Genome-Wide Association Study of Neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that most commonly affects young children and is often lethal. The etiology of this embryonal cancer is not known. We have performed a whole genome scan for association of neuroblastoma with SNP genotypes and copy number variation to discover predisposition loci. We therefore initiated a genome-wide association study (GWAS) in 2007 focused on neuroblastoma patients identified through the Children's Oncology Group (COG; 238 member institutions). Control patients for this study are children cared for at the Children's Hospital of Philadelphia (CHOP) without a diagnosis of cancer. The study was designed to collect up to 5000 neuroblastoma cases and 10,000 controls and is powered to detect common susceptibility variants in Caucasian and African American patients. Whole genome genotyping is being performed on the Illumina HH550 SNP array.]]>
A Genome-Wide Association Study Identifies A Susceptibility Locus to Clinically Aggressive Neuroblastoma at 6p22Supplementary InformationSupplementary InformationThis resulted in 464,934 SNPs being utilized in the subsequent analyses. In addition, 33 samples had genotype yields < 90% and were removed (23 cases and 10 controls). Finally, since the case samples were accrued nation-wide, while the control set was recruited locally in Philadelphia, we performed principal components analyses to identify outlier samples in order to reduce the effects of population stratification. This approach removed 379 samples (196 cases and 183 controls), leaving 1,032 cases and 2,043 controls for our discovery case series with self-reported ethnicity of Caucasian.Of the 1,032 patients included in the discovery case series, clinical and biological covariate data obtained at diagnosis was available for most. A total of 883 patients (85.6%) had complete outcome data available with a median follow-up interval of 4.02 years for patients without an event.
]]>Genome-wide genotyping data was generated on the Illumina HumanHap550 Beadchip for 1,627 neuroblastoma patients and 3,254 genetically matched disease-free controls. All samples passed our pre-specified quality control measures, and 1,529 neuroblastoma cases have complete clinical phenotype data, as provided by the COG. To correct for potential effects of population structure, genome-wide IBS estimates for all pair-wise comparisons among all case subjects and control subjects were analyzed to identify two matched controls for each case. SNPs were excluded from further analysis if they showed: 1) deviation from Hardy Weinberg equilibrium with P < 0.001; 2) individual SNP genotype yield < 95%; 3) minor allele frequency (MAF) < 5%; or 4) were not present on both version 1 (V1) and version 3 (V3). This resulted in 480,279 SNPs being utilized in the subsequent analyses.Cases: Diagnosis of neuroblastoma and informed consent on a COG Biology Protocol for banking of biological samples with at least 1.0 µg of high quality constitutional DNA available. Controls: No diagnosis of cancer and informed consent for genome-wide genotyping obtained at CHOP.]]>
As of December 6, 2010 a total of 3758 neuroblastoma cases have been genotyped. Of these, a total of 1662 neuroblastoma cases are self-identified as Caucasian and included in the version 2 data release.]]>