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

Mitchell Machiela 1 Thomas Grünewald 2, 3, 4 Didier Surdez 5, 6 Stephanie Reynaud 6, 7 Olivier Mirabeau 5, 6 Eric Karlins 1, 8 Rebeca Alba Rubio 2 Sakina Zaïdi 5, 6 Sandrine Grossetete-Lalami 5, 6 Stelly Ballet 6, 7 Eve Lapouble 6, 7 Valérie Laurence 6 Jean Michon 6 Gaëlle Pierron 6, 7 Heinrich Kovar 9 Nathalie Gaspar 10 Udo Kontny 11 Anna González-Neira 12 Piero Picci 13 Javier Alonso 14 Ana Patiño-García 15 Nadège Corradini 16 Perrine Marec Bérard 16 Neal Freedman 1 Nathaniel Rothman 1 Casey Dagnall 1, 8 Laurie Burdett 1, 8 Kristine Jones 1, 8 Michelle Manning 1, 8 Kathleen Wyatt 1, 8 Weiyin Zhou 1, 8 Meredith Yeager 1, 8 David Cox 17 Robert Hoover 1 Javed Khan 18 Gregory Armstrong 19 Wendy Leisenring 20 Smita Bhatia 21 Leslie Robison 19 Andreas Kulozik 22 Jennifer Kriebel 23, 24, 25 Thomas Meitinger 26, 27 Markus Metzler 28 Wolfgang Hartmann 29 Konstantin Strauch 30, 31 Thomas Kirchner 3, 4, 32 Uta Dirksen 33 Lindsay Morton 1 Lisa Mirabello 1 Margaret Tucker 1 Franck Tirode 5, 6 Stephen Chanock 1, * Olivier Delattre 5, 6, *
* Corresponding author
Abstract : Ewing 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.
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Mitchell Machiela, Thomas Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, et al.. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nature Communications, Nature Publishing Group, 2018, 9 (1), ⟨10.1038/s41467-018-05537-2⟩. ⟨inserm-02440583⟩

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