PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome
PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome
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DOI：
10.1093/neuonc/nos140
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发表时间：
2012-09-01
期刊：
影响因子：
15.9
通讯作者：
Haas-Kogan, Daphne A.
中科院分区：
文献类型：
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作者：
Mueller, Sabine;Phillips, Joanna;Haas-Kogan, Daphne A.
儿童神经胶质瘤发病机制的信号转导途径知之甚少。我们的特点PI 3 K/Akt/mTOR通路在所有级别的小儿胶质瘤。使用免疫组织化学，我们通过评估下游信号分子磷酸化（p）-S6、磷酸化（p）-4BP1和磷酸化（p）-PRAS 40、PTEN和PTEN启动子甲基化以及MIB标记指数来评估PI 3 K/Akt/mTOR通路的活化。我们将这些发现与48例神经胶质瘤患儿的临床结果进行了相关性分析。80%的高级别胶质瘤（12/15）显示基于p-S6和p-4 EBP 1表达的PI 3 K/Akt/mTOR通路活化。大多数高级别胶质瘤PTEN表达阴性（10/15），50%有PTEN启动子甲基化（IQ级：2/4; IV级：3/6）。低级别胶质瘤中14/32例（43.8%）通过p-S6和16/32例（50%）通过p-4 EBP 1显示PI 3 K/Akt/mTOR通路活化。超过50%的I级（6/11）和几乎所有的II级肿瘤（6/7）显示PTEN启动子甲基化。肿瘤分级与PTEN表达呈负相关，与p-S6和p-4 EBP 1表达呈正相关（PTEN：P = .0025; pS 6：P= .0075; p-4 EBP 1：P = .0066）。PTEN启动子甲基化与PTEN蛋白表达呈负相关（P = 0.0990），p-S6和p-4 EBP 1表达与无进展生存率相关（pS 6：P = 0.0874; p-4 EBP 1：P = 0.0475）。没有PTEN表达的肿瘤具有较高的MIB标记指数（P = .007）。大多数儿童胶质瘤显示PI 3 K/Akt/mTOR通路的激活，其中PTEN启动子的甲基化在这些肿瘤中常见。
The signaling pathways that underlie the pathogenesis of pediatric gliomas are poorly understood. We characterized the PI3K/Akt/mTOR pathway in pediatric gliomas of all grades. Using immunohistochemistry, we assessed activation of the PI3K/Akt/mTOR pathway by evaluating the downstream signaling molecules phospho(p)-S6, phospho(p)-4BP1, and phospho(p)-PRAS40; PTEN; and PTEN promoter methylation, as well as the MIB labeling index. We correlated these findings with the clinical outcomes of 48 children with gliomas. Eighty percent of high-grade gliomas (12/15) showed activation of the PI3K/Akt/mTOR pathway based on p-S6 and p-4EBP1 expression. The majority of high-grade gliomas were negative for PTEN expression (10/15), and 50% had PTEN promoter methylation (grade IQ: 2/4; grade IV: 3/6). Low-grade gliomas demonstrated PI3K/Akt/mTOR pathway activation in 14/32 (43.8%) by p-S6 and 16/32 (50%) by p-4EBP1. Over 50% of grade I (6/11) and almost all grade II tumors (6/7) showed PTEN promoter methylation. Tumor grade correlated negatively with PTEN expression and positively with expression of p-S6 and p-4EBP1 (PTEN: P = .0025; pS6: P= .0075; p-4EBP1: P = .0066). There was a trend toward inverse correlation of methylation of the PTEN promoter with expression of PTEN protein (P = .0990) and direct correlation of expression of p-S6 and p-4EBP1 with poorer clinical outcome, as measured by progression-free survival (pS6: P = .0874; p-4EBP1: P = .0475). Tumors with no PTEN expression had a higher MIB labeling index (P = .007). The majority of pediatric gliomas show activation of the PI3K/Akt/mTOR pathway, with methylation of the PTEN promoter occurring commonly in these tumors.