Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease

To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). We 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 c...

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Published in:Journal of clinical oncology Vol. 28; no. 18; p. 3061
Main Authors: Paugh, Barbara S, Qu, Chunxu, Jones, Chris, Liu, Zhaoli, Adamowicz-Brice, Martyna, Zhang, Junyuan, Bax, Dorine A, Coyle, Beth, Barrow, Jennifer, Hargrave, Darren, Lowe, James, Gajjar, Amar, Zhao, Wei, Broniscer, Alberto, Ellison, David W, Grundy, Richard G, Baker, Suzanne J
Format: Journal Article
Language:English
Published: United States 20.06.2010
Subjects:
Adolescent
Adult
Biomarkers, Tumor - genetics
Brain Neoplasms - genetics
Brain Neoplasms - pathology
Child
Child, Preschool
Chromosomes, Human, Pair 1 - genetics
Cranial Irradiation
Gene Expression Profiling
Glioma - genetics
Glioma - pathology
Humans
Infant
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide - genetics
Prognosis
Receptor, Platelet-Derived Growth Factor alpha - genetics
Young Adult
ISSN:1527-7755, 1527-7755
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Summary:To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). We 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. Significant 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 PDGFRalpha 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. Integrated 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. PDGFRalpha may be a useful target for pediatric HGG, including diffuse pontine gliomas.
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ISSN:1527-7755
1527-7755
DOI:10.1200/JCO.2009.26.7252