Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma

作者：Barbara S. Paugh, Alberto Broniscer, Chunxu Qu, Claudia P. Miller, Junyuan Zhang, Ruth Tatevossian, James M. Olson, Jeffrey Russell Geyer, Susan N Chi, Nasjla Saba da Silva, Arzu Onar‐Thomas, Justin Nathaniel Baker, Amar J. Gajjar, David W. Ellison, Suzanne J. Baker · 发表于：Journal of Clinical Oncology · 年份：2011 · DOI：10.1200/jco.2011.35.5677 · 被引用次数：326 · 研究领域：Glioma Diagnosis and Treatment、Neurofibromatosis and Schwannoma Cases、Ocular Oncology and Treatments

PURPOSE: Long-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 METHODS: Single-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. RESULTS: Frequencies 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 gl...