Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays

Abstract

BackgroundNeuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array.FindingsMultiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case.ConclusionsThis analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy.

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

“…17 Recent data revealed that in every cohort at least one of 10 MNA samples displayed coamplification of the ALK gene. 5,14,56 Moreover, ALK amplification was identified in samples derived from patients with poor prognosis, 17,55 which is in line with our data (Table 1).…”

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

“…17 Recent data revealed that in every cohort at least one of 10 MNA samples displayed coamplification of the ALK gene. 5,14,56 Moreover, ALK amplification was identified in samples derived from patients with poor prognosis, 17,55 which is in line with our data (Table 1).…”

Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression

“…3A and 3B). This is consistent with previously published data showing that the MYCN amplicon varies in size, there are often multiple genes coamplified with MYCN, and there are also independent noncontiguous amplicons on chromosome 2 (Beheshti et al, 2003;Chen et al, 2004;George et al, 2007). These latter cases were not examples of general genomic instability as amplicons were typically not present elsewhere in the genome.…”

VCF2CNA: A tool for efficiently detecting copy-number alterations in VCF genotype data and tumor purity

“…We used VCF2CNA to perform cghMCR analysis with CNA profiles and observed a genome pattern similar to that reported for SNP array platforms (Fig. 6A) 32 . In addition to loss of large regions on chr1p, 3p, and 11q and a broad gain of chr17q, VCF2CNA found frequent focal amplifications of MYCN in NBL tumors and several potential cancer-related CNAs, including high-level amplifications of CDK4 (1 tumor), and ALK (2 tumors) (Fig.…”

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

“…17 Recent data revealed that in every cohort at least one of 10 MNA samples displayed coamplification of the ALK gene. 5,14,56 Moreover, ALK amplification was identified in samples derived from patients with poor prognosis, 17,55 which is in line with our data (Table 1).…”

Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression

“…3A and 3B). This is consistent with previously published data showing that the MYCN amplicon varies in size, there are often multiple genes coamplified with MYCN, and there are also independent noncontiguous amplicons on chromosome 2 (Beheshti et al, 2003;Chen et al, 2004;George et al, 2007). These latter cases were not examples of general genomic instability as amplicons were typically not present elsewhere in the genome.…”

VCF2CNA: A tool for efficiently detecting copy-number alterations in VCF genotype data and tumor purity

“…We used VCF2CNA to perform cghMCR analysis with CNA profiles and observed a genome pattern similar to that reported for SNP array platforms (Fig. 6A) 32 . In addition to loss of large regions on chr1p, 3p, and 11q and a broad gain of chr17q, VCF2CNA found frequent focal amplifications of MYCN in NBL tumors and several potential cancer-related CNAs, including high-level amplifications of CDK4 (1 tumor), and ALK (2 tumors) (Fig.…”

Genes Proximal and Distal to MYCN Are Highly Expressed in Human Neuroblastoma as Visualized by Comparative Expressed Sequence Hybridization

“…17 Recent data revealed that in every cohort at least one of 10 MNA samples displayed coamplification of the ALK gene. 5,14,56 Moreover, ALK amplification was identified in samples derived from patients with poor prognosis, 17,55 which is in line with our data (Table 1).…”

Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression

“…3A and 3B). This is consistent with previously published data showing that the MYCN amplicon varies in size, there are often multiple genes coamplified with MYCN, and there are also independent noncontiguous amplicons on chromosome 2 (Beheshti et al, 2003;Chen et al, 2004;George et al, 2007). These latter cases were not examples of general genomic instability as amplicons were typically not present elsewhere in the genome.…”

VCF2CNA: A tool for efficiently detecting copy-number alterations in VCF genotype data and tumor purity

“…We used VCF2CNA to perform cghMCR analysis with CNA profiles and observed a genome pattern similar to that reported for SNP array platforms (Fig. 6A) 32 . In addition to loss of large regions on chr1p, 3p, and 11q and a broad gain of chr17q, VCF2CNA found frequent focal amplifications of MYCN in NBL tumors and several potential cancer-related CNAs, including high-level amplifications of CDK4 (1 tumor), and ALK (2 tumors) (Fig.…”