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

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, Perrine Marec Bérard, 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, Andreas E. Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock () and Olivier Delattre ()
Additional contact information
Mitchell J. Machiela: National Cancer Institute
Thomas G. P. Grünewald: LMU
Didier Surdez: Institut Curie
Stephanie Reynaud: Institut Curie
Olivier Mirabeau: Institut Curie
Eric Karlins: National Cancer Institute
Rebeca Alba Rubio: LMU
Sakina Zaidi: Institut Curie
Sandrine Grossetete-Lalami: Institut Curie
Stelly Ballet: Institut Curie
Eve Lapouble: Institut Curie
Valérie Laurence: Institut Curie
Jean Michon: Institut Curie
Gaelle Pierron: Institut Curie
Heinrich Kovar: St. Anna Kinderkrebsforschung
Nathalie Gaspar: Institut Gustave Roussy
Udo Kontny: RWTH Aachen University
Anna González-Neira: Spanish National Cancer Research Centre
Piero Picci: Istituto Ortopedico Rizzoli di Bologna
Javier Alonso: Instituto de Salud Carlos III
Ana Patino-Garcia: University of Navarra, University Clinic of Navarra, IdiSNA
Nadège Corradini: University of Lyon
Perrine Marec Bérard: University of Lyon
Neal D. Freedman: National Cancer Institute
Nathaniel Rothman: National Cancer Institute
Casey L. Dagnall: National Cancer Institute
Laurie Burdett: National Cancer Institute
Kristine Jones: National Cancer Institute
Michelle Manning: National Cancer Institute
Kathleen Wyatt: National Cancer Institute
Weiyin Zhou: National Cancer Institute
Meredith Yeager: National Cancer Institute
David G. Cox: Centre Léon Bérard, INSERM U1052
Robert N. Hoover: National Cancer Institute
Javed Khan: National Cancer Institute
Gregory T. Armstrong: St. Jude Children’s Research Hospital
Wendy M. Leisenring: Fred Hutchinson Cancer Research Center
Smita Bhatia: University of Alabama
Leslie L. Robison: St. Jude Children’s Research Hospital
Andreas E. Kulozik: University Children’s Hospital of Heidelberg
Jennifer Kriebel: German Research Center for Environmental Health
Thomas Meitinger: German Research Center for Environmental Health
Markus Metzler: University Children’s Hospital of Erlangen
Wolfgang Hartmann: University Hospital of Münster
Konstantin Strauch: German Research Center for Environmental Health
Thomas Kirchner: German Consortium for Cancer Research (DKTK)
Uta Dirksen: University Children’s Hospital of Essen
Lindsay M. Morton: National Cancer Institute
Lisa Mirabello: National Cancer Institute
Margaret A. Tucker: National Cancer Institute
Franck Tirode: Institut Curie
Stephen J. Chanock: National Cancer Institute
Olivier Delattre: Institut Curie

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05537-2

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