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

Author

Listed:
  • Mitchell J. Machiela

    (National Cancer Institute)

  • Thomas G. P. Grünewald

    (LMU
    German Consortium for Cancer Research (DKTK)
    German Cancer Research Center (DKFZ))

  • Didier Surdez

    (Institut Curie
    Institut Curie)

  • Stephanie Reynaud

    (Institut Curie
    Centre Hospitalier)

  • Olivier Mirabeau

    (Institut Curie
    Institut Curie)

  • Eric Karlins

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • Rebeca Alba Rubio

    (LMU)

  • Sakina Zaidi

    (Institut Curie
    Institut Curie)

  • Sandrine Grossetete-Lalami

    (Institut Curie
    Institut Curie)

  • Stelly Ballet

    (Institut Curie
    Centre Hospitalier)

  • Eve Lapouble

    (Institut Curie
    Centre Hospitalier)

  • Valérie Laurence

    (Institut Curie)

  • Jean Michon

    (Institut Curie)

  • Gaelle Pierron

    (Institut Curie
    Centre Hospitalier)

  • 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
    Leidos Biomedical Research Inc)

  • Laurie Burdett

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • Kristine Jones

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • Michelle Manning

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • Kathleen Wyatt

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • Weiyin Zhou

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • Meredith Yeager

    (National Cancer Institute
    Leidos Biomedical Research Inc)

  • 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
    German Research Center for Environmental Health
    German Center for Diabetes Research (DZD))

  • Thomas Meitinger

    (German Research Center for Environmental Health
    Technische Universität München)

  • Markus Metzler

    (University Children’s Hospital of Erlangen)

  • Wolfgang Hartmann

    (University Hospital of Münster)

  • Konstantin Strauch

    (German Research Center for Environmental Health
    LMU)

  • Thomas Kirchner

    (German Consortium for Cancer Research (DKTK)
    German Cancer Research Center (DKFZ)
    LMU)

  • 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
    Institut Curie)

  • Stephen J. Chanock

    (National Cancer Institute)

  • Olivier Delattre

    (Institut Curie
    Institut Curie)

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.

Suggested Citation

  • 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 & Ev, 2018. "Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05537-2
    DOI: 10.1038/s41467-018-05537-2
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