Abstract A13: Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility
Authors: Machiela Mitchell J. , Grünewald Thomas G.P. , Surdez Didier , Reynaud Stephanie , Mirabeau Olivier , Karlins Eric , Rubio Rebeca Alba , Zaidi Sakina , Grossetete-Lalami Sandrine , Ballet Stelly , Lapouble Eve , Laurence Valérie , Michon Jean , Pierron Gaelle , Kovar Heinrich , Gaspar Nathalie , Kontny Udo , González-Neira Anna , Picci Piero , Alonso Javier , Patino-Garcia Ana , Corradini Nadège , Freedman Neal D. , Rothman Nathaniel , Dagnall Casey L. , Burdett Laurie , Jones Kristine , Manning Michelle , Wyatt Kathleen , Zhou Weiyin , Yeager Meredith , Cox David G. , Hoover Robert N. , Khan Javed , Armstrong Gregory T. , Leisenring Wendy M. , Bhatia Smita , Robison Leslie L. , Dirksen Uta , Metzler Markus , Hartmann Wolfgang , Strauch Konstantin , Kirchner Thomas , Kulozik Andreas E. , Morton Lindsay M. , Mirabello Lisa , Tucker Margaret A. , Tirode Franck , Chanock Stephen , Delattre Olivier 
Published: February 2019

Ewing sarcoma (EWS), a pediatric tumor predominantly occurring in children of European ancestry, is characterized by the EWSR1-FLI1 fusion oncogene. We performed a genome-wide association study (GWAS) of 749 EWS cases and 1,378 unaffected individuals of European ancestry. Our study replicated previously reported susceptibility loci at 1p36.22, 10q21.3, and 15q15.1 and identified new loci at 6p25.1, 8q24.23, 20p11.22, and 20p11.23 (P-values &lt;5x10-8). Effect estimates exhibited odds ratios (ORs) 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. In expression quantitative trait locus (eQTL) analyses, we observed altered expression patterns for plausible candidate genes at 6p25.1 with RREB1, a RAS-responsive element, and at 20p11.23 with KIZ, a centrosomal stabilization protein. The 20p11.22 locus is also near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences where binding of the EWSR1-FLI1 fusion protein occurs. The seven EWS susceptibility loci discovered in only 749 cases make EWS one of the most productive GWAS studied cancers when considering a locus-to-case discovery ratio. The substantive estimated ORs suggest a distinctive underlying genetic architecture for EWS in which moderate-risk SNPs likely constitute a significant fraction and may interact with EWSR1-FLI1 binding.

Citation Format: Mitchell J. Machiela, Thomas G.P. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Uta Dirksen, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Andreas E. Kulozik, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen Chanock, Olivier Delattre. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A13.