Neuroblastoma is a common pediatric malignancy that occasionally may be inherited as an autosomal dominant trait with high penetrance. We hypothesize that familial predisposition to neuroblastoma occurs due to a germline mutation in one allele of a tumor suppressor gene and that tumors arise following a somatically acquired inactivating mutation of the other allele. Furthermore, we predict that many sporadic neuroblastomas occur following biallelic inactivation of the same tumor suppressor gene. We therefore aim to localize, clone and characterize the neuroblastoma predisposition gene (FNB1). First, we will use a multifaceted approach to localize the gene. We have previously excluded linkage to twelve candidate loci. We now propose a a genome-wide search for linkage using traditional genotyping methods. In addition, we will use comparative genomic hybridization, representational differential analysis and genomic mismatch scanning as alternative methods designed to complement and confirm the results of the genome-wide linkage approach. Second, once FNB1 is localized, we will develop a clinical assay to determine genetic susceptibility to develop neuroblastoma. This will initially be applicable only to families with two or more affected individuals, but we plan to develop mutational-based assays following gene isolation. Finally, we will clone and characterize FNB1. Localization of the gene will be refined by using a high density panel of polymorphic markers that will identify informative recombinant haplotypes and tumors with loss of heterozygosity. These data will define the minimal critical region for the location of FNB1. We will then pursue either candidate gene/transcript analysis or more conventional positional cloning strategies depending on the maturity of the FNB1 locus physical map and known sequence. This phase of the project will be aided by our ongoing positional cloning efforts at chromosome bands 1p36 and 11q14-24. Once FNB1 is cloned, we will characterize the genomic structure, expression pattern and predicted protein structure/function. We will then determine the mechanism of both germline and somatic inactivation of FNB1 in both familial and nonfamilial neuroblastomas, as well as selected other pediatric and adult neoplasms. The successful completion of these studies should have considerable impact on the diagnosis and management of all children with neuroblastoma, a malignancy for which no causal genetic alterations have been identified.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078545-05
Application #
6513291
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Okano, Paul
Project Start
1998-08-14
Project End
2003-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
5
Fiscal Year
2002
Total Cost
$254,777
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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