Whole-Genome Profiling of Pediatric Diffuse Intrinsic Pontine Gliomas Highlights Platelet-Derived Growth Factor Receptor {alpha} and Poly (ADP-ribose) Polymerase As Potential Therapeutic Targets

Whole-Genome Profiling of Pediatric Diffuse Intrinsic Pontine Gliomas Highlights Platelet-Derived Growth Factor Receptor and Poly (ADP-ribose) Polymerase As Potential Therapeutic Targets

From the Divisions of Pathology and Haematology and Oncology, The Labatt Brain Tumor Research Centre, The Hospital for Sick Children; and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Corresponding author: Cynthia Hawkins, MD PhD, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada, M5G 1X8; e-mail: cynthia.hawkins@sickkids.ca .

Purpose Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of pediatric malignancies and one for which no effective therapy exists. A major contributor to the failure of therapeutic trials is the assumption that biologic properties of brainstem tumors in children are identical to cerebral high-grade gliomas of adults. A better understanding of the biology of DIPG itself is needed in order to develop agents targeted more specifically to these children's disease. Herein, we address this lack of knowledge by performing the first high-resolution single nucleotide polymorphism (SNP) –based DNA microarray analysis of a series of DIPGs.

Patients and Methods Eleven samples (nine postmortem and two pretreatment surgical samples), the largest series thus far examined, were hybridized to SNP arrays (250 k or 6.0). The study was approved by the research ethics board at our institution. All array findings were validated using quantitative polymerase chain reaction, fluorescence in situ hybridization, immunohistochemistry, and/or microsatellite analysis.

Results Analysis of DIPG copy number alterations showed recurrent changes distinct from those of pediatric supratentorial high-grade astrocytomas. Thirty-six percent of DIPGs had gains in platelet-derived growth factor receptor alpha (PDGFRA; 4 to 18 copies) and all showed PDGFR- expression. Low-level gains in poly (ADP-ribose) polymerase (PARP) -1 were identified in three cases. Pathway analysis revealed genes with loss of heterozygosity were enriched for DNA repair pathways.

Conclusion To our knowledge, our data provides the first, comprehensive high-resolution genomic analysis of pediatric DIPG. Our findings of recurrent involvement of the PDGFR pathway as well as defects in DNA repair pathways coupled with gain of PARP-1 highlight two potential, biologically based, therapeutic targets directed specifically at this devastating disease.

Supported by an operating grant from the Canadian Institutes of Health Research (MOP 82727) and by a grant from B.R.A.I.N. Child.

Presented in abstract format at the American Association for Neuropathologists meeting, June 11-14, 2009, San Antonio, TX.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

We are excited to announce Dr. Huang has recieved funding for this research from the Children's Brain Tumor Foundation.

The full article is not yet available for reproduction.  To view the orginal abstract go to http://jco.ascopubs.org/cgi/content/abstract/28/8/1337