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

Author:

Paugh Barbara S.1,Broniscer Alberto1,Qu Chunxu1,Miller Claudia P.1,Zhang Junyuan1,Tatevossian Ruth G.1,Olson James M.1,Geyer J. Russell1,Chi Susan N.1,da Silva Nasjla Saba1,Onar-Thomas Arzu1,Baker Justin N.1,Gajjar Amar1,Ellison David W.1,Baker Suzanne J.1

Affiliation:

1. Barbara S. Paugh, Alberto Broniscer, Chunxu Qu, Claudia P. Miller, Junyuan Zhang, Ruth G. Tatevossian, Arzu Onar-Thomas, Justin N. Baker, Amar Gajjar, David W. Ellison, and Suzanne J. Baker, St Jude Children's Research Hospital; Alberto Broniscer and Amar Gajjar, University of Tennessee Health Sciences Center, Memphis, TN; James M. Olson and J. Russell Geyer, University of Washington, Seattle, WA; Susan N. Chi, Dana-Farber Cancer Institute, Boston, MA; and Nasjla Saba da Silva, Universidade Federal de...

Abstract

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 gliomas were similar. Conclusion DIPGs 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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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