Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: A highly lethal subset associated with poor chemoresponse Journal Article


Authors: Huang, H. Y.; Illei, P. B.; Zhao, Z.; Mazumdar, M.; Huvos, A. G.; Healey, J. H.; Wexler, L. H.; Gorlick, R.; Meyers, P.; Ladanyi, M.
Article Title: Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: A highly lethal subset associated with poor chemoresponse
Abstract: Purpose: EWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/p14ARF have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic analysis of these three molecular parameters in ES. Patients and Methods: We studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/p14ARF, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively. Results: Eight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/p14ARF deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/p14ARF showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutation alone (P < .001), either p53 or p16/p14ARF alteration (P < .001), and stage (P < .01). In multivariate analysis, alterations of p55 and/or p16/p14ARF as a single variable, was the most adverse prognostic factor (P < .001), followed by stage (P = .04). In a multivariate analysis with alterations of p53 and p16/p14ARF as separate variables, both were significant (P < .001 and P = .03, respectively). Six cases with p16/p14ARF deletion were also studied for co-deletion of the contiguous methylthioadenosine phosphorylase gene, and this was detected in four cases. Conclusion: Alterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse. © 2005 by American Society of Clinical Oncology.
Keywords: survival; adolescent; adult; cancer survival; child; controlled study; human tissue; preschool child; treatment outcome; aged; bone neoplasms; child, preschool; middle aged; survival analysis; bone tumor; cancer surgery; oncoprotein; major clinical study; overall survival; gene deletion; genetics; sequence deletion; doxorubicin; cancer radiotherapy; cancer staging; follow up; follow-up studies; neoplasm staging; in situ hybridization, fluorescence; protein p16; etoposide; transcription factor; cyclophosphamide; vincristine; pathology; protein p53; ifosfamide; transcription factors; ewing sarcoma; homozygosity; tumor suppressor gene; fluorescence in situ hybridization; infant; microarray analysis; nucleotide sequence; oncogene proteins, fusion; dna mutational analysis; tumor suppressor protein p14arf; point mutation; transcription factor fli 1; sarcoma, ewing's; proto-oncogene protein c-fli-1; genes, p53; genes, p16; protein p14arf; 5' methylthioadenosine phosphorylase; ews fli1 fusion protein; ews-fli1 fusion protein
Journal Title: Journal of Clinical Oncology
Volume: 23
Issue: 3
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2005-01-20
Start Page: 548
End Page: 558
Language: English
DOI: 10.1200/jco.2005.02.081
PUBMED: 15659501
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 100" - "Export Date: 24 October 2012" - "CODEN: JCOND" - "Source: Scopus"
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MSK Authors
  1. Hsuan-Yin Huang
    23 Huang
  2. Madhu Mazumdar
    120 Mazumdar
  3. Richard G Gorlick
    120 Gorlick
  4. Leonard H Wexler
    130 Wexler
  5. Zhiquan Zhao
    11 Zhao
  6. Peter Illei
    26 Illei
  7. Marc Ladanyi
    864 Ladanyi
  8. Paul Meyers
    244 Meyers
  9. John H Healey
    374 Healey
  10. Andrew G Huvos
    202 Huvos