The MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide

Neuro Oncol. 2015 Dec;17(12):1589-98. doi: 10.1093/neuonc/nov064. Epub 2015 Apr 24.


Background: Promoter methylation of O(6)-methylguanine-DNA methyltransferase (MGMT) is an important predictive biomarker in glioblastoma. The T variant of the MGMT promoter-enhancer single nucleotide polymorphism (SNP; rs16906252) has been associated with the presence of MGMT promoter methylation in other cancers. We examined the association of the T allele of rs16906252 with glioblastoma development, tumor MGMT methylation, MGMT protein expression, and survival outcomes.

Methods: Two independent temozolomide-treated glioblastoma cohorts-one Australian (Australian Genomics and Clinical Outcomes of Glioma, n = 163) and the other American (University of California Los Angeles/Kaiser Permanente Los Angeles, n = 159)-were studied. Allelic bisulphite sequencing was used to determine if methylation was specific to the T allele. Additionally, we compared the incidence of the T allele between glioblastoma cases and matched controls to assess whether it was a risk factor for developing MGMT methylated glioblastoma.

Results: Carriage of the T allele of the rs16906252 SNP was associated with both MGMT methylation and low MGMT protein expression and predicted significantly longer survival in temozolomide-treated patients with both MGMT methylated and nonmethylated glioblastoma. Methylation was linked to the T allele, inferring that the T variant plays a key role in the acquisition of MGMT methylation. Carriage of the T allele was associated with a significantly elevated risk of developing glioblastoma (adjusted odds ratio, 1.96; P = .013), increasing further when glioblastoma was classified by the presence of MGMT methylation (adjusted odds ratio, 2.86; P = .001).

Conclusions: The T allele of the rs16906252 SNP is a key determinant in the acquisition of MGMT methylation in glioblastoma. Temozolomide-treated patients with the rs16906252 T genotype have better survival, irrespective of tumor methylation status.

Keywords: MGMT methylation; SNP; survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Biomarkers / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • DNA Modification Methylases / genetics*
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Female
  • Genotype
  • Glioblastoma / drug therapy*
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Methylation
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Risk Factors
  • Temozolomide
  • Treatment Outcome
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Antineoplastic Agents, Alkylating
  • Biomarkers
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide