Deletion or loss of heterozygosity (LOH) for the short arm of chromosome 1 (1p) is the most characteristic genetic change in neuroblastomas. We have mapped the region of consistent loss to about 800 kb on 1p36.3. We have identified 10 genes so far that map to this region. We hypothesize that a tumor suppressor gene in this region is homozygously inactivated during the pathogenesis of aggressive neuroblastomas. We will identify all the expressed genes from the SRO and identify the candidate TSG. We have already identified 10 genes from approximately 800 kb SRO, but a portion remains unsequenced. We will develop a completely sequenced contig of the entire SRO on 1p36.3. We will analyze a panel of neuroblastoma cell lines and tumors for homozygous deletion, rearrangement or inactivating mutations of all candidate TSGs. We will completely characterize strong candidate(s) for the TSG at the DNA, RNA and protein levels. We will determine a complete sequence annotation of the gene, intragenic regions, and flanking intergenic regions, and identify the important regulatory domains. We will examine the mRNA size and expression and determine if there are splice variants by Northern analysis and RT-PCR. We will analyze the protein for cellular and subcellular localization as well as functional experiments. We will fully characterize the tumor suppressive effects of the TSG and determine the functional domains responsible for suppressing tumorigenicity. We will transfect the TSG cDNA into neuroblastoma cell lines with and without 1p36 deletions, and we will determine if this alters cell proliferation, differentiation or survival, as well as clonigenicity and tumorigenicity. We will also determine the effect of transfection on the expression of other genes critical to neuroblastoma biology (e.g., MYCN TrkA, TrkB) by RT-PCR experiments and by microarray analyses. We will knock out the TSG gene in mice to determine if they develop neural or other tumors. We will knock out the TSG gene in embryonic stem (ES) cells and develop mice heterozygous for this gene. We will cross these mice to develop homozygous knockouts, if they are viable. We will analyze heterozygous and homozygous knockouts for tumor predisposition and for developmental defects. If these mice have severe defects, we will use a Cre-LoxP system and the tyrosine hydroxylase promoter to selectively knock out this gene in sympathetic nerve cells. The successful completion of these studies should provide critical insights into the molecular pathogenesis of neuroblastoma, and it may provide a novel target on which future therapeutic efforts could be focused. Finally, deletions of 1p36 are found in many other cancers, so the identification of this TSG could have broad implications for many forms of neoplasia.
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| 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 |
| Kolla, Venkatadri; Naraparaju, Koumudi; Zhuang, Tiangang et al. (2015) The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex. Biochem J 468:345-52 |
| Brodeur, Garrett M; Bagatell, Rochelle (2014) Mechanisms of neuroblastoma regression. Nat Rev Clin Oncol 11:704-13 |
| Zhuang, Tiangang; Hess, Rex A; Kolla, Venkatadri et al. (2014) CHD5 is required for spermiogenesis and chromatin condensation. Mech Dev 131:35-46 |
| Kolla, Venkatadri; Zhuang, Tiangang; Higashi, Mayumi et al. (2014) Role of CHD5 in human cancers: 10 years later. Cancer Res 74:652-8 |
| Brodeur, Garrett M; Iyer, Radhika; Croucher, Jamie L et al. (2014) Therapeutic targets for neuroblastomas. Expert Opin Ther Targets 18:277-92 |
| Garcia, Idoia; Mayol, Gemma; Rios, Jose et al. (2012) A three-gene expression signature model for risk stratification of patients with neuroblastoma. Clin Cancer Res 18:2012-23 |
| 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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