title: The T genotype of the MGMT C>T (rs16906252) enhancer single-nucleotide polymorphism (SNP) is associated with promoter methylation and longer survival in glioblastoma patients.
abstract: Clinical studies in patients with newly diagnosed glioblastoma treated with temozolomide have shown that the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is both predictive and prognostic of outcome. Methylation of the promoter region of MGMT is the most clinically relevant measure of MGMT expression and its assessment has become integral in current and planned clinical trials in glioblastoma. Our study confirmed that MGMT methylation, assessed by pyrosequencing, is associated with a significant survival benefit in glioblastoma patients treated with temozolomide (either concurrently with radiotherapy or sequential treatment). More interestingly, our study demonstrated that a promoter variant, the c.-56C>T (rs16906252) single nucleotide polymorphism (SNP) located within a cis-acting enhancer element at the proximal end of MGMT, is associated with the presence of MGMT promoter methylation in de novo glioblastoma. Furthermore, we show that the overall survival of patients carrying both the SNP and MGMT methylation showed a strong survival benefit when compared to either molecular event on their own. Promoter reporter experiments in MGMT methylated glioblastoma cell lines showed the T allele conferred a ∼30% reduction in normalised MGMT promoter activity compared to the wild-type haplotype. This might account for the propensity of the T allele to undergo promoter methylation, and in turn, the improved survival observed in carriers of the T allele. An independent validation on larger cohorts is required to confirm the prognostic and predictive value of individuals carrying the T allele.
authors.affiliation: Prince of Wales Clinical School, University of NSW, Australia. k.mcdonald@unsw.edu.au
authors.forename: K L
authors.initials: KL
authors.lastname: McDonald
authors.forename: R W
authors.initials: RW
authors.lastname: Rapkins
authors.forename: J
authors.initials: J
authors.lastname: Olivier
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.forename: K
authors.initials: K
authors.lastname: Nozue
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Tiwari
authors.forename: J
authors.initials: J
authors.lastname: Kuroiwa-Trzmielina
authors.forename: J
authors.initials: J
authors.lastname: Brewer
authors.forename: H R
authors.initials: HR
authors.lastname: Wheeler
authors.forename: M P
authors.initials: MP
authors.lastname: Hitchins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016019:Survival Analysis; D000077204:Temozolomide; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide