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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 Stéphanie Reynaud 5 Didier Surdez 6, 7 Olivier Mirabeau 6, 7 Eric Karlins 1, 8 Rebeca Alba Rubio 2 Sakina Zaïdi 6, 7 Sandrine Grossetete-Lalami 6, 7 Stelly Ballet 7, 9 Eve Lapouble 7, 9 Valérie Laurence 7 Jean Michon 7 Gaëlle Pierron 7, 9 Heinrich Kovar 10 Nathalie Gaspar 11 Udo Kontny 12 Anna González-Neira 13 Piero Picci 14 Javier Alonso 15 Ana Patiño-García 16 Nadège Corradini 17 Perrine Marec Bérard 17 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 18 Robert Hoover 1 Javed Khan 19 Gregory Armstrong 20 Wendy Leisenring 21 Smita Bhatia 22 Leslie Robison 20 Andreas Kulozik 23 Jennifer Kriebel 24, 25, 26 Thomas Meitinger 27, 28 Markus Metzler 29 Wolfgang Hartmann 30 Konstantin Strauch 31, 32 Thomas Kirchner 3, 4, 33 Uta Dirksen 34 Lindsay Morton 1 Lisa Mirabello 1 Margaret Tucker 1 Franck Tirode 6, 7 Stephen Chanock 1, * Olivier Delattre 6, 7, *
* 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, Stéphanie Reynaud, Didier Surdez, 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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