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Integrative Genomics Identifies Distinct Molecular Classes of Neuroblastoma and Shows That Multiple Genes Are Targeted by Regional Alterations in DNA Copy Number

Divisions of ¹ Oncology and ² Biostatistics, Children's Hospital of Philadelphia and Department of Pediatrics and ³ Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine; ⁴ Center for Bioinformatics, University of Pennsylvania, Philadelphia, Pennsylvania; ⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; ⁶ Memorial Sloan-Kettering Cancer Center, New York, New York; ⁷ Department of Statistics, University of Florida and Children's Oncology Group, Gainesville, Florida; and ⁸ University of California at San Francisco School of Medicine, San Francisco, California

Requests for reprints: John M. Maris, Division of Oncology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399. Phone: 215-590-2821; Fax: 215-590-3770; E-mail: maris{at}chop.edu.

Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1p36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma transcriptome is a sensitive marker of underlying tumor biology and that chromosomal deletion events in this cancer likely target multiple genes through alteration in mRNA dosage. Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies. (Cancer Res 2006; 66(12): 6050-62)

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