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

Nat Commun. 2018 Aug 9;9(1):3184. doi: 10.1038/s41467-018-05537-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Cell Cycle Proteins / genetics
  • Cell Proliferation / genetics
  • DNA-Binding Proteins / genetics
  • European Continental Ancestry Group
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Homeodomain Proteins / genetics
  • Humans
  • Oncogene Proteins, Fusion / genetics
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Quality Control
  • Quantitative Trait Loci
  • RNA-Binding Protein EWS / genetics
  • Risk
  • Sarcoma, Ewing / ethnology
  • Sarcoma, Ewing / genetics*
  • Transcription Factors / genetics
  • Zebrafish Proteins

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • EWS-FLI fusion protein
  • Homeodomain Proteins
  • KIZ protein, human
  • Nkx2.2 protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • RREB1 protein, human
  • Transcription Factors
  • Zebrafish Proteins