title: The MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide.
abstract: 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.
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Robert W
authors.initials: RW
authors.lastname: Rapkins
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: HuyTram N
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Wendy
authors.initials: W
authors.lastname: Ha
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Megan P
authors.initials: MP
authors.lastname: Hitchins
authors.affiliation: Cure Brain Cancer Neuro-oncology Laboratory, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia (R.W.R., W.H., K.L.M.); Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Stanford, California (F.W., M.P.H.); School of Public Health, Harbin Medical University, Harbin, People's Republic of China (F.W.); Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California (H.N.N., T.F.C., A.L.); School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (A.N.).
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: McDonald
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008745:Methylation; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: MGMT methylation; SNP; survival