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

Author Paugh, Barbara S. Google Scholar
Broniscer, Alberto Google Scholar
Qu, Chunxu Google Scholar
Miller, Claudia P. Google Scholar
Zhang, Junyuan Google Scholar
Tatevossian, Ruth G. Google Scholar
Olson, James M. Google Scholar
Geyer, J. Russell Google Scholar
Chi, Susan N. Google Scholar
Silva, Nasjla Saba da Autor UNIFESP Google Scholar
Onar-Thomas, Arzu Google Scholar
Baker, Justin N. Google Scholar
Gajjar, Amar Google Scholar
Ellison, David W. Google Scholar
Baker, Suzanne J. Google Scholar
Institution St Jude Childrens Hosp
Univ Tennessee
Univ Washington
Dana Farber Canc Inst
Universidade Federal de São Paulo (UNIFESP)
Abstract 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.
Language English
Sponsor National Institutes of Health
National Brain Tumor Society
Cure Starts Now Foundation
Smile for Sophie Forever Foundation
Tyler's Treehouse Foundation
Musicians Against Childhood Cancer
Noyes Brain Tumor Foundation
Pediatric Low Grade Astrocytoma Foundation
American Lebanese Syrian Associated Charities
Grant number National Institutes of Health: P01 CA096832
Date 2011-10-20
Published in Journal of Clinical Oncology. Alexandria: Amer Soc Clinical Oncology, v. 29, n. 30, p. 3999-4006, 2011.
ISSN 0732-183X (Sherpa/Romeo, impact factor)
Publisher Amer Soc Clinical Oncology
Extent 3999-4006
Access rights Closed access
Type Article
Web of Science ID WOS:000296551700015

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