RASSF1 protein, human
  • Receptors, Retinoic Acid
  • Tumor Suppressor Proteins
  • retinoic acid receptor beta
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes