title: Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme.
abstract: BACKGROUND
  Resistance of the highly aggressive glioblastoma multiforme (GBM) to drug therapy is a major clinical problem resulting in a poor patient's prognosis. Beside promoter methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene the efflux transporters ABCB1 and ABCG2 have been suggested as pivotal factors contributing to drug resistance, but the methylation of ABCB1 and ABCG2 has not been assessed before in GBM.
  
  
  METHODS
  Therefore, we evaluated the proportion and prognostic significance of promoter methylation of MGMT, ABCB1 and ABCG2 in 64 GBM patient samples using pyrosequencing technology. Further, the single nucleotide polymorphisms MGMT C-56 T (rs16906252), ABCB1 C3435T (rs1045642) and ABCG2 C421A (rs2231142) were determined using the restriction fragment length polymorphism method (RFLP). To study a correlation between promoter methylation and gene expression, we analyzed MGMT, ABCB1 and ABCG2 expression in 20 glioblastoma and 7 non-neoplastic brain samples.
  
  
  RESULTS
  Despite a significantly increased MGMT and ABCB1 promoter methylation in GBM tissue, multivariate regression analysis revealed no significant association between overall survival of glioblastoma patients and MGMT or ABCB1 promoter methylation. However, a significant negative correlation between promoter methylation and expression could be identified for MGMT but not for ABCB1 and ABCG2. Furthermore, MGMT promoter methylation was significantly associated with the genotypes of the MGMT C-56 T polymorphism showing a higher methylation level in the T allele bearing GBM.
  
  
  CONCLUSIONS
  In summary, the data of this study confirm the previous published relation of MGMT promoter methylation and gene expression, but argue for no pivotal role of MGMT, ABCB1 and ABCG2 promoter methylation in GBM patients' survival.
authors.forename: Moritz C
authors.initials: MC
authors.lastname: Oberstadt
authors.forename: Sandra
authors.initials: S
authors.lastname: Bien-Möller
authors.forename: Kerstin
authors.initials: K
authors.lastname: Weitmann
authors.forename: Susann
authors.initials: S
authors.lastname: Herzog
authors.forename: Katharina
authors.initials: K
authors.lastname: Hentschel
authors.forename: Christian
authors.initials: C
authors.lastname: Rimmbach
authors.forename: Silke
authors.initials: S
authors.lastname: Vogelgesang
authors.forename: Ellen
authors.initials: E
authors.lastname: Balz
authors.forename: Matthias
authors.initials: M
authors.lastname: Fink
authors.forename: Heike
authors.initials: H
authors.lastname: Michael
authors.forename: Jan-Philip
authors.initials: JP
authors.lastname: Zeden
authors.forename: Henrike
authors.initials: H
authors.lastname: Bruckmüller
authors.forename: Anneke N
authors.initials: AN
authors.lastname: Werk
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoffmann
authors.forename: Dieter
authors.initials: D
authors.lastname: Rosskopf
authors.forename: Henry W S
authors.initials: HW
authors.lastname: Schroeder
authors.affiliation: Department of Pharmacology, Ernst-Moritz-Arndt-University, Greifswald, Germany. heyo.kroemer@med.uni-goettingen.de.
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012008:Recurrence; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes