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Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

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dc.contributor.authorMachiela, Mitchell J
dc.contributor.authorGrünewald, Thomas G P
dc.contributor.authorSurdez, Didier
dc.contributor.authorReynaud, Stephanie
dc.contributor.authorMirabeau, Olivier
dc.contributor.authorKarlins, Eric
dc.contributor.authorRubio, Rebeca Alba
dc.contributor.authorZaidi, Sakina
dc.contributor.authorGrossetête-Lalami, Sandrine
dc.contributor.authorBallet, Stelly
dc.contributor.authorLapouble, Eve
dc.contributor.authorLaurence, Valérie
dc.contributor.authorMichon, Jean
dc.contributor.authorPierron, Gaelle
dc.contributor.authorKovar, Heinrich
dc.contributor.authorGaspar, Nathalie
dc.contributor.authorKontny, Udo
dc.contributor.authorGonzález-Neira, Anna
dc.contributor.authorPicci, Piero
dc.contributor.authorAlonso, Javier
dc.contributor.authorPatiño-García, Ana
dc.contributor.authorCorradini, Nadège
dc.contributor.authorBérard, Perrine Marec
dc.contributor.authorFreedman, Neal D
dc.contributor.authorRothman, Nathaniel
dc.contributor.authorDagnall, Casey L
dc.contributor.authorBurdett, Laurie
dc.contributor.authorJones, Kristine
dc.contributor.authorManning, Michelle
dc.contributor.authorWyatt, Kathleen
dc.contributor.authorZhou, Weiyin
dc.contributor.authorYeager, Meredith
dc.contributor.authorCox, David G
dc.contributor.authorHoover, Robert N
dc.contributor.authorKhan, Javed
dc.contributor.authorArmstrong, Gregory T
dc.contributor.authorLeisenring, Wendy M
dc.contributor.authorBhatia, Smita
dc.contributor.authorRobison, Leslie L
dc.contributor.authorKulozik, Andreas E
dc.contributor.authorKriebel, Jennifer
dc.contributor.authorMeitinger, Thomas
dc.contributor.authorMetzler, Markus
dc.contributor.authorHartmann, Wolfgang
dc.contributor.authorStrauch, Konstantin
dc.contributor.authorKirchner, Thomas
dc.contributor.authorDirksen, Uta
dc.contributor.authorMorton, Lindsay M
dc.contributor.authorMirabello, Lisa
dc.contributor.authorTucker, Margaret A
dc.contributor.authorTirode, Franck
dc.contributor.authorChanock, Stephen J
dc.contributor.authorDelattre, Olivier
dc.contributor.funderUnión Europea
dc.date.accessioned2020-03-17T11:53:47Z
dc.date.available2020-03-17T11:53:47Z
dc.date.issued2018
dc.description.abstractEwing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipThis work was supported by the Intramural Research Program of the U.S. National Cancer Institute and the Intramural Research Program of the American Cancer Society. 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 ANR-10-EQPX-03 from the Agence Nationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC-2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supported by FP7 grant “EURO EWING Consortium” No. 602856 and the following associations: Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M la vie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin and the Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the ‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the Wilhelm Sander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 and DKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). We thank the following clinicians for providing samples used in this study: 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. Gandemer-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. This work was supported by the Instituto de Salud Carlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa de Alex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y Oncología Pediátricas. The Childhood Cancer Survivor Study is supported by the National Cancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding for genotyping from the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.es_ES
dc.format.number1es_ES
dc.format.page3184es_ES
dc.format.volume9es_ES
dc.identifier.citationNat Commun. 2018 Aug 9;9(1):3184.es_ES
dc.identifier.doi10.1038/s41467-018-05537-2es_ES
dc.identifier.e-issn2041-1723es_ES
dc.identifier.issn2041-1723es_ES
dc.identifier.journalNature communicationses_ES
dc.identifier.pubmedID30093639es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9263
dc.language.isoenges_ES
dc.publisherNature Publishing Group
dc.relation.projectIDInfo:eu-repo/grantAgreement/ANR-10-EQPX-03es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/ERA-649 NET TRANSCAN JTC-2011es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/FP7-HEALTH-2010-259348es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/2016.167.1es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/DKH-111886es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/DKH-70112257es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/INCa-DGOS-4654es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/PI16CIII / 00026)es_ES
dc.relation.projectIDInfo:eu-repo/grantAgreement/CA55727es_ES
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-018-05537-2es_ES
dc.repisalud.centroISCIII::Instituto de Investigación de Enfermedades Rarases_ES
dc.repisalud.institucionISCIIIes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.meshAlleleses_ES
dc.subject.meshCell Cycle Proteinses_ES
dc.subject.meshCell Proliferationes_ES
dc.subject.meshDNA-Binding Proteinses_ES
dc.subject.meshEuropean Continental Ancestry Groupes_ES
dc.subject.meshGene Expression Regulation, Neoplastices_ES
dc.subject.meshGenotypees_ES
dc.subject.meshHomeodomain Proteinses_ES
dc.subject.meshHumanses_ES
dc.subject.meshOncogene Proteins, Fusiones_ES
dc.subject.meshPolymorphism, Single Nucleotidees_ES
dc.subject.meshProto-Oncogene Protein c-fli-1es_ES
dc.subject.meshQuality Controles_ES
dc.subject.meshQuantitative Trait Locies_ES
dc.subject.meshRNA-Binding Protein EWSes_ES
dc.subject.meshRiskes_ES
dc.subject.meshSarcoma, Ewinges_ES
dc.subject.meshTranscription Factorses_ES
dc.subject.meshZebrafish Proteinses_ES
dc.subject.meshGene Expression Profilinges_ES
dc.subject.meshGenetic Predisposition to Diseasees_ES
dc.subject.meshGenome-Wide Association Studyes_ES
dc.titleGenome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibilityes_ES
dc.typeresearch articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
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relation.isAuthorOfPublication.latestForDiscovery7416f724-f758-4723-8e95-ca2ff70ee53c
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