CNRS/UMR6061, Institut de Génétique et Développement, Université de Rennes 1, Rennes, France.
BMC Genomics. 2010 Dec 14;11:701. doi: 10.1186/1471-2164-11-701.
Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies.
We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04).
This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.
已有研究报道，在胶质母细胞瘤中，参与关键生物学途径的基因启动子 DNA 甲基化模式发生改变。目前需要进行全基因组范围内的 DNA 甲基化水平评估，以解析胶质母细胞瘤侵袭性表型相关的表观遗传事件，并指导新的治疗策略。
我们对 40 例新诊断的胶质母细胞瘤患者的甲基化和基因表达谱进行了全基因组综合分析。我们还在 50 例接受手术、放疗和化疗联合辅助替莫唑胺（STUPP 方案）治疗的患者队列中，筛选了 CpG 位点甲基化水平与总生存期之间的相关性。甲基化分析在胶质母细胞瘤和对照脑之间鉴定出 616 个差异甲基化 CpG 位点，其中四分之一以一致的方式差异表达。在具有一致 CpG 位点的 13 个基因中，其启动子甲基化与胶质母细胞瘤中的表达水平呈负相关：B3GNT5、FABP7、ZNF217、BST2、OAS1、SLC13A5、GSTM5、ME1、UBXD3、TSPYL5、FAAH、C7orf13 和 C3orf14。生存分析确定了 6 个与总生存期相关的 CpG 位点。SOX10 启动子甲基化状态（两个 CpG 位点）将患者分层与 MGMT 状态相似，但曲线下面积更高（0.78 比 0.71，p 值 < 5e-04）。FNDC3B、TBX3、DGKI 和 FSD1 启动子的甲基化状态鉴定出对 STUPP 治疗无反应的 MGMT 甲基化肿瘤患者（p 值 < 1e-04）。
本研究提供了首例从同一 GBM 队列获得的 DNA 甲基化和基因表达谱的全基因组综合分析。我们还针对有史以来最大的一组经过统一治疗的 GBM 队列之一进行了基于甲基组的生存分析，共涉及超过 27000 个 CpG 位点。我们已经鉴定出表达可能受表观遗传机制严格调控的基因，以及可能指导治疗决策的标志物。
