title: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma.
abstract: OBJECTIVE
  More than 90% of Ewing's sarcomas (ES) contain a fusion of the EWS and FLI1 genes, due to the t(11;22)(q24;q12) translocation. At the molecular level, the EWS-FLI1 rearrangements show great diversity. Specifically, many different combinations of exons from EWS and FLI1 encode in-frame fusion transcripts and result in differences in the length and composition of the chimeric protein, which functions as an oncogenic aberrant transcription factor. In the most common fusion type (type 1), EWS exon 7 is linked in frame with exon 6 of FLI1. As the fundamental pathogenetic lesion in ES, the molecular heterogeneity of these fusion transcripts may have functional and clinical significance.
  
  
  METHODS
  We performed a clinical and pathologic analysis of 112 patients with ES in which EWS-FLI1 fusion transcripts were identified by reverse-transcriptase polymerase chain reaction (RT-PCR). Adequate treatment and follow-up data were available in 99 patients treated with curative intent. Median follow-up in these 99 patients was 26 months (range, 1 to 140 months). Univariate and multivariate survival analyses were performed that included other prognostic factors, such as age, tumor location, size, and stage.
  
  
  RESULTS
  Among the 99 patients suitable for survival analysis, the tumors in 64 patients contained the type 1 fusion and in 35 patients contained less common fusion types. Stage at presentation was localized in 74 patients and metastatic in 25. Metastases (relative risk [RR] = 2.6; P = .008), and type 1 EWS-FLI1 fusion (RR = 0.37; P = .014) were, respectively, independent negative and positive prognostic factors for overall survival by multivariate analysis. Among 74 patients with localized tumors, the type 1 EWS-FLI1 fusion was also a significant positive predictor of overall survival (RR = 0.32; P = .034) by multivariate analysis.
  
  
  CONCLUSIONS
  EWS-FLI1 fusion type appears to be prognostically relevant in ES, independent of tumor site, stage, and size. Further studies are needed to clarify the biologic basis of this phenomenon.
authors.affiliation: Clinica Universitaria de Navarra, Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: de Alava
authors.forename: A
authors.initials: A
authors.lastname: Kawai
authors.forename: J H
authors.initials: JH
authors.lastname: Healey
authors.forename: I
authors.initials: I
authors.lastname: Fligman
authors.forename: P A
authors.initials: PA
authors.lastname: Meyers
authors.forename: A G
authors.initials: AG
authors.lastname: Huvos
authors.forename: W L
authors.initials: WL
authors.lastname: Gerald
authors.forename: S C
authors.initials: SC
authors.lastname: Jhanwar
authors.forename: P
authors.initials: P
authors.lastname: Argani
authors.forename: C R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: F J
authors.initials: FJ
authors.lastname: Pardo-Mindan
authors.forename: J
authors.initials: J
authors.lastname: Ginsberg
authors.forename: R
authors.initials: R
authors.lastname: Womer
authors.forename: E R
authors.initials: ER
authors.lastname: Lawlor
authors.forename: J
authors.initials: J
authors.lastname: Wunder
authors.forename: I
authors.initials: I
authors.lastname: Andrulis
authors.forename: P H
authors.initials: PH
authors.lastname: Sorensen
authors.forename: F G
authors.initials: FG
authors.lastname: Barr
authors.forename: M
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D015514:Oncogene Proteins, Fusion / Q000145:classification / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D016019:Survival Analysis
chemical_list: D015514:Oncogene Proteins, Fusion