PLoS ONE (Jan 2020)

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

  • Shu-Hong Lin,
  • Joshua N Sampson,
  • Thomas G P Grünewald,
  • Didier Surdez,
  • Stephanie Reynaud,
  • Olivier Mirabeau,
  • Eric Karlins,
  • Rebeca Alba Rubio,
  • Sakina Zaidi,
  • Sandrine Grossetête-Lalami,
  • Stelly Ballet,
  • Eve Lapouble,
  • Valérie Laurence,
  • Jean Michon,
  • Gaelle Pierron,
  • Heinrich Kovar,
  • Udo Kontny,
  • Anna González-Neira,
  • Javier Alonso,
  • Ana Patino-Garcia,
  • Nadège Corradini,
  • Perrine Marec Bérard,
  • Jeremy Miller,
  • Neal D Freedman,
  • Nathaniel Rothman,
  • Brian D Carter,
  • 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,
  • Manuela Krumbholz,
  • Wolfgang Hartmann,
  • Konstantin Strauch,
  • Thomas Kirchner,
  • Uta Dirksen,
  • Lisa Mirabello,
  • Margaret A Tucker,
  • Franck Tirode,
  • Lindsay M Morton,
  • Stephen J Chanock,
  • Olivier Delattre,
  • Mitchell J Machiela

DOI
https://doi.org/10.1371/journal.pone.0237792
Journal volume & issue
Vol. 15, no. 9
p. e0237792

Abstract

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BackgroundEwing 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.MethodsWe 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).ResultsWe 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 ConclusionsThese findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.ImpactMotivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.