Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma
Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma
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DOI：
10.1200/jco.2011.35.5677
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发表时间：
2011-10-20
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.;Broniscer, Alberto;Baker, Suzanne J.
目的儿童弥漫性桥脑胶质瘤（DIPG）的长期生存率不足10%，迫切需要新的治疗靶点。我们评估了一个大的DIPG队列，以确定复发的基因组异常和DIPG的基因表达特征。患者和方法单核苷酸多态性阵列被用来比较43个DIPG和8个低级别脑干胶质瘤的基因组拷贝数异常的频率，数据来自成人和儿童（非DIPG）胶质母细胞瘤，并使用基因表达阵列评估27个DIPG，6个低级别脑干胶质瘤，和66 nonbrainstem低级别glioma. ResultsFrequencyofspecific大规模和局灶性失衡DIPG和nonbrainstem小儿胶质母细胞瘤之间的显着差异。在47%的DIPG中发现受体酪氨酸激酶-Ras-磷酸肌醇3-激酶信号通路内的基因的局灶性扩增，其中最常见的涉及PDGFRA和MET。30%的DIPG含有控制视网膜母细胞瘤蛋白（RB）磷酸化的细胞周期调控基因的局部扩增，21%的DIPG同时扩增了两种途径的基因。一些肿瘤在扩增模式上表现出异质性。DIPG表现出不同的基因表达的签名与非脑干儿童高级别胶质瘤的发展过程相比，而低级别的脑干和非脑干胶质瘤的表达签名是similar. ConclusionDIPG包括一个分子相关的，但不同的儿童胶质瘤亚组。基因组研究表明，靶向抑制受体酪氨酸激酶和RB调节蛋白可能是DIPG的有效治疗方法。
PurposeLong-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG.Patients and MethodsSingle-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas.ResultsFrequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar.ConclusionDIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.