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Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

  1. Author:
    Lin, Shu-Hong
    Sampson, Joshua N.
    Gruenewald, Thomas G. P.
    Surdez, Didier
    Reynaud, Stephanie
    Mirabeau, Olivier
    Karlins,Eric
    Rubio, Rebeca Alba
    Zaidi, Sakina
    Grossetete-Lalami, Sandrine
    Ballet, Stelly
    Lapouble, Eve
    Laurence, Valerie
    Michon, Jean
    Pierron, Gaelle
    Kovar, Heinrich
    Kontny, Udo
    Gonzalez-Neira, Anna
    Alonso, Javier
    Patino-Garcia, Ana
    Corradini, Nadege
    Berard, Perrine Marec
    Miller, Jeremy
    Freedman, Neal D.
    Rothman, Nathaniel
    Carter, Brian D.
    Dagnall,Casey
    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.
    Kulozik, Andreas E.
    Kriebel, Jennifer
    Meitinger, Thomas
    Metzler, Markus
    Krumbholz, Manuela
    Hartmann, Wolfgang
    Strauch, Konstantin
    Kirchner, Thomas
    Dirksen, Uta
    Mirabello, Lisa
    Tucker, Margaret A.
    Tirode, Franck
    Morton, Lindsay M.
    Chanock, Stephen J.
    Delattre, Olivier
    Machiela, Mitchell J.

  2. Author Address

    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.Ludwig Maximilians Univ LMU, Max Eder Res Grp Pediat Sarcoma Biol, Munich, Germany.German Canc Consortium DKTK, Div Translat Pediat Sarcoma Res, German Canc Res Ctr DKFZ, Heidelberg, Germany.Heidelberg Univ Hosp, Inst Pathol, Heidelberg, Germany.PSL Univ, Inst Curie, Equipe Labellises LNCC, Inserm U830, Paris, France.Inst Curie, SIREDO Oncol Ctr, Paris, France.Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Genom Res Lab, Frederick, MD USA.St Anna Kinderkrebsforsch, Childrens Canc Res Inst, Vienna, Austria.Uniklin RWTH Aachen, Div Pediat Hematol Oncol & Stem Cell Transplantat, Aachen, Germany.Spanish Natl Canc Res Ctr, Human Genotyping Unit CeGen, Human Canc Genet Programme, Madrid, Spain.Inst Salud Carlos III, Unidad Tumores Solidos Infantiles IIER ISCIII, Majadahonda, Spain.Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CB06 07, Majadahonda, Spain.Univ Clin Navarra, Lab Pediat, Ctr Appl Med Res CIMA, Program Solid Tumors, Pamplona, Spain.Navarras Hlth Res Inst IdiSNA, Pamplona, Spain.Univ Lyon, Leon Berard Canc Ctr, Inst Paediat Haematol & Oncol, Lyon, France.Informat Management Serv Inc, Calverton, MD USA.Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30329 USA.Inst Natl Sante & Rech Med INSERM, Paris, France.NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA.St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA.Fred Hutchinson Canc Res Ctr, Canc Prevent & Clin Stat Programs, 1124 Columbia St, Seattle, WA 98104 USA.Univ Alabama Birmingham, Inst Canc Outcomes & Survivorship, Birmingham, AL USA.Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany.Heidelberg Univ, Hopp Children Canc Ctr, Heidelberg, Germany.German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.German Ctr Diabet Res DZD, Neuherberg, Germany.Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany.Tech Univ Munich, Inst Human Genet, Munich, Germany.Univ Hosp Erlangen, Dept Paediat & Adolescent Med, Erlangen, Germany.Univ Hosp Munster, Gerhard Domagk Inst Pathol, Div Translat Pathol, Munster, Germany.Ludwig Maximilians Univ Munchen, Inst Genet Epidemiol, Munich, Germany.Ludwig Maximilians Univ Munchen, Inst Pathol, Fac Med, Munich, Germany.Univ Hosp Essen, West German Canc Ctr, Pediat 3, Essen, Germany.Ctr Essen, German Canc Consortium DKTK, Heidelberg, Germany.
    1. Year: 2020
    2. Date: SEP 3
  2. Journal: PLOS ONE
  3. PUBLIC LIBRARY SCIENCE,
    1. 15
    2. 9
  5. Type of Article: Article
  6. Article Number: e0237792
  7. ISSN: 1932-6203
  1. Abstract:

    Background Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.

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External Sources

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  2. DOI: 10.1371/journal.pone.0237792
  3. View record in Web of Science®
  4. WOS: 000571063300022

Library Notes

  1. Fiscal Year: FY2020-2021
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