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High-Resolution Analysis of Chromosomal Breakpoints and Genomic Instability Identifies PTPRD as a Candidate Tumor Suppressor Gene in Neuroblastoma

¹ Children's Cancer Research Institute and Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas; ² Division of Oncology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ³ The Tumor Bank, Children's Hospital at Westmead, Sydney, New South Wales, Australia; and Departments of ⁴ Pathology and ⁵ Oncology, Our Lady's Hospital for Sick Children, Dublin, Ireland

Requests for reprints: Raymond L. Stallings, Children's Cancer Research Institute and Department of Pediatrics, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Drive, Mail Code 7784, San Antonio, TX 78229-3900. Phone: 210-562-9028; Fax: 210-562-9014; E-mail: Stallings{at}uthscsa.edu.

Although neuroblastoma is characterized by numerous recurrent, large-scale chromosomal imbalances, the genes targeted by such imbalances have remained elusive. We have applied whole-genome oligonucleotide array comparative genomic hybridization (median probe spacing 6 kb) to 56 neuroblastoma tumors and cell lines to identify genes involved with disease pathogenesis. This set of tumors was selected for having either 11q loss or MYCN amplification, abnormalities that define the two most common genetic subtypes of metastatic neuroblastoma. Our analyses have permitted us to map large-scale chromosomal imbalances and high-level amplifications at exon-level resolution and to identify novel microdeletions and duplications. Chromosomal breakpoints (n = 467) generating imbalances >2 Mb were mapped to intervals ranging between 6 and 50 kb in size, providing substantial information on each abnormality. For example, breakpoints leading to large-scale hemizygous loss of chromosome 11q were highly clustered and preferentially associated with segmental duplications. High-level amplifications of MYCN were extremely complex, often resulting in a series of discontinuous regions of amplification. Imbalances (n = 540) <2 Mb long were also detected. Although the majority (78%) of these imbalances mapped to segmentally duplicated regions and primarily reflect constitutional copy number polymorphisms, many subtle imbalances were detected that are likely somatically acquired alterations and include genes involved with tumorigenesis, apoptosis, or neural cell differentiation. The most frequent microdeletion involved the PTPRD locus, indicating a possible tumor suppressor function for this gene. (Cancer Res 2006; 66(7): 3673-80)

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