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

Sophie Postel-Vinay; Amélie S. Véron; Franck Tirode; Gaelle Pierron; Stéphanie Reynaud; Heinrich Kovar; Odile Oberlin; Eve Lapouble; Stelly Ballet; Carlo Lucchesi; Udo Kontny; Anna González-Neira; Piero Picci; Javier Alonso; Ana Patino-Garcia; Brigitte Bressac De Paillerets; Karine Laud; Christian Dina; Philippe Froguel; Franoise Clavel-Chapelon; Francois Doz; Jean Michon; Stephen J. Chanock; Gilles Thomas; David G. Cox; Olivier Delattre

doi:10.1038/ng.1085

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

Sophie Postel-Vinay, Amélie S. Véron, Franck Tirode, Gaelle Pierron, Stéphanie Reynaud, Heinrich Kovar, Odile Oberlin, Eve Lapouble, Stelly Ballet, Carlo Lucchesi, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Brigitte Bressac De Paillerets, Karine Laud, Christian Dina, Philippe Froguel, Franoise Clavel-ChapelonFrancois Doz, Jean Michon, Stephen J. Chanock, Gilles Thomas, David G. Cox, Olivier Delattre

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

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Résumé

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.

langue originale	Anglais
Pages (de - à)	323-327
Nombre de pages	5
journal	Nature Genetics
Volume	44
Numéro de publication	3
Les DOIs	https://doi.org/10.1038/ng.1085
état	Publié - 1 mars 2012
Modification externe	Oui

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10.1038/ng.1085

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Postel-Vinay, S., Véron, A. S., Tirode, F., Pierron, G., Reynaud, S., Kovar, H., Oberlin, O., Lapouble, E., Ballet, S., Lucchesi, C., Kontny, U., González-Neira, A., Picci, P., Alonso, J., Patino-Garcia, A., De Paillerets, B. B., Laud, K., Dina, C., Froguel, P., ... Delattre, O. (2012). Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nature Genetics, 44(3), 323-327. https://doi.org/10.1038/ng.1085

@article{75f84ea489c548bb808fb44152a583cf,

title = "Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma",

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.",

author = "Sophie Postel-Vinay and V{\'e}ron, {Am{\'e}lie S.} and Franck Tirode and Gaelle Pierron and St{\'e}phanie Reynaud and Heinrich Kovar and Odile Oberlin and Eve Lapouble and Stelly Ballet and Carlo Lucchesi and Udo Kontny and Anna Gonz{\'a}lez-Neira and Piero Picci and Javier Alonso and Ana Patino-Garcia and {De Paillerets}, {Brigitte Bressac} and Karine Laud and Christian Dina and Philippe Froguel and Franoise Clavel-Chapelon and Francois Doz and Jean Michon and Chanock, {Stephen J.} and Gilles Thomas and Cox, {David G.} and Olivier Delattre",

note = "Funding Information: 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. Almaz{\'a}n, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Bel{\'e}ndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D. Chauveaux, C. Calvo, A. Carbon{\'e}, 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. Garc{\'i}a-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O. Lejars, R. L{\'o}pez-Almaraz, B. L{\'o}pez-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec B{\'e}rard, G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G. Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscard{\'o}, 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{\textquoteright}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 labellis{\'e}e, Carte d{\textquoteright}Identit{\'e} des Tumeurs program and Recherche Epid{\'e}miologique 2009 program), the R{\'e}gion 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 Soci{\'e}t{\'e} Fran{\c c}aise des Cancers de l{\textquoteright}Enfant, the Spanish Ministry of Science and Technology (SAF2009-10158), the Fundaci{\'o}n de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer, the Fundaci{\'o}n Mar{\'i}a Francisca de Roviralta and the Sociedad Espa{\~n}ola de Hematolog{\'i}a y Oncolog{\'i}a Pedi{\'a}tricas and the following associations: Courir pour Mathieu, Dans les pas du G{\'e}ant, Olivier Chape, Les Bagouzamanon, Enfants et Sant{\'e} and les Amis de Claire.",

year = "2012",

month = mar,

day = "1",

doi = "10.1038/ng.1085",

language = "English",

volume = "44",

pages = "323--327",

journal = "Nature Genetics",

issn = "1061-4036",

number = "3",

}

Postel-Vinay, S, Véron, AS, Tirode, F, Pierron, G, Reynaud, S, Kovar, H, Oberlin, O, Lapouble, E, Ballet, S, Lucchesi, C, Kontny, U, González-Neira, A, Picci, P, Alonso, J, Patino-Garcia, A, De Paillerets, BB, Laud, K, Dina, C, Froguel, P, Clavel-Chapelon, F, Doz, F, Michon, J, Chanock, SJ, Thomas, G, Cox, DG & Delattre, O 2012, 'Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma', Nature Genetics, VOL. 44, Numéro 3, p. 323-327. https://doi.org/10.1038/ng.1085

TY - JOUR

T1 - Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

AU - Postel-Vinay, Sophie

AU - Véron, Amélie S.

AU - Tirode, Franck

AU - Pierron, Gaelle

AU - Reynaud, Stéphanie

AU - Kovar, Heinrich

AU - Oberlin, Odile

AU - Lapouble, Eve

AU - Ballet, Stelly

AU - Lucchesi, Carlo

AU - Kontny, Udo

AU - González-Neira, Anna

AU - Picci, Piero

AU - Alonso, Javier

AU - Patino-Garcia, Ana

AU - De Paillerets, Brigitte Bressac

AU - Laud, Karine

AU - Dina, Christian

AU - Froguel, Philippe

AU - Clavel-Chapelon, Franoise

AU - Doz, Francois

AU - Michon, Jean

AU - Chanock, Stephen J.

AU - Thomas, Gilles

AU - Cox, David G.

AU - Delattre, Olivier

N1 - Funding Information: 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.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - 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.

AB - 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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U2 - 10.1038/ng.1085

DO - 10.1038/ng.1085

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