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

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

Author information

1
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.).

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.

KEYWORDS:

MGMT methylation; SNP; survival

PMID:
25910840
PMCID:
PMC4633927
DOI:
10.1093/neuonc/nov064
[Indexed for MEDLINE]
Free PMC Article

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