title: Molecular inversion probe analysis detects novel copy number alterations in Ewing sarcoma.
abstract: 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.
authors.affiliation: Center for Children's Cancer Research (C3R), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Mona S
authors.initials: MS
authors.lastname: Jahromi
authors.forename: Angelica R
authors.initials: AR
authors.lastname: Putnam
authors.forename: Colleen
authors.initials: C
authors.lastname: Druzgal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wright
authors.forename: Holly
authors.initials: H
authors.lastname: Spraker-Perlman
authors.forename: Michelle
authors.initials: M
authors.lastname: Kinsey
authors.forename: Holly
authors.initials: H
authors.lastname: Zhou
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Lucas
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Dafydd
authors.initials: D
authors.lastname: Thomas
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
mesh_terms: D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D015335:Molecular Probes; D009419:Nerve Tissue Proteins / Q000235:genetics; D016612:Paraffin Embedding; D000091042:Reelin Protein; D000071796:SMARCB1 Protein; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C000717127:RELN protein, human; D012697:Serine Endopeptidases