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.
OBJECTIVE
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.


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-alpha 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.


CONCLUSIONS
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.
Division of Pathology andHaematology, The Labatt Brain Tumor Research Centre, The Hospital for Sick Children,Toronto, Ontario, Canada.
Maryam
M
Zarghooni
Ute
U
Bartels
Eric
E
Lee
Pawel
P
Buczkowicz
Andrew
A
Morrison
Annie
A
Huang
Eric
E
Bouffet
Cynthia
C
Hawkins
D001344:Autopsy; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D018628:Gene Dosage; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019656:Loss of Heterozygosity; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D004273:DNA, Neoplasm; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020796:Receptor, Platelet-Derived Growth Factor alpha