title: Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse.
abstract: OBJECTIVE
  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.
  
  
  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 p53 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.forename: Peter B
authors.initials: PB
authors.lastname: Illei
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Zhao
authors.forename: Madhu
authors.initials: M
authors.lastname: Mazumdar
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Huvos
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Paul
authors.initials: P
authors.lastname: Meyers
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF