Neuroblastoma is a common and lethal pediatric malignancy, but the genetic events that initiate tumorigenesis are largely unknown. We hypothesize that neuroblastoma is a complex disease that results from the interaction of mutant alleles with relatively low to moderate effect on tumor initiation. We now plan to discover neuroblastoma susceptibility genes by performing a definitive whole genome association study in ~5000 neuroblastoma patients from the Children's Oncology Group using a high-density single nucleotide polymorphism (SNP)-based replicative study design. We will compare our cases to two control sets: both pediatric non-cancer patients accessioned from our institution, and adult control subjects matched by region across the country. We propose four Specific Aims: First, we will perform a whole genome scan for association of neuroblastoma with SNPs and SNP haplotypes in 2000 neuroblastoma cases and an equal number of matched controls (both children and adults in parallel analyses). Over 550K SNPs will be surveyed, and we anticipate identifying 25,000-50,000 candidate SNPs for further evaluation. Second, we will identify true disease-associated SNP alleles using a customized genotyping platform enriched for haplotype analyses in an independent set of 2000 cases and again two large control sets. By leveraging the HapMap project and controlling for population substructure, we anticipate that this Aim will identify 10-20 genomic regions as candidates for association with neuroblastoma. Third, we will validate at least 5-10 disease-associated regions in a final independent sample set of 675 cases and two sets of ~675 controls. We will again use a gene-centric haplotyping approach to determine true disease associated variants and candidate genes. Finally, we will definitively identify neuroblastoma predisposition genes through direct resequencing of candidate regions in a carefully selected set of 100 neuroblastoma cases and 100 controls, each equally proportioned between the presence or absence of the SNP/haplotype variant associated with neuroblastoma. Our large panel of tumor reagents and genomics databases will be leveraged to assist in region prioritization and identification of candidate genes for further analysis. The successful completion of this project will provide insight into the underlying genetic etiology of neuroblastoma tumorigenesis. We ultimately plan to translate the discovered neuroblastoma predisposition genes into a prognostic biomarkers and/or a target for new treatment approaches. In addition, the data generated here will rapidly be made available to any academically qualified petitioner interested in associating the SNP genotypes with the robust phenotypic information that we have captured including clinical characteristics, tumor biology, response to therapy and disease outcome. Finally, this project should also help catalyze the field of childhood cancer applied genomics research, and if past lessons from other childhood cancers are repeated, it will identify genes that are fundamentally important in human cancer in general.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124709-05
Application #
8213485
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Zanetti, Krista A
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-02-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$602,864
Indirect Cost
$217,646
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Capasso, Mario; Diskin, Sharon; Cimmino, Flora et al. (2014) Common genetic variants in NEFL influence gene expression and neuroblastoma risk. Cancer Res 74:6913-24
Diskin, Sharon J; Capasso, Mario; Diamond, Maura et al. (2014) Rare variants in TP53 and susceptibility to neuroblastoma. J Natl Cancer Inst 106:dju047
Pugh, Trevor J; Morozova, Olena; Attiyeh, Edward F et al. (2013) The genetic landscape of high-risk neuroblastoma. Nat Genet 45:279-84
Bosse, Kristopher R; Diskin, Sharon J; Cole, Kristina A et al. (2012) Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res 72:2068-78
Latorre, Valeria; Diskin, Sharon J; Diamond, Maura A et al. (2012) Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiol Biomarkers Prev 21:658-63
Nguyen, Le B; Diskin, Sharon J; Capasso, Mario et al. (2011) Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci. PLoS Genet 7:e1002026
Wang, Kai; Diskin, Sharon J; Zhang, Haitao et al. (2011) Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 469:216-20
Devoto, Marcella; Specchia, Claudia; Laudenslager, Marci et al. (2011) Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma. Hum Hered 71:135-9
Li, Hongzhe; Wei, Zhi; Maris, John (2010) A hidden Markov random field model for genome-wide association studies. Biostatistics 11:139-50
Mosse, Yael P; Wood, Andrew; Maris, John M (2009) Inhibition of ALK signaling for cancer therapy. Clin Cancer Res 15:5609-14

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