Abstract
Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRalpha) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRalpha were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRalpha was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression.
Highlights
Brain tumors are the most common solid tumors in children and, despite recent advances in multimodality therapy, have the highest mortality rate of all solid tumors in this patient population
A single nucleotide polymorphic (SNP) locus that was AB genotype in blood DNA but AA or BB genotype in the corresponding tumor DNA was considered a potential site of loss of heterozygosity (LOH)
Its deletion was further confirmed by real-time quantitative PCR as zero copy. This is the first report of genomic analysis of pediatric gliomas by SNP array, which allows detection of both DNA copy number changes and LOH
Summary
Brain tumors are the most common solid tumors in children and, despite recent advances in multimodality therapy, have the highest mortality rate of all solid tumors in this patient population. After undergoing maximal tumor resection, children with a high-grade glioma are treated with radiation, ongoing clinical trials continue to investigate potential contributions of chemotherapy agents, such as temozolomide. In the Children’s Cancer Group high-grade glioma study CCG-945 [2], 70 of 250 ‘‘high-grade’’ gliomas were reclassified as ‘‘low-grade’’ tumors after a central consensus review by five independent neuropathologists. These ‘‘misdiagnoses’’ from a multi-institutional trial indicate a need for biomarkers to improve the accuracy of neuropathologic classification of pediatric gliomas; further functional characterizations of such markers potentially could lead to novel therapies
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