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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 7; pp. 3673 - 3680
• Main Authors: Stallings, Raymond L., Nair, Prakash, Maris, John M., Catchpoole, Daniel, McDermott, Michael, O'Meara, Anne, Breatnach, Fin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2006
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Chromosome Aberrations; Chromosome Breakage; Gene Amplification; Gene Deletion; Genes, Tumor Suppressor; Genomic Instability; Humans; Medical sciences; N-Myc Proto-Oncogene Protein; Neuroblastoma - genetics; Neurology; Nuclear Proteins - genetics; Oligonucleotide Array Sequence Analysis; Oncogene Proteins - genetics; Pharmacology. Drug treatments; Protein Tyrosine Phosphatases - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Tumors; Tumors of the nervous system. Phacomatoses; Breakpoint; Nervous system diseases; High resolution; Genomics; Chromosome; Malignant tumor; Neuroblastoma; Genetics; Instability; Candidate gene; Autonomic neuropathy; Genome; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-4154

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)