title: TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.
abstract: OBJECTIVE
  Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma.
  
  
  METHODS
  One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors.
  
  
  RESULTS
  Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome.
  
  
  CONCLUSIONS
  We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5. wunder@mshri.on.ca
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.forename: Nalan
authors.initials: N
authors.lastname: Gokgoz
authors.forename: Robert
authors.initials: R
authors.lastname: Parkes
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Bull
authors.forename: Sasha
authors.initials: S
authors.lastname: Eskandarian
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Davis
authors.forename: Chris P
authors.initials: CP
authors.lastname: Beauchamp
authors.forename: Ernest U
authors.initials: EU
authors.lastname: Conrad
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Grimer
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: D C
authors.initials: DC
authors.lastname: Mangham
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rock
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bell
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis; D015139:Blotting, Southern; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D012516:Osteosarcoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor