Abstract
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.
Highlights
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion
Our analysis was restricted to individuals of >80% estimated European ancestry based on a principal component analysis of population substructure
While no statistically significant Expression quantitative trait locus (eQTL) was observed between this locus and nearby genes (Table 2), the nearest transcript, NKX2-2, is of high interest; NKX2-2, NK2 homeobox 2, encodes a homeobox domain protein that is a likely nuclear transcription factor, which is overexpressed in the presence of EWSR1-FLI1 fusions in EWS tumors[27,28]
Summary
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. We investigate EWS associations across 6,876,682 SNPs (genotyped plus high quality imputed) with an overall meta-analysis lambda value of 1.035 (Supplementary Figure 1).
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