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

Hubbard AK, Neyret-Kahn H, Müller-Nurasiyd M, Löw D, Strauch K, Lee OW, Raduski AR, Yang T, Zhou W, Stratton EW, Jay O, Grossetête S, Song AJ, Dutta D, Hutchinson AA, Hicks BD, Manning M, Liu J, Boyce C, Hartmann W, Dirksen U, Kulozik AE, Metzler M, Krumbholz M, Teumer A, Völzke H, Völker U, Schiffman JD, Khan J, Hudson MM, Ness KK, Wang Z, Janeway KA, Lupo PJ, Spector LG, Huang WY, Moore SC, Chanock SJ, Grünewald TGP, Delattre O, Machiela MJ. Genome-wide association study meta-analysis identifies susceptibility loci informing Ewing sarcoma etiology and potential mechanisms of risk. medRxiv. 2026 Feb 9;. doi: 10.64898/2026.02.06.26345779. PubMed PMID: 41728338; PubMed Central PMCID: PMC12919121.

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.