Abstract | BACKGROUND: Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with Ewing sarcoma or peripheral neuroectodermal tumor (ES/ PNET). The primary genetic alteration in ES/ PNET, the fusion of the EWS gene with FLI1 or ERG, is diagnostically highly specific for these tumors, and molecular variation in the structure of the EWS-FLI1 fusion gene also is of prognostic significance. In contrast, secondary genetic alterations, such as P53 alterations, are relatively uncommon in ES/ PNET, and their prognostic impact has not been extensively studied. METHODS: Prechemotherapy, paraffin embedded, nondecalcified, primary tumor material in a well-characterized series of 55 patients with ES/ PNET with defined EWS-FLI1 fusion transcripts (32 patients with type 1 and 23 patients with other types) was studied retrospectively by immunohistochemical techniques for cell cycle regulators and proliferative markers, such as P53, P21(WAF1), and Ki-67, as well as by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique for apoptosis. Nuclear P53 expression in > 20% of tumor cells was scored as aberrant overexpression. Histologic response to neoadjuvant chemotherapy was assessed. RESULTS: Aberrant P53 expression (in > 20% of tumor cells) was present in 6 patients (11%) but showed no statistically significant correlation with disease stage, tumor size, proliferation rate (Ki-67), apoptotic rate (TUNEL), or EWS-FLI1 fusion type. By univariate analysis, the P53 > 20% group showed a significantly poorer overall survival among patients with localized disease (n = 43 patients) (P = 0.001) and in the entire study group (P = 0.01). In multivariate Cox analyses of overall survival, P53 > 20% was the strongest negative factor among prognostic factors available at the time of diagnosis (P = 0.001; relative risk [RR] = 9) and when chemotherapy response was included in the analysis (P53 > 20%: P = 0.01; RR = 10). CONCLUSIONS: P53 alteration appears to define a small clinical subset of patients with ES/ PNET with a markedly poor outcome. The current observations warrant a systematic prospective study with comprehensive P53 mutation analysis. [See related article on pages 793-9, this issue.]
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Authors | E de Alava, C R Antonescu, A Panizo, D Leung, P A Meyers, A G Huvos, F J Pardo-Mindán, J H Healey, M Ladanyi |
Journal | Cancer
(Cancer)
Vol. 89
Issue 4
Pg. 783-92
(Aug 15 2000)
ISSN: 0008-543X [Print] United States |
PMID | 10951341
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright 2000 American Cancer Society. |
Chemical References |
- Antineoplastic Agents
- Biomarkers, Tumor
- EWS-FLI fusion protein
- Oncogene Proteins, Fusion
- Proto-Oncogene Protein c-fli-1
- RNA-Binding Protein EWS
- Transcription Factors
- Tumor Suppressor Protein p53
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Topics |
- Adolescent
- Adult
- Antineoplastic Agents
(therapeutic use)
- Biomarkers, Tumor
(metabolism)
- Bone Neoplasms
(diagnosis, drug therapy, metabolism, mortality)
- Child
- Child, Preschool
- Female
- Humans
- Immunohistochemistry
- Male
- Neoplasm Staging
- Oncogene Proteins, Fusion
(genetics, metabolism)
- Point Mutation
- Prognosis
- Prospective Studies
- Proto-Oncogene Protein c-fli-1
- RNA-Binding Protein EWS
- Sarcoma, Ewing
(diagnosis, drug therapy, metabolism, mortality)
- Transcription Factors
(genetics, metabolism)
- Treatment Outcome
- Tumor Suppressor Protein p53
(genetics, metabolism)
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