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

Aubrey K. Hubbard; Hélène Neyret‐Kahn; Martina Müller‐Nurasyid; Dominik Löw; Konstantin Strauch; Olivia W. Lee; Andrew R. Raduski; Tianzhong Yang; Weiyin Zhou; Elliot Stratton; Orson Jay; Sandrine Grossetête; Andrew J. Song; Diptavo Dutta; Amy A. Hutchinson; Belynda D. Hicks; Michelle Manning; Jia Liu; Carrie Boyce; Wolfgang Hartmann; Uta Dirksen; Andreas E. Kulozik; Markus Metzler; Manuela Krumbholz; Alexander Teumer; Henry Völzke; Uwe Völker; Joshua David Schiffman; Javed Mohammed Khan; Melissa Maria Hudson

doi:10.64898/2026.02.06.26345779

Genetic & Genomic MedicinemedRxivFeb 9, 2026

Preprint

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

Aubrey K. Hubbard iD, Hélène Neyret‐Kahn iD, Martina Müller‐Nurasyid iD, Dominik Löw, Konstantin Strauch iD, Olivia W. Lee iD, Andrew R. Raduski iD, Tianzhong Yang iD, Weiyin Zhou iD, Elliot Stratton, Orson Jay iD, Sandrine Grossetête iD, Andrew J. Song, Diptavo Dutta iD, Amy A. Hutchinson, Belynda D. Hicks iD, Michelle Manning, Jia Liu iD, Carrie Boyce, Wolfgang Hartmann iD, Uta Dirksen iD, Andreas E. Kulozik iD, Markus Metzler iD, Manuela Krumbholz iD, Alexander Teumer iD, , Mitchell J. Machiela iD

Abstract

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{square}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.

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