Genome-wide association study meta-analysis identifies susceptibility loci informing Ewing sarcoma etiology and potential mechanisms of risk
Hubbard, A. K.; Neyret-Kahn, H.; Müller-Nurasiyd, M.; Löw, D.; Strauch, K.; Lee, O. W.; Raduski, A. R.; Yang, T.; Zhou, W.; Stratton, E.; Jay, O.; Grossetete, S.; Song, A. J.; Dutta, D.; Hutchinson, A. A.; Hicks, B. D.; Manning, M.; Liu, J.; Boyce, C.; Hartmann, W.; Dirksen, U.; Kulozik, A. E.; Metzler, M.; Krumbholz, M.; Teumer, A.; Völzke, H.; Völker, U.; Schiffman, J. D.; Khan, J.; Hudson, M. M.; Ness, K. K.; Wang, Z.; Janeway, K. A.; Lupo, P. J.; Spector, L. G.; Huang, W.-Y.; Moore, S. C.; Chanock, S. J.; Grünewald, T. G. P.; Delattre, O.; Machiela, M. J.
Show 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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