title: Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas.
abstract: BACKGROUND
  Gliomas are the most common neoplasm of the brain. High-grade gliomas often resist treatment even with aggressive surgical resection and adjuvant radiation and chemotherapy. Despite the combined treatment, they frequently recur with the same or higher-grade histology. Genetic instability is commonly associated with inactivation of the normal DNA repair function and tumour suppressor genes as well as activation of oncogenes resulting from alterations of promoter hypermethylation, but the molecular mechanisms of the histological and clinical progression of gliomas are still poorly understood.
  
  
  METHODS
  This study involved longitudinal analysis samples of primary and recurrent gliomas to determine whether the progression of low- and high-grade gliomas is associated with the promoter methylation of the DNMT1, MGMT and EGFR genes by PCR-based restriction enzyme assay. Epigenetic inactivation of these three important glioma-associated genes was analyzed in paired biopsy samples from 18 patients with tumour recurrence.
  
  
  RESULTS
  The methylation analysis of the CpG sites in the DNA methyltransferase (DNMT1) promoter revealed a total of 6 hypermethylations (6/18), the methylguanine-DNA methyltransferase (MGMT) promoter revealed a total of 10 hypermethylations (10/18) and the epithelial grow factor receptor (EGFR) promoter revealed a total of 12 (12/18) hypermethylations respectively in recurrent gliomas. The results demonstrated that DNMT1 promoter hypermethylation does not occur in low-grade gliomas, it was mainly observed in secondary glioblastomas. Additionally, the MGMT and EGFR promoter was hypermethylated in both low-and high-grade GLs and their corresponding histological transformed GLs.
  
  
  CONCLUSIONS
  This study has provided further evidence that the histological transformation and progression of gliomas may be associated with the inactivation of the EGFR and MGMT genes. It seems that EGFR and MGMT promoter hypermethylations are early events in the clonal evolution of gliomas and this gene inactivation has proved to be stable even in tumour recurrence. However, the DNMT hypermethylation is a late part of glioma progression.
  The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935054011612460.
authors.affiliation: Department of Pathology, Faculty of Medicine, Pécs University, Hungary. eva.gomori@kk.pte.hu
authors.forename: Eva
authors.initials: E
authors.lastname: Gömöri
authors.forename: József
authors.initials: J
authors.lastname: Pál
authors.forename: Bernadett
authors.initials: B
authors.lastname: Kovács
authors.forename: Tamás
authors.initials: T
authors.lastname: Dóczi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000032:analysis / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics*; D018450:Disease Progression; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics*; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C515491:MGMT protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D045643:DNA Repair Enzymes