title: Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.
abstract: OBJECTIVE
  Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma.
  
  
  METHODS
  Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival.
  
  
  RESULTS
  (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (P<0.001) but not with survival. (2) PCR revealed two patients with increasing expression of MLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation.
  
  
  CONCLUSIONS
  Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Stark
authors.forename: Alexander
authors.initials: A
authors.lastname: Doukas
authors.forename: Heinz-Herrmann
authors.initials: HH
authors.lastname: Hugo
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hedderich
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hattermann
authors.forename: H
authors.initials: H
authors.lastname: Maximilian Mehdorn
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000401:mortality; D009687:Nuclear Proteins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: Gene targeting; Glioblastoma,; Mismatch repair,