Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion

A highly lethal subset associated with poor chemoresponse

Hsuan Ying Huang, Peter B. Illei, Zhiquan Zhao, Madhu Mazumdar, Andrew G. Huvos, John H. Healey, Leonard H. Wexler, Richard Gorlick, Paul Meyers, Marc Ladanyi

Research output: Contribution to journalArticle

189 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)548-558
Number of pages11
JournalJournal of Clinical Oncology
Volume23
Issue number3
DOIs
StatePublished - 2005
Externally publishedYes

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Tumor Suppressor Protein p14ARF
Ewing's Sarcoma
Mutation
Multivariate Analysis
Sequence Deletion
Fluorescence In Situ Hybridization
Point Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion : A highly lethal subset associated with poor chemoresponse. / Huang, Hsuan Ying; Illei, Peter B.; Zhao, Zhiquan; Mazumdar, Madhu; Huvos, Andrew G.; Healey, John H.; Wexler, Leonard H.; Gorlick, Richard; Meyers, Paul; Ladanyi, Marc.

In: Journal of Clinical Oncology, Vol. 23, No. 3, 2005, p. 548-558.

Research output: Contribution to journalArticle

Huang, HY, Illei, PB, Zhao, Z, Mazumdar, M, Huvos, AG, Healey, JH, Wexler, LH, Gorlick, R, Meyers, P & Ladanyi, M 2005, 'Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: A highly lethal subset associated with poor chemoresponse', Journal of Clinical Oncology, vol. 23, no. 3, pp. 548-558. https://doi.org/10.1200/JCO.2005.02.081
Huang, Hsuan Ying ; Illei, Peter B. ; Zhao, Zhiquan ; Mazumdar, Madhu ; Huvos, Andrew G. ; Healey, John H. ; Wexler, Leonard H. ; Gorlick, Richard ; Meyers, Paul ; Ladanyi, Marc. / Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion : A highly lethal subset associated with poor chemoresponse. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 3. pp. 548-558.
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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.",
author = "Huang, {Hsuan Ying} and Illei, {Peter B.} and Zhiquan Zhao and Madhu Mazumdar and Huvos, {Andrew G.} and Healey, {John H.} and Wexler, {Leonard H.} and Richard Gorlick and Paul Meyers and Marc Ladanyi",
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TY - JOUR

T1 - Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion

T2 - A highly lethal subset associated with poor chemoresponse

AU - Huang, Hsuan Ying

AU - Illei, Peter B.

AU - Zhao, Zhiquan

AU - Mazumdar, Madhu

AU - Huvos, Andrew G.

AU - Healey, John H.

AU - Wexler, Leonard H.

AU - Gorlick, Richard

AU - Meyers, Paul

AU - Ladanyi, Marc

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

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