Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma
Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma
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DOI：
10.1215/15228517-2007-003
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发表时间：
2007-07-01
期刊：
影响因子：
15.9
通讯作者：
Stokoe, David
中科院分区：
文献类型：
--
作者：
Wiencke, John K.;Zheng, Shichun;Stokoe, David
多形性胶质母细胞瘤(GBM)既可表现为新生肿瘤，也可表现为继发性肿瘤，起源于先前诊断的低级别胶质瘤。虽然这些肿瘤类型在表型上难以区分，但新生和继发性的基底膜与不同的遗传特征有关。PTEN突变导致磷脂酰肌醇3-激酶(PI3K)信号转导通路的激活，在新生肿瘤中很常见，但在继发性GBM或其先前的低级别肿瘤中并不常见。结果我们的研究结果显示，II级星形细胞瘤、少突胶质细胞瘤和少突胶质细胞瘤通常表现出PTEN启动子的甲基化，这种甲基化在非肿瘤脑组织标本中缺失，在新生胶质细胞瘤中很少见。PTEN启动子的甲基化与蛋白激酶B(PKB/Akt)的磷酸化有关，反映了PI3K通路的功能激活。我们的结果还表明，在III级星形细胞瘤和继发性胶质瘤中，PTEN启动子频繁甲基化，这与这些肿瘤起源于较低级别前体的假设一致。PTEN甲基化在新生GBM中很少见，并且与PTEN突变互斥。我们得出结论，PTEN启动子的甲基化可能代表了PI3K信号在II级和III级胶质瘤以及继发性胶质瘤中增加的另一种机制，这一发现为这些患者提供了新的治疗方法。
Glioblastoma multiforme (GBM) can present as either de novo or secondary tumors arising from previously diagnosed low-grade gliomas. Although these tumor types are phenotypically indistinguishable, de novo and secondary GBMs are associated with distinct genetic characteristics. PTEN mutations, which result in activation of the phosphoinositide 3-kinase (PI3K) signal transduction pathway, are frequent in de novo but not in secondary GBMs or their antecedent low-grade tumors. Results we present here show that grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas commonly display methylation of the PTEN promoter, finding that is absent in nontumor brain specimens and rare in de novo GBMs. Methylation of the PTEN promoter correlates with protein kinase B (PKB/Akt) phosphorylation, reflecting functional activation of the PI3K pathway. Our results also demonstrate frequent methylation of the PTEN promoter in grade III astrocytomas and secondary GBMs, consistent with the hypothesis that these tumors arise from lower grade precursors. PTEN methylation is rare in de novo GBMs and is mutually exclusive with PTEN mutations. We conclude that methylation of the PTEN promoter may represent an alternate mechanism by which PI3K signaling is increased in grade II and III gliomas as well as secondary GBMs, finding that offers new therapeutic approaches in these patients.