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Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Nature Genetics volume 44, pages 323–327 (2012)Cite this article

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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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Figure 1: Manhattan plots for the GWAS of Ewing sarcoma cases.
Figure 2: Association and linkage disequilibrium at loci selected for replication.
Figure 3: Expression of candidate genes in Ewing sarcomas.

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References

  1. Delattre, O. et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359, 162–165 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Aurias, A. et al. Chromosome translocation in Ewing's sarcoma. N. Engl. J. Med. 309, 496–498 (1983).

    Google Scholar 

  3. Toomey, E.C., Schiffman, J.D. & Lessnick, S.L. Recent advances in the molecular pathogenesis of Ewing's sarcoma. Oncogene 29, 4504–4516 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Linden, G. & Dunn, J.E. Ewing's sarcoma in Negroes. Lancet 295, 1171 (1970).

    Article  Google Scholar 

  5. Jensen, R.D. & Drake, R.M. Rarity of Ewing's tumour in Negroes. Lancet 295, 777 (1970).

    Article  Google Scholar 

  6. Li, F.P. et al. Rarity of Ewing's sarcoma in China. Lancet 315, 1255 (1980).

    Article  Google Scholar 

  7. Jawad, M.U. et al. Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973–2005. Cancer 115, 3526–3536 (2009).

    Article  PubMed  Google Scholar 

  8. Worch, J. et al. Racial differences in the incidence of mesenchymal tumors associated with EWSR1 translocation. Cancer Epidemiol. Biomarkers Prev. 20, 449–453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hutter, R.V., Francis, K.C. & Foote, F.W. Jr. Ewing's sarcoma in siblings: report of the second known occurrence. Am. J. Surg. 107, 598–603 (1964).

    Article  CAS  PubMed  Google Scholar 

  10. Joyce, M.J. et al. Ewing's sarcoma in female siblings. A clinical report and review of the literature. Cancer 53, 1959–1962 (1984).

    Article  CAS  PubMed  Google Scholar 

  11. Fraley, C. & Raftery, A.E. MCLUST version 3 for R: normal mixture modeling and model-based clustering (technical report no. 504) (Department of Statistics, University of Washington, Seattle, Washington, 2006).

  12. Brisset, S. et al. CGH analysis of secondary genetic changes in Ewing tumors: correlation with metastatic disease in a series of 43 cases. Cancer Genet. Cytogenet. 130, 57–61 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Savola, S. et al. Combined use of expression and CGH arrays pinpoints novel candidate genes in Ewing sarcoma family of tumors. BMC Cancer 9, 17 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Clavel-Chapelon, F. et al. E3N, a French cohort study on cancer risk factors. E3N Group. Etude Epidémiologique auprès de femmes de l'Education Nationale. Eur. J. Cancer Prev. 6, 473–478 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Barmada, S.J. & Finkbeiner, S. Pathogenic TARDBP mutations in amyotrophic lateral sclerosis and frontotemporal dementia: disease-associated pathways. Rev. Neurosci. 21, 251–272 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Chiang, P.M. et al. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc. Natl. Acad. Sci. USA 107, 16320–16324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lagier-Tourenne, C., Polymenidou, M. & Cleveland, D.W. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet. 19, R46–R64 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dominy, J.E. et al. Discovery and characterization of a second mammalian thiol dioxygenase, cysteamine dioxygenase. J. Biol. Chem. 282, 25189–25198 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Schneider-Maunoury, S. et al. Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain. Cell 75, 1199–1214 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Topilko, P. et al. Krox-20 controls myelination in the peripheral nervous system. Nature 371, 796–799 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Berger, P., Niemann, A. & Suter, U. Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease). Glia 54, 243–257 (2006).

