Genome-wide association study meta-analysis identifies susceptibility loci informing Ewing sarcoma etiology and potential mechanisms of risk.

Ewing sarcoma (EwS) is a rare, aggressive pediatric malignancy driven by FET::ETS family fusions (EWSR1::FLI1 in >85% of cases) with no established environmental risk factors. To investigate germline predisposition, we analyzed 2,014 EwS cases and 10,525 cancer-free controls in a two-stage analysis that combined an international genome-wide association study and a case parent trio study. The combined meta-analysis identified 18 variants at 14 susceptibility loci (9 novel, 5 replicated) with moderate effect sizes (odds ratios≥1.25). Integrative analyses of the EwS loci revealed enrichment of expanded GGAA microsatellites, with evidence for binding of the EWSR1::FLI1 chimeric oncogenic activator. EWSR1::ETS knockdown in EwS cell lines resulted in dysregulated genes at susceptibility loci related to skeletal/muscle development, RNA binding/processing, and chromatin regulation. Our findings provide insights into the inherited component of EwS, highlighting a genetic architecture in which common germline variations with moderate effects interact with somatic EWSR1::FLI1 fusions to promote sarcomagenesis by dysregulating local genes.