Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
J Natl Cancer Inst. 2011 Jan 19;103(2):143-53. doi: 10.1093/jnci/djq497. Epub 2010 Dec 16.
Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated.
DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided.
We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72).
The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.
虽然人们已经了解了许多区分神经胶质瘤组织学亚型的分子和染色体特征，但神经胶质瘤的 DNA 甲基化模式及其与其他肿瘤特征（如异柠檬酸脱氢酶 [IDH] 基因突变）的关联，直到最近才开始被研究。
从加利福尼亚大学旧金山分校脑肿瘤研究中心的胶质母细胞瘤、星形细胞瘤、少突胶质细胞瘤、少突星形细胞瘤、室管膜瘤和毛细胞星形细胞瘤（n = 131）以及非肿瘤脑组织（n = 7）中评估了 DNA 甲基化，采用 Illumina GoldenGate 甲基化阵列。对甲基化数据进行递归分区混合建模（RPMM）以得出甲基化类。还评估了肿瘤和非肿瘤之间的差异 DNA 甲基化。使用单变量和多变量分析测试了 IDH 突变（IDH1 和 IDH2）与甲基化类之间的关联，该分析适用于具有测序底物的肿瘤（n = 95）。使用多变量 Cox 比例风险模型和 Kaplan-Meier 分析比较了携带突变 IDH 的神经胶质瘤患者（n = 57）和携带野生型 IDH 的患者（n = 38）的生存情况。所有统计检验均为双侧。
我们观察到 RPMM 甲基化类与神经胶质瘤组织学亚型之间存在统计学显著关联（P < 2.2 × 10(-16)）。与非肿瘤脑组织相比，在神经胶质瘤肿瘤的组织学亚型中，CpG 位点的差异甲基化比率具有统计学显著差异（置换 P <.0001）。甲基化类与神经胶质瘤中的 IDH 突变强烈相关（P = 3.0 × 10(-16)）。与肿瘤携带野生型 IDH 的神经胶质瘤患者相比，肿瘤携带突变型 IDH 的患者的生存情况有统计学显著改善（死亡风险比为 0.27，95%置信区间为 0.10 至 0.72）。
尽管 IDH 突变的神经胶质瘤具有组织学多样性，但它们的甲基化类具有同质性，这表明 IDH 突变与神经胶质瘤中独特的 DNA 甲基化表型和代谢特征改变相关。
