Abstract
Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10−20; odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10−17; OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10−9; OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.
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Acknowledgements
We thank E. Thomas from Synergie Lyon Cancer for advice on statistical methods. We thank the staff from the Integragen Company for excellent service and V. Chene for outstanding assistance. We thank the following clinicians for providing samples used in this work: C. Alenda, F. Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D. Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles, V. Gendemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L. Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O. Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard, G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G. Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A. Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet, M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre, M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L. Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. We also thank the European Prospective Investigation into Cancer and Nutrition (EPIC) Steering Committee (E. Riboli, Principal Investigator) for access to genotype data from the EPIC cohorts and the Children's Cancer and Leukaemia Group (CCLG) Tissue Bank (funded by Cancer Research UK) for access to specimens. This work was supported by grants from the Institut Curie, the Inserm, the Ligue Nationale Contre le Cancer (Equipe labellisée, Carte d'Identité des Tumeurs program and Recherche Epidémiologique 2009 program), the Région Ile de France, the Institut National du Cancer (2008-044, 0627 and ZP09-027-EPI), the Synergie Lyon Cancer foundation, the KCK and European Embryonal Tumor (EET) pipeline programs, the Société Française des Cancers de l'Enfant, the Spanish Ministry of Science and Technology (SAF2009-10158), the Fundación de la Asociación Española Contra el Cáncer, the Fundación María Francisca de Roviralta and the Sociedad Española de Hematología y Oncología Pediátricas and the following associations: Courir pour Mathieu, Dans les pas du Géant, Olivier Chape, Les Bagouzamanon, Enfants et Santé and les Amis de Claire.
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S.P.-V. contributed to the design of the study and wrote all documents required for ethical issues as well as information for patients and referent oncologists. A.S.V., D.C. and G.T. analyzed the GWAS data. G.P., S.B. and S.R. prepared all samples and performed genotyping of replication cohorts. F.T. and C.L. analyzed transcriptomic data and performed genotype-expression correlation analyses. H.K., O.O., U.K., A.G.-N., P.P., J.A., A.P.-G., B.B.d.P., F.D., J.M. and O.D. recruited Ewing sarcoma patients and participated in the diagnostic evaluations. E.L. collected informed consents. K.L. contributed the conditional Ewing cell model and performed the in vivo experiments. C.D., P.F. and F.C.-C. contributed French, E3N and EPIC controls. S.P.V., G.T., S.J.C., D.G.C. and O.D. contributed to the overall design of the study. All coauthors contributed to manuscript writing.
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Postel-Vinay, S., Véron, A., Tirode, F. et al. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet 44, 323–327 (2012). https://doi.org/10.1038/ng.1085
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DOI: https://doi.org/10.1038/ng.1085
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