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ABSTRACT: Identification of candidate neuroblastoma genes by combining genomic and expression microarrays

REPOSITORIES: ENA

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Project description:Gene expression analysis was performed on 30 Neuroblastomas to identify genes whose transcription is significantly altered by recurrent chromosomal alterations. Genomic copy number losses and gains had been delineated in the tumours using FISH and SNP arrays. We have identified genes significantly altered by 7 recurrent alterations: 1p, 3p, 4p, 10q and 11q loss, 2p and 17q gain, and genes co-amplified and over-expressed as a result of MYCN amplification. Subsequently, correlation of microarray data with survival and expression within rodent neuroblastomas were used to identify genes likely to be involved in the disease progression, and identified a significant excess of differentially expressed genes which correlated with survival within the minimally altered regions on 17q and 4p Identifying genes whose expression is consistently altered by chromosomal gains or losses is an important step in defining genes of biological relevance in a wide variety of tumour types. However, additional criteria are needed to discriminate further among the large number of candidate genes identified. This is particularly true for neuroblastoma, where multiple genomic copy number changes of proven prognostic value exist. We have used Affymetrix microarrays and a combination of fluorescent in-situ hybridisation and single nucleotide polymorphism (SNP) microarrays to establish expression profiles and delineate copy number alterations in 30 primary neuroblastomas. Correlation of microarray data with patient survival and analysis of expression within rodent neuroblastoma cell lines were then used to further define genes likely to be involved in the disease process. Using this approach we identify >1000 genes within 8 recurrent genomic alterations (loss of 1p, 3p, 4p, 10q and 11q, 2p gain, 17q gain, and the MYCN amplicon) whose expression is consistently altered by copy number change. Of these, 84 correlate with patient survival, with the minimal regions of 17q gain and 4p loss being significantly enriched for such genes. Orthologues of all but one of these genes on 17q are overexpressed in rodent neuroblastoma cell lines. A significant excess of SNPs whose copy number correlates with survival is also observed on proximal 4p in stage 4 tumours, and we find that deletion of 4p is associated with improved outcome in an extended cohort of tumours. These results define the major impact of genomic copy number alterations upon transcription within neuroblastoma, and highlight genes on distal 17q and proximal 4p for downstream analyses. They also suggest that integration of discriminators such as survival and comparative gene expression with microarray data may be useful in the identification of critical genes within regions of loss or gain in many human cancers. Keywords: Disease State Analysis

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