Martinez Ramon, Martin-Subero Jose I, Rohde Veit, Kirsch Matthias, Alaminos Miguel, Fernandez Agustin F, Ropero Santiago, Schackert Gabriele, Esteller Manel
Department of Neurosurgery, University of Goettingen, Goettingen WT-084071, Germany.
Epigenetics. 2009 May 16;4(4):255-64. doi: 10.4161/epi.9130. Epub 2009 May 29.
Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. The presence of epigenetic lesions, like hypermethylation of known tumor suppressor genes such as MGMT, has been widely described in GBM, but to our knowledge, a genome-wide profile of DNA methylation changes in these lethal tumors is not yet available. In the present analysis, we have quantified the DNA methylation level of 1,505 CpG dinucleotides (807 genes) in 87 consecutive GBMs using universal BeadArrays. Supervised cluster analyses identified 25 and seven genes that were respectively hypermethylated and hypomethylated in more than 20% of the cases studied. The most frequently hypermethylated genes were HOXA11, CD81, PRKCDBP, TES, MEST, TNFRSF10A and FZD9, being involved in more than half of the cases. Studying the biological features of hypermethylated genes, we found that the group of genes hypermethylated in GBM was highly enriched (41%, p < 0.001) for targets of the PRC2 (Polycomb repressive complex 2) in embryonic stem cells. This suggests that GBM might be derived from precursor cells with stem cell-like features. DNA methylation profiles were associated with overall survival in GBM, and we confirmed the favorable prognostic impact of MGMT methylation in patients treated with alkylating agents. Furthermore, we identified that promoter hypermethylation of the transcription factor gene GATA6 (occurring in 30% of GBM) was significantly associated with unfavorable patient survival.
多形性胶质母细胞瘤（GBM）是成人中最常见且最具毁灭性的原发性脑肿瘤。表观遗传病变的存在，如已知肿瘤抑制基因（如MGMT）的高甲基化，在GBM中已被广泛描述，但据我们所知，这些致命肿瘤中DNA甲基化变化的全基因组概况尚不可得。在本分析中，我们使用通用微珠芯片对87例连续的GBM中1505个CpG二核苷酸（807个基因）的DNA甲基化水平进行了定量。监督聚类分析确定了25个和7个基因，在所研究的病例中分别有超过20%发生了高甲基化和低甲基化。最常发生高甲基化的基因是HOXA11、CD81、PRKCDBP、TES、MEST、TNFRSF10A和FZD9，超过半数的病例涉及这些基因。研究高甲基化基因的生物学特征时，我们发现GBM中高甲基化的基因组在胚胎干细胞中高度富集（41%，p<0.001）为PRC2（多梳抑制复合物2）的靶标。这表明GBM可能源自具有干细胞样特征的前体细胞。DNA甲基化谱与GBM的总生存期相关，我们证实了MGMT甲基化对接受烷化剂治疗患者的良好预后影响。此外，我们发现转录因子基因GATA6的启动子高甲基化（在30%的GBM中出现）与患者不良生存显著相关。
