Neuroblastomas are characterized genetically by deletion of the distal short arm of chromosome 1 (1p36), and amplification of the N-myc proto- oncogene. Indeed, these two features characterize a very aggressive subset of neuroblastomas. We have localized the region of consistent deletion in these tumors to 1p36.1. There is recent evidence that deletion or rearrangement of this locus may be responsible for genetic predisposition to develop neuroblastoma. We hypothesize that a neuroblastoma suppressor gene (NB1) is located in this region. Deletion or mutation of this gene constitutionally may predispose to development of neuroblastoma, and homozygous deletion or inactivation in a single neuroblast may be an important step in the development of this disease. We plan to clone the region of consistent deletion (estimated to be <2 Mb) in YACS and identify expressed sequences in the region. Then we will determine which gene is consistently deleted or rearranged in neuroblastomas in order to identify and characterize the NB1 suppressor gene. In addition, we will determine the prevalence of mutations of this gene in neuroblastomas, as well as in constitutional DNA of familial cases. N-myc amplification is highly associated with advanced stages of disease and rapid tumor progression. N-myc does not appear to be activated frequently by other mechanisms, and no other oncogenes have been shown to be amplified or otherwise activated in these tumors. Recently we have cloned and mapped an entire N-myc amplicon from a neuroblastoma cell line. The amplicon was 1.2 Mb and had a circular, head-to-tail organization. We propose to develop a high-resolution cosmid map of the core domain flanking the N-myc gene that is consistently amplified in neuroblastomas to identify any other expressed sequences that might contribute to the malignant phenotype associated with N-myc amplification (rapid growth, invasion, metastasis, resistance to treatment). Also, we will identify and characterize sites of recombination that have led to or resulted from the amplification process. Together, these findings should provide substantial insights into the mechanisms that result in this clinically important rearrangement in neuroblastomas, and possibly other tumors with oncogene amplification. Finally, some tumor samples cannot have N-myc copy number determined because they are too small, degraded or fixed. We are developing a PCR- based technique to identify N-myc amplification in these cases. In addition, we are developing a fluorescence in-situ hybridization (FISH) approach to analyze mixed samples of normal and tumor cells. Together these techniques will be more rapid and efficient. They will be extended to all samples studied, and they should allow us to address issues of tumor heterogeneity and progression within and between primary and metastatic lesions.
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