EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma Journal Article

Authors: de Alava, E.; Kawai, A.; Healey, J. H.; Fligman, I.; Meyers, P. A.; Huvos, A. G.; Gerald, W. L.; Jhanwar, S. C.; Argani, P.; Antonescu, C. R.; Pardo-Mindan, F. J.; Ginsberg, J.; Womer, R.; Lawlor, E. R.; Wunder, J.; Andrulis, I.; Sorensen, P. H. B.; Barr, F. G.; Ladanyi, M.
Article Title: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma
Abstract: Purpose: 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 mast 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. Patients and 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. Conclusion: 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.
Keywords: adolescent; adult; aged; bone neoplasms; survival analysis; major clinical study; exons; doxorubicin; polymerase chain reaction; protein domain; reverse transcription polymerase chain reaction; tumor volume; antineoplastic combined chemotherapy protocols; alkylating agent; cyclophosphamide; genetic transcription; cell differentiation; ifosfamide; ewing sarcoma; amino terminal sequence; gene fusion; oncogene proteins, fusion; chromosome translocation; multivariate analysis; sarcoma, ewing's; gene structure; multigene family; neuroectoderm; humans; prognosis; human; male; female; priority journal; article
Journal Title: Journal of Clinical Oncology
Volume: 16
Issue: 4
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1998-04-01
Start Page: 1248
End Page: 1255
Language: English
PUBMED: 9552022
PROVIDER: scopus
DOI: 10.1200/JCO.1998.16.4.1248
Notes: Article -- Export Date: 12 December 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Akira Kawai
    15 Kawai
  2. Cristina R Antonescu
    606 Antonescu
  3. William L Gerald
    367 Gerald
  4. Marc Ladanyi
    864 Ladanyi
  5. Paul Meyers
    244 Meyers
  6. Suresh C Jhanwar
    210 Jhanwar
  7. John H Healey
    374 Healey
  8. Andrew G Huvos
    202 Huvos