Rapkins Robert W, Wang Fan, Nguyen HuyTram N, Cloughesy Timothy F, Lai Albert, Ha Wendy, Nowak Anna K, Hitchins Megan P, McDonald Kerrie L
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.).
Neuro Oncol. 2015 Dec;17(12):1589-98. doi: 10.1093/neuonc/nov064. Epub 2015 Apr 24.
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.
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.
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).
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.
O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化是胶质母细胞瘤的一种重要预测生物标志物。MGMT启动子-增强子单核苷酸多态性（SNP；rs16906252）的T变体已与其他癌症中MGMT启动子甲基化的存在相关。我们研究了rs16906252的T等位基因与胶质母细胞瘤发生、肿瘤MGMT甲基化、MGMT蛋白表达及生存结局之间的关联。
研究了两个独立的接受替莫唑胺治疗的胶质母细胞瘤队列——一个是澳大利亚队列（澳大利亚胶质瘤基因组学与临床结局研究，n = 163），另一个是美国队列（加利福尼亚大学洛杉矶分校/洛杉矶凯撒医疗中心，n = 159）。采用等位基因亚硫酸氢盐测序来确定甲基化是否特异于T等位基因。此外，我们比较了胶质母细胞瘤病例与匹配对照中T等位基因的发生率，以评估其是否为发生MGMT甲基化胶质母细胞瘤的危险因素。
rs16906252 SNP的T等位基因携带与MGMT甲基化及低MGMT蛋白表达均相关，并预测接受替莫唑胺治疗的MGMT甲基化和非甲基化胶质母细胞瘤患者生存期显著延长。甲基化与T等位基因相关，提示T变体在MGMT甲基化的获得中起关键作用。携带T等位基因与发生胶质母细胞瘤的风险显著升高相关（调整优势比，1.96；P = .013），当按MGMT甲基化状态对胶质母细胞瘤进行分类时，风险进一步增加（调整优势比 ，2.86；P = .001）。
rs16906252 SNP的T等位基因是胶质母细胞瘤中MGMT甲基化获得的关键决定因素。接受替莫唑胺治疗的rs16906252 T基因型患者生存期更好，无论肿瘤甲基化状态如何。
