Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences With the Adult Disease
Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences With the Adult Disease
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DOI：
10.1200/jco.2009.26.7252
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发表时间：
2010-06-20
影响因子：
45.3
通讯作者：
Baker, Suzanne J.
中科院分区：
文献类型：
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作者：
Paugh, Barbara S.;Qu, Chunxu;Baker, Suzanne J.
目的探讨小儿高级别胶质瘤（HGG）的拷贝数改变和基因表达特征。患者和方法我们使用单核苷酸多态性微阵列分析对78例新生HGGs进行了高分辨率的基因组失衡分析，其中包括7例弥漫性内在脑桥胶质瘤和10例因既往癌症接受颅脑照射的儿童HGGs。用基因表达芯片分析53例肿瘤的基因表达。结果与成人肿瘤的公开数据进行了比较。结果儿童和成人胶质母细胞瘤在拷贝数改变上存在显著差异。PDGFRA是儿童HGG（包括弥漫性内生性脑桥胶质瘤）局灶扩增的主要靶点，基因表达分析支持PDGFR α信号失调在儿童HGG中的重要作用。在儿童肿瘤中未发现IDH1热点突变，突出了与成人继发性胶质母细胞瘤的分子差异。小儿和成人胶质母细胞瘤明显区别于染色体1q的频繁增加（分别为30% v 9%）、染色体7的低频率增加（分别为13% v 74%）和染色体10q的减少（分别为35% v 80%）。PDGFRA扩增和1q增加在辐照诱导的肿瘤中发生的频率明显更高，这表明这些是儿童胶质瘤形成的起始事件。儿童hgg的一个子集显示最小的拷贝数变化。综合分子分析显示儿童和成人HGG的分子特征存在显著差异，表明成人肿瘤的发现不能简单地推断到年轻患者。PDGFR α可能是儿童HGG的有用靶点，包括弥漫性脑桥胶质瘤。
PurposeTo define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG).Patients and MethodsWe conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors.ResultsSignificant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFR alpha signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes.ConclusionIntegrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFR alpha may be a useful target for pediatric HGG, including diffuse pontine gliomas.