Molecular inversion probe analysis detects novel copy number alterations in Ewing sarcoma

Cancer Genet. Jul-Aug 2012;205(7-8):391-404. doi: 10.1016/j.cancergen.2012.05.012.


Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples, which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7-10% of clinically diagnosed ES tumors in three separate cohorts (University of Utah [N = 40], Children's Oncology Group [N = 31], and University of Michigan [N = 55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P < 0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk stratification in future clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / pathology
  • Cell Adhesion Molecules, Neuronal / genetics
  • Child
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA-Binding Proteins / genetics
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Deletion
  • Gene Dosage*
  • Humans
  • Immunohistochemistry
  • Infant
  • Loss of Heterozygosity
  • Male
  • Molecular Probes*
  • Nerve Tissue Proteins / genetics
  • Paraffin Embedding
  • SMARCB1 Protein
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / pathology
  • Serine Endopeptidases / genetics
  • Transcription Factors / genetics
  • Young Adult


  • Cell Adhesion Molecules, Neuronal
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • Molecular Probes
  • Nerve Tissue Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors
  • Serine Endopeptidases
  • reelin protein