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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-08-09

AUTHORS

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, Olivier Delattre

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. More... »

PAGES

3184

References to SciGraph publications

Journal

TITLE

Nature Communications

ISSUE

1

VOLUME

9

Author Affiliations

  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, 20892, Bethesda, MD, USA
  • German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
  • SIREDO Oncology Centre, Institut Curie, 75005, Paris, France
  • Unité de Génétique Somatique, Institut Curie, Centre Hospitalier, 75005, Paris, France
  • Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, 21701, Frederick, MD, USA
  • Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU, 80337, Munich, Germany
  • Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090, Vienna, Austria
  • Department of Oncology for Child and Adolescent, Institut Gustave Roussy, 94800, Villejuif, France
  • Division of Pediatric Hematology Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, 52062, Aachen, Germany
  • Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, 28029, Madrid, Spain
  • Laboratorio di Oncologia Sperimentale, Istituto Ortopedico Rizzoli di Bologna, 40136, Bologna, Italy
  • Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, 28220, Majadahonda, Spain
  • Laboratory of Pediatrics, University of Navarra, University Clinic of Navarra, IdiSNA, 31008, Pamplona, Spain
  • Institute for Paediatric Haematology and Oncology, Leon Bérard Cancer Centre, University of Lyon, 69008, Lyon, France
  • Centre Léon Bérard, INSERM U1052, 69008, Lyon, France
  • Genetics Branch, Center for Cancer Research, National Cancer Institute, 20892, Bethesda, MD, USA
  • Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, 38105, Memphis, TN, USA
  • Cancer Prevention and Clinical Statistics Programs, Fred Hutchinson Cancer Research Center, 98109, Seattle, WA, USA
  • Institute for Cancer Outcomes and Survivorship, University of Alabama, 35294, Birmingham, AL, USA
  • University Children’s Hospital of Heidelberg, 69120, Heidelberg, Germany
  • German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
  • Institute of Human Genetics, Technische Universität München, 80333, Munich, Germany
  • University Children’s Hospital of Erlangen, 91054, Erlangen, Germany
  • Gerhard-Domagk Institute of Pathology, University Hospital of Münster, 48149, Münster, Germany
  • Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, 80539, Munich, Germany
  • Institute of Pathology, Faculty of Medicine, LMU, 80337, Munich, Germany
  • University Children’s Hospital of Essen, 45147, Essen, Germany
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-05537-2

    DOI

    http://dx.doi.org/10.1038/s41467-018-05537-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1105993569

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30093639


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