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 <i>FET</i>::<i>ETS</i> family fusions (<i>EWSR1</i>::<i>FLI1</i> 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. <i>EWSR1::ETS</i> 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 <i>EWSR1</i>::<i>FLI1</i> fusions to promote sarcomagenesis by dysregulating local genes.

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Publication Details

Journal
medRxiv
Published
2026-02-09
DOI
https://doi.org/10.64898/2026.02.06.26345779
Primary Topic
Sarcoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Aubrey K. Hubbard, Manuela Krumbholz, Joshua David Schiffman, Tianzhong Yang et al.
medRxiv
Sarcoma Diagnosis and Treatment
article

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

Aubrey K. Hubbard, Manuela Krumbholz, Joshua David Schiffman, Tianzhong Yang, Diptavo Dutta, Kirsten K. Ness, Sandrine Grossetête, Hélène Neyret‐Kahn, Andrew R. Raduski, Wladick Hartmann, O Delattre, Carrie Boyce, Weiyin Zhou, Dirksen Uta, Markus Metzler, Michelle Manning, Uwe Voelker, Philip J. Lupo, Wen-Yi Huang, Konstantin Strauch, Jia Liu, Elliot Stratton, Martina Müller-Nurasiyd, Andreas E. Kulozik, Katherine A. Janeway, Olivia W. Lee, Amy A. Hutchinson, Stephen J. Chanock, Zhaoming Wang, Orson Jay, Henry Völzke, Logan G. Spector, Melissa M Hudson, Thomas G.P. Grünewald, Andrew J. Song, Steven C. Moore, Javed Khan, Dominik Löw
article en

Abstract

Ewing sarcoma (EwS) is a rare, aggressive pediatric malignancy driven by <i>FET</i>::<i>ETS</i> family fusions (<i>EWSR1</i>::<i>FLI1</i> 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. <i>EWSR1::ETS</i> 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 <i>EWSR1</i>::<i>FLI1</i> fusions to promote sarcomagenesis by dysregulating local genes.

medRxiv
University of Minnesota (US), St. Jude Children's Research Hospital (US), Westat (United States) (US), Inserm (FR), German Cancer Research Center (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Johannes Gutenberg University Mainz (DE), University of Utah (US), Heidelberg University (DE), Université Paris Sciences et Lettres (FR), Universitätsmedizin Greifswald (DE), Huntsman Cancer Institute (US), University Hospital Heidelberg (DE), Helmholtz Zentrum München (DE), Universitätsklinikum Erlangen (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), University Hospital Münster (DE), West Cancer Center (US), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), German Centre for Cardiovascular Research (DE), Frederick National Laboratory for Cancer Research (US), University of Minnesota Medical Center (US), National Cancer Institute (US), Children's Healthcare of Atlanta (US), Center for Cancer Research (US), West German Heart and Vascular Center Essen (DE), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), Division of Cancer Epidemiology and Genetics, Deutsches Konsortium für Translationale Krebsforschung (DE), Ludwig-Maximilians-Universität München (DE)
U.S. Department of Health and Human Services, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Cancer Institute
Openalex Percentile: Top 62%
Sarcoma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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