Neuro-Oncology Advance Access published online on October 15, 2009
Neuro-Oncology, doi:10.1093/neuonc/nop001
Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas
Departments of Paediatrics and Human Genetics, Montreal Children's Hospital (H.-Q.Q., C.P.); Division of Hemato-Oncology, Departments of Paediatrics and Human Genetics, Montreal Children's Hospital Research Institute (K.J., D.B., D.F., N.J.); Molecular Diagnostic Laboratory, Department of Genetics, Montreal Children's Hospital Research Institute (R.M.); Division of Neurosurgery, Montreal Children's Hospital (J.-P.F.); and Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada (S.A.); INSERM U 830, Institut Curie, Paris, France (S.F., O.D.); McGill University and Genome Quebec Innovation Centre, Montreal, Canada (B.G., A.M.); Division of Pathology, The Hospital for Sick Children, Toronto, Canada (L.S., C.H.); 2nd Department of Paediatrics, Faculty of Medicine, Semmelweis University, Budapest, Hungary (P.H., M.G.); Division of Neuro-Surgery, Division of Pathology, National Institute of Neurosurgery, Budapest, Hungary (L.B.); Department of Neurosurgery, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary (Z.H.)
Corresponding Author: Constantin Polychronakos, M.D., Montreal Children's Hospital, 2300 Tupper, Montreal, Que., Canada, H3H 1P3 (constantin.polychronakos{at}mcgill.ca).
 |
Abstract |
|---|
Available data on genetic events in pediatric grade IV astrocytomas (glioblastoma [pGBM]) are scarce. This has traditionally been a major impediment in understanding the pathogenesis of this tumor and in developing ways for more effective management. Our aim is to chart DNA copy number aberrations (CNAs) and get insight into genetic pathways involved in pGBM. Using the Illumina Infinium Human-1 bead-chip-array (100K single-nucleotide polymorphisms [SNPs]), we genotyped 18 pediatric and 6 adult GBMs. Results were compared to BAC-array profiles harvested on 16 of the same pGBM, to an independent data set of 9 pediatric high-grade astrocytomas (HGAs) analyzed on Affymetrix 250K-SNP arrays, and to existing data sets on HGAs. CNAs were additionally validated by real-time qPCR in a set of genes in pGBM. Our results identify with nonrandom clustering of CNAs in several novel, previously not reported, genomic regions, suggesting that alterations in tumor suppressors and genes involved in the regulation of RNA processing and the cell cycle are major events in the pathogenesis of pGBM. Most regions were distinct from CNAs in aGBMs and show an unexpectedly low frequency of genetic amplification and homozygous deletions and a high frequency of loss of heterozygosity for a high-grade I rapidly dividing tumor. This first, complete, high-resolution profiling of the tumor cell genome fills an important gap in studies on pGBM. It ultimately guides the mapping of oncogenic networks unique to pGBM, identification of the related therapeutic predictors and targets, and development of more effective therapies. It further shows that, despite commonalities in a few CNAs, pGBM and aGBMs are two different diseases.
Keywords: pediatric high-grade astrocytomas, brain tumors, SNP arrays, LOH
Received June 11, 2008; Accepted May 6, 2009