The long term focus of this laboratory is to identify and characterize genes responsible for regulating growth and differentiation in human neuroblastomas. We have identified a specific deletion of the short arm of chromosome 1 (at or distal to 1p32). This is the probable site of a putative neuroblastoma (Nb) suppressor gene, the loss of which predisposes the cell to malignant transformation. We are taking a molecular approach to identify and characterized the putative Nb gene. Restriction fragment length polymporphism (RFLP) and loss of heterozygosity (LOH) will be used to localize the region that is consistently deleted. Then we will use pulsed-field gel electrophoresis (PFGE) and yeast artificial chromosome (YAC) vector technology to clone the region of interest. Candidate gene(s) from this region that are consistently deleted or rearranged in neuroblastomas will be cloned and their patterns of expression characterized. Finally, we will determine if the candidate gene(s) can induce differentiation or suppress tumorigenicity by transfection into, neuroblastoma cells in vitro, or injection of tansfected cells in nude mice. We have demonstrated that the oncogene N-myc is amplified in about a third of primary neuroblastomas. We also have recent evidence that 20-25% of tumors with a single copy of N-myc can overexpress this gene at the mRNA and/or protein level. We plan to analyze human neuroblastomas for N-myc activation at the DNA, RNA or protein level. We will determine if some tumors without N-myc amplification have activation of this gene by more precise analysis of the amount and size of message, as well as the amount, size and pattern of protein expression. N-myc amplification is associated with advanced stages of disease, rapid tumor progression and a poor prognosis in neuroblastoma patients. In addition, deletions of the short arm of chromosome 1 also appear to confer a poor prognosis, independent of N-myc amplification. We will determine the contribution of N-myc activation and chromosome 1p deletions as prognostic markers in this disease.

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National Cancer Institute (NCI)
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Mammalian Genetics Study Section (MGN)
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Washington University
Schools of Medicine
Saint Louis
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Naraparaju, Koumudi; Kolla, Venkatadri; Zhuang, Tiangang et al. (2016) Role of microRNAs in epigenetic silencing of the CHD5 tumor suppressor gene in neuroblastomas. Oncotarget 7:15977-85
Thompson, Daria; Vo, Kieuhoa T; London, Wendy B et al. (2016) Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project. Cancer 122:935-45
Higashi, Mayumi; Kolla, Venkatadri; Iyer, Radhika et al. (2015) Retinoic acid-induced CHD5 upregulation and neuronal differentiation of neuroblastoma. Mol Cancer 14:150
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Schleiermacher, G; Mosseri, V; London, W B et al. (2012) Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer 107:1418-22

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