睾丸衍生转录基因启动子的高甲基化与胶质母细胞瘤患者的不良预后显著相关。

Hypermethylation of testis derived transcript gene promoter significantly correlates with worse outcomes in glioblastoma patients.

机构信息

Department of Immunology, Capital Medical University, Beijing, China.

出版信息

Chin Med J (Engl). 2013;126(11):2062-6.

Abstract

BACKGROUND

Glioblastoma is the most common and lethal cancer of the central nervous system. Global genomic hypomethylation and some CpG island hypermethylation are common hallmarks of these malignancies, but the effects of these methylation abnormalities on glioblastomas are still largely unclear. Methylation of the O6-methylguanine-DNA methyltransferase promoter is currently an only confirmed molecular predictor of better outcome in temozolomide treatment. To better understand the relationship between CpG island methylation status and patient outcome, this study launched DNA methylation profiles for thirty-three primary glioblastomas (pGBMs) and nine secondary glioblastomas (sGBMs) with the expectation to identify valuable prognostic and therapeutic targets.

METHODS

We evaluated the methylation status of testis derived transcript (TES) gene promoter by microarray analysis of glioblastomas and the prognostic value for TES methylation in the clinical outcome of pGBM patients. Significance analysis of microarrays was used for genes significantly differently methylated between 33 pGBM and nine sGBM. Survival curves were calculated according to the Kaplan-Meier method, and differences between curves were assessed using the log-rank test. Then, we treated glioblastoma cell lines (U87 and U251) with 5-aza-2-deoxycytidines (5-aza-dC) and detected cell biological behaviors.

RESULTS

Microarray data analysis identified TES promoter was hypermethylated in pGBMs compared with sGBMs (P < 0.05). Survival curves from the Kaplan-Meier method analysis revealed that the patients with TES hypermethylation had a short overall survival (P < 0.05). This abnormality is also confirmed in glioblastoma cell lines (U87 and U251). Treating these cells with 5-aza-dC released TES protein expression resulted in significant inhibition of cell growth (P = 0.013).

CONCLUSIONS

Hypermethylation of TES gene promoter highly correlated with worse outcome in pGBM patients. TES might represent a valuable prognostic marker for glioblastoma.

摘要

背景

胶质母细胞瘤是中枢神经系统最常见和最致命的癌症。全基因组低甲基化和一些 CpG 岛超甲基化是这些恶性肿瘤的常见标志，但这些甲基化异常对胶质母细胞瘤的影响在很大程度上仍不清楚。O6-甲基鸟嘌呤-DNA 甲基转移酶启动子的甲基化目前是替莫唑胺治疗中唯一被证实的分子预后预测因子。为了更好地了解 CpG 岛甲基化状态与患者预后之间的关系，本研究对 33 例原发性胶质母细胞瘤（pGBM）和 9 例继发性胶质母细胞瘤（sGBM）进行了 DNA 甲基化谱分析，以期确定有价值的预后和治疗靶点。

方法

我们通过微阵列分析评估了睾丸衍生转录物（TES）基因启动子在胶质母细胞瘤中的甲基化状态，以及 TES 甲基化对 pGBM 患者临床结局的预后价值。采用差异倍数分析（Significance analysis of microarrays，SAM）比较 33 例 pGBM 和 9 例 sGBM 之间甲基化差异显著的基因。根据 Kaplan-Meier 方法计算生存曲线，并用对数秩检验评估曲线之间的差异。然后，我们用 5-氮杂-2-脱氧胞苷（5-aza-dC）处理胶质母细胞瘤细胞系（U87 和 U251），并检测细胞生物学行为。

结果

微阵列数据分析显示，pGBM 中 TES 启动子与 sGBM 相比呈超甲基化（P < 0.05）。Kaplan-Meier 方法分析的生存曲线显示，TES 高甲基化的患者总生存期较短（P < 0.05）。这一异常在胶质母细胞瘤细胞系（U87 和 U251）中也得到了证实。用 5-aza-dC 处理这些细胞，释放 TES 蛋白表达，导致细胞生长明显受到抑制（P = 0.013）。