title: Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas.
abstract: Epigenetic silencing of the O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care.
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Niklas
authors.initials: N
authors.lastname: Thon
authors.forename: Sabina
authors.initials: S
authors.lastname: Eigenbrod
authors.forename: Bettina
authors.initials: B
authors.lastname: Hentschel
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sabel
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Friedrich Wilhelm
authors.initials: FW
authors.lastname: Kreth
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Markus
authors.initials: M
authors.lastname: Löffler
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Tonn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000532:radiotherapy / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000077204:Temozolomide
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes; D000077204:Temozolomide