Abstract A46: Genomic ancestry is associated with risk group and survival in children with neuroblastoma
Authors: Pinto Navin R. , Gamazon Eric R. , Konkashbaev Anuar , Cox Nancy J. , Dolan M. Eileen , Diskin Sharon J. , London Wendy B. , Devoto Marcella , Maris John M. , Cohn Susan L. 
Published: June 2012

Background: In a cohort of 3539 children with neuroblastoma, we have previously reported that self-reported black race is significantly associated with high-risk disease (p &lt; 0.001) and late relapse or death (p = 0.04) [1]. To investigate if the component of genomic variation that co-segregates with African ancestry is associated with risk group and survival in neuroblastoma, we interrogated genome-wide SNP genotypes against those phenotypes in 3180 neuroblastoma patients.

Methods: Genome-wide SNP genotypes from 3404 children with neuroblastoma were obtained from 3 Illumina platforms: HumanHap550 v1, HumanHap550 v3 and HumanQuad 610. Quality filtering removed 17 patients who were genotyped twice, 15 patients with ambiguous sex, 72 patients with some degree of relatedness and 120 patients with poor genotype call rates (defined as &gt;5% total SNPs interrogated without a genotype call). Genotypes from the remaining 3180 patients were included in the analysis. Using ancestral reference populations from the International HapMap Project (Caucasian - CEU, African - YRI and Asian – CHB/JPT) and the EIGENSTRAT method, a principal components analysis for each of the three genotyping platforms was performed and an ancestry map of all patients was created. Pricincipal Component 2 (PC2), which separated black neuroblastoma patients and the YRI HapMap samples from all other ethnic groups, was used as a continuous variable for linear regressions with both event-free survival and risk group.

Results: PC2 was correlated with event-free survival in patients with intermediate- and high-risk neuroblastoma (those patients that receive chemotherapy), showing that degree of African ancestry was associated poorer outcome (p = 0.047). Furthermore, linear regression of PC2 versus risk group classification showed that degree of African ancestry was associated with high-risk disease (p = 0.05).

Discussion: Here we show that the component of genomic variation that co-segregates with African ancestry is associated with high-risk disease and a poorer event-free survival. We hypothesize that germline genetic variants associated with both high-risk neuroblastoma and event-free survival after chemotherapy will have different allelic frequencies in Caucasian and African populations and that patients of African ancestry may also harbor unique genetic variants associated with high-risk disease and event-free survival not found in Caucasian patients. Efforts to identify these genetic variants are underway. These results underscore the need to perform association studies from a variety of ancestries, as each group may yield novel associations.

Reference:

1. Henderson, T. O., Bhatia, S., Pinto, N., London, W. B., McGrady, P., Crotty, C., Sun, C. L. & Cohn, S. L. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children's Oncology Group study. J Clin Oncol, 2011, 29, 76–82.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A46.