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

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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