    Article  PubMed  Google Scholar 

  22. Levi, G. et al. Defective bone formation in Krox-20 mutant mice. Development 122, 113–120 (1996).

    CAS  PubMed  Google Scholar 

  23. Gabet, Y. et al. Krox20/EGR2 deficiency accelerates cell growth and differentiation in the monocytic lineage and decreases bone mass. Blood 116, 3964–3971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Leclerc, N. et al. Opposing effects of glucocorticoids and Wnt signaling on Krox20 and mineral deposition in osteoblast cultures. J. Cell. Biochem. 103, 1938–1951 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Hancock, J.D. & Lessnick, S.L. A transcriptional profiling meta-analysis reveals a core EWS-FLI gene expression signature. Cell Cycle 7, 250–256 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Tirode, F. et al. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11, 421–429 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Chung, C.C. & Chanock, S.J. Current status of genome-wide association studies in cancer. Hum. Genet. 130, 59–78 (2011).

    Article  PubMed  Google Scholar 

  28. Maris, J.M. et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N. Engl. J. Med. 358, 2585–2593 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second locus at 8q24. Nat. Genet. 39, 645–649 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Williamson, D. Fusion gene–negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J. Clin. Oncol. 28, 2151–2158 (2010).

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Author notes

  1. Sophie Postel-Vinay and Amélie S Véron: These authors contributed equally to this work.

  2. David G Cox and Olivier Delattre: These authors jointly directed this work.

Authors and Affiliations

  1. INSERM, U830 Génétique et Biologie des Cancers, Institut Curie, Paris, France

    Sophie Postel-Vinay, Franck Tirode, Carlo Lucchesi, Karine Laud & Olivier Delattre

  2. Institut Curie, Centre de Recherche, Paris, France

    Sophie Postel-Vinay, Franck Tirode, Carlo Lucchesi, Karine Laud & Olivier Delattre

  3. Léon-Bérard Cancer Center, Cancer Research Center of Lyon, INSERM U 1052, Lyon, France

    Amélie S Véron, Gilles Thomas & David G Cox

  4. Unité de Génétique Somatique, Institut Curie, Centre Hospitalier, Paris, France

    Gaelle Pierron, Stéphanie Reynaud, Eve Lapouble, Stelly Ballet & Olivier Delattre

  5. Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria

    Heinrich Kovar

  6. Service de Pédiatrie, Institut Gustave Roussy, Villejuif, France

    Odile Oberlin

  7. Universitätsklinikum Freiburg Zentrum für Kinder und Jugendmedizin, Freiburg, Germany

    Udo Kontny

  8. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain

    Anna González-Neira

  9. Laboratorio di Oncologia Sperimentale, Istituto Ortopedico Rizzoli di Bologna, Bologna, Italy

    Piero Picci

  10. Unidad de Tumores Solidos Infantiles, Instituto de Salud Carlos III, Majahonda, Spain

    Javier Alonso

  11. Laboratory of Pediatrics, University of Navarra, University Clinic, Pamplona, Spain

    Ana Patino-Garcia

  12. Service de Génétique, Institut Gustave Roussy, Villejuif, France

    Brigitte Bressac de Paillerets

  13. INSERM U 915, Institut du Thorax, Institut de Recherche Thérapeutique–Université de Nantes (IRT-UN), Nantes, France

    Christian Dina

  14. School of Public Health, Imperial College London, South Kensington Campus, London, UK

    Philippe Froguel

  15. Centre National de la Recherche Scientifique Unité Mixte de Recherche 1018, Institut Gustave Roussy, Villejuif, France

    Françoise Clavel-Chapelon

  16. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Francois Doz

  17. Département de Pédiatrie, Institut Curie, Centre Hospitalier, Paris, France

    Francois Doz & Jean Michon

  18. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Stephen J Chanock

  19. Synergie Lyon Cancer, Lyon, France

    Gilles Thomas

Authors
  1. Sophie Postel-Vinay
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Contributions

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.

Corresponding author

Correspondence to Olivier Delattre.

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The authors declare no competing financial interests.

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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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