Machiela, Mitchell JGrünewald, Thomas G PSurdez, DidierReynaud, StephanieMirabeau, OlivierKarlins, EricRubio, Rebeca AlbaZaidi, SakinaGrossetête-Lalami, SandrineBallet, StellyLapouble, EveLaurence, ValérieMichon, JeanPierron, GaelleKovar, HeinrichGaspar, NathalieKontny, UdoGonzález-Neira, AnnaPicci, PieroAlonso, JavierPatiño-García, AnaCorradini, NadègeBérard, Perrine MarecFreedman, Neal DRothman, NathanielDagnall, Casey LBurdett, LaurieJones, KristineManning, MichelleWyatt, KathleenZhou, WeiyinYeager, MeredithCox, David GHoover, Robert NKhan, JavedArmstrong, Gregory TLeisenring, Wendy MBhatia, SmitaRobison, Leslie LKulozik, Andreas EKriebel, JenniferMeitinger, ThomasMetzler, MarkusHartmann, WolfgangStrauch, KonstantinKirchner, ThomasDirksen, UtaMorton, Lindsay MMirabello, LisaTucker, Margaret ATirode, FranckChanock, Stephen JDelattre, Olivier2020-03-172020-03-172018Nat Commun. 2018 Aug 9;9(1):3184.2041-1723http://hdl.handle.net/20.500.12105/9263Ewing 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.engVoRhttp://creativecommons.org/licenses/by/4.0/AllelesCell Cycle ProteinsCell ProliferationDNA-Binding ProteinsEuropean Continental Ancestry GroupGene Expression Regulation, NeoplasticGenotypeHomeodomain ProteinsHumansOncogene Proteins, FusionPolymorphism, Single NucleotideProto-Oncogene Protein c-fli-1Quality ControlQuantitative Trait LociRNA-Binding Protein EWSRiskSarcoma, EwingTranscription FactorsZebrafish ProteinsGene Expression ProfilingGenetic Predisposition to DiseaseGenome-Wide Association StudyAtribución 4.0 Internacional3009363991318410.1038/s41467-018-05537-22041-1723Nature communicationsopen access