Chromosomal localization of DNA amplifications in neuroblastoma tumors using cDNA microarray comparative genomic hybridization - PubMed (original) (raw)
Comparative Study
Chromosomal localization of DNA amplifications in neuroblastoma tumors using cDNA microarray comparative genomic hybridization
Ben Beheshti et al. Neoplasia. 2003 Jan-Feb.
Abstract
Conventional comparative genomic hybridization (CGH) profiling of neuroblastomas has identified many genomic aberrations, although the limited resolution has precluded a precise localization of sequences of interest within amplicons. To map high copy number genomic gains in clinically matched stage IV neuroblastomas, CGH analysis using a 19,200-feature cDNA microarray was used. A dedicated (freely available) algorithm was developed for rapid in silico determination of chromosomal localizations of microarray cDNA targets, and for generation of an ideogram-type profile of copy number changes. Using these methodologies, novel gene amplifications undetectable by chromosome CGH were identified, and larger MYCN amplicon sizes (in one tumor up to 6 Mb) than those previously reported in neuroblastoma were identified. The genes HPCAL1, LPIN1/KIAA0188, NAG, and NSE1/LOC151354 were found to be coamplified with MYCN. To determine whether stage IV primary tumors could be further subclassified based on their genomic copy number profiles, hierarchical clustering was performed. Cluster analysis of microarray CGH data identified three groups: 1) no amplifications evident, 2) a small MYCN amplicon as the only detectable imbalance, and 3) a large MYCN amplicon with additional gene amplifications. Application of CGH to cDNA microarray targets will help to determine both the variation of amplicon size and help better define amplification-dependent and independent pathways of progression in neuroblastoma.
Figures
Figure 1
Validation of the cDNA array CGH technique. Genomic DNA from the neuroblastoma cell line IMR32 was used in both conventional CGH on metaphase chromosomes (inset, A) and cDNA array CGH (B). In the ideogram profiles generated for the cDNA array CGH results, the normalized fluorescence intensity ratios from individual replicates (n=4) are given in yellow, and their average is plotted in red. Note the profile for chromosome Y is not shown due to the low representation of genes from this chromosome on the microarray. Chromosome CGH of IMR32 showed expected MYCN amplification at 2p24, with an additional amplification at 2p15 (A). These changes were also observed by cDNA array CGH, but at higher resolution (B). cDNA array CGH was able to determine that the gene amplification at 2p15 corresponded to MEIS1, which was recently reported using other methods.
Figure 2
Comparison of resolution of chromosome CGH (A) and cDNA array CGH (B) techniques for determining genomic amplifications in a neuroblastoma patient P1071. Fluorescence in situ hybridization with labeled MYCN probe was used to verify copy number amplification of MYCN in interphase nuclei (C). (A) CGH on metaphase chromosomes showed amplification along the distal short arm of chromosome 2, but due to the limited resolution of the technique was not able to resolve the region to smaller than approximately 60 Mb (2pter-2p22). (B) cDNA array CGH profile of genomic imbalances in the same patient (n=3 replicates) clearly delineated the 2p24 amplification to involve MYCN as well as other 2p24 genes in the vicinity of MYCN. Although it is expected that the technical issues dealing with low detection sensitivity will be resolved in the future, this study has focused on discussion of genes showing dosage changes of greater than 25 copies.
Figure 3
Relationships between the neuroblastomas as defined by unsupervised two-dimensional hierarchical clustering of gene dosage change patterns derived from cDNA array CGH results. The full cluster results are provided as supplementary information online (
http://www.utoronto.ca/cancyto/NB2003/
).
Figure 4
Categorization of neuroblastomas based on hierarchical clustering of cDNA array CGH results, as represented by changes on chromosome 2. Groups 1, 2, and 3 are defined as having no detectable genomic amplifications; MYCN amplification as the only evident genomic copy number change, or a small MYCN amplicon; and MYCN amplification with additional amplification of a number of the genes in the vicinity of the MYCN locus; respectively.
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