title: O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme.
abstract: OBJECTIVE
  In glioblastoma multiforme (GBM), the cytotoxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolamide is dependent on O(6) alkylation, which correlates inversely with expression of the DNA repair enzyme O(6)-methyl-guanine-DNA methyltransferase (MGMT). Thus, MGMT assessment can be useful in predicting response in GBM, but the scarcity of neoplastic cells limits the practicality of MGMT assessment in these tumors. Although GBM grows within the skull, we investigated the concordance of methylation in glioma tissue, and paired serum DNA and the potential correlation with response and time to progression.
  
  
  METHODS
  Using MSP assay, we assessed the methylation of MGMT, p16, DAPK, and RASSF1A in tumor and serum DNA from 28 GBM patients treated with BCNU or with temozolamide plus cisplatin.
  
  
  RESULTS
  The concordance between methylation in tumor and serum was highly significant. Overall, response plus stable disease was noted in 10 of 11 (90.9%) patients with MGMT methylation and in 5 of 14 (35.7%) patients without (P = 0.01). In the 16 patients treated with temozolamide plus cisplatin, no significant correlation between MGMT methylation status and response was observed, whereas in BCNU-treated patients, a significant difference was observed in favor of those with methylated MGMT. Time to progression was 29.9 weeks in 12 patients with MGMT methylation and 15.7 weeks in 10 patients without (P = 0.006). No correlation was observed between response or time to progression and p16, DAPK, or RASSF1A methylation.
  
  
  CONCLUSIONS
  Methylated MGMT, p16, DAPK, and RASSF1A were found in serum DNA of GBM patients, with a good correlation between serum and primary tumor tissue. Serum MGMT methylation predicted response and time to progression in BCNU-treated GBM patients. The methylation-specific PCR assay in serum DNA could be a good predictive tool for selecting GBM patients to be treated with BCNU or alternatively with the combination of temozolamide plus cisplatin.
authors.affiliation: Medical Oncology Service, Hospital Germans Trias i Pujol, 08916 Badalona (Barcelona), Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Balaña
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ramirez
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
authors.forename: Yannis
authors.initials: Y
authors.lastname: Roussos
authors.forename: Aurelio
authors.initials: A
authors.lastname: Ariza
authors.forename: Rosa
authors.initials: R
authors.lastname: Ballester
authors.forename: Carme
authors.initials: C
authors.lastname: Sarries
authors.forename: Pedro
authors.initials: P
authors.lastname: Mendez
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sanchez
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D018899:CpG Islands; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D003606:Dacarbazine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin; D002330:Carmustine; D000077204:Temozolomide