TP53 mutations and outcome in osteosarcoma: A prospective, multicenter study

Jay S. Wunder, Nalan Gokgoz, Robert Parkes, Shelley B. Bull, Sasha Eskandarian, Aileen M. Davis, Chris P. Beauchamp, Ernest U. Conrad, Robert J. Grimer, John H. Healey, David Malkin, D. C. Mangham, Michael J. Rock, Robert S. Bell, Irene L. Andrulis

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Abstract

Purpose: 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. Patients and 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 7P53 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 (≤ 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1483-1490
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number7
DOIs
StatePublished - 2005

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Osteosarcoma
Multicenter Studies
Prospective Studies
Mutation
p53 Genes
Recurrence
Drug Therapy
Neoplasms
Extremities
Nonsense Codon
Missense Mutation
Tertiary Healthcare
Adjuvant Chemotherapy
Survival Analysis
DNA Sequence Analysis
Genes
Necrosis
Multivariate Analysis
Neoplasm Metastasis
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wunder, J. S., Gokgoz, N., Parkes, R., Bull, S. B., Eskandarian, S., Davis, A. M., ... Andrulis, I. L. (2005). TP53 mutations and outcome in osteosarcoma: A prospective, multicenter study. Journal of Clinical Oncology, 23(7), 1483-1490. https://doi.org/10.1200/JCO.2005.04.074

TP53 mutations and outcome in osteosarcoma : A prospective, multicenter study. / Wunder, Jay S.; Gokgoz, Nalan; Parkes, Robert; Bull, Shelley B.; Eskandarian, Sasha; Davis, Aileen M.; Beauchamp, Chris P.; Conrad, Ernest U.; Grimer, Robert J.; Healey, John H.; Malkin, David; Mangham, D. C.; Rock, Michael J.; Bell, Robert S.; Andrulis, Irene L.

In: Journal of Clinical Oncology, Vol. 23, No. 7, 2005, p. 1483-1490.

Research output: Contribution to journalArticle

Wunder, JS, Gokgoz, N, Parkes, R, Bull, SB, Eskandarian, S, Davis, AM, Beauchamp, CP, Conrad, EU, Grimer, RJ, Healey, JH, Malkin, D, Mangham, DC, Rock, MJ, Bell, RS & Andrulis, IL 2005, 'TP53 mutations and outcome in osteosarcoma: A prospective, multicenter study', Journal of Clinical Oncology, vol. 23, no. 7, pp. 1483-1490. https://doi.org/10.1200/JCO.2005.04.074
Wunder JS, Gokgoz N, Parkes R, Bull SB, Eskandarian S, Davis AM et al. TP53 mutations and outcome in osteosarcoma: A prospective, multicenter study. Journal of Clinical Oncology. 2005;23(7):1483-1490. https://doi.org/10.1200/JCO.2005.04.074
Wunder, Jay S. ; Gokgoz, Nalan ; Parkes, Robert ; Bull, Shelley B. ; Eskandarian, Sasha ; Davis, Aileen M. ; Beauchamp, Chris P. ; Conrad, Ernest U. ; Grimer, Robert J. ; Healey, John H. ; Malkin, David ; Mangham, D. C. ; Rock, Michael J. ; Bell, Robert S. ; Andrulis, Irene L. / TP53 mutations and outcome in osteosarcoma : A prospective, multicenter study. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 7. pp. 1483-1490.
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abstract = "Purpose: 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. Patients and 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 7P53 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 (≤ 90{\%} necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. Conclusion: 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.",
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T1 - TP53 mutations and outcome in osteosarcoma

T2 - A prospective, multicenter study

AU - Wunder, Jay S.

AU - Gokgoz, Nalan

AU - Parkes, Robert

AU - Bull, Shelley B.

AU - Eskandarian, Sasha

AU - Davis, Aileen M.

AU - Beauchamp, Chris P.

AU - Conrad, Ernest U.

AU - Grimer, Robert J.

AU - Healey, John H.

AU - Malkin, David

AU - Mangham, D. C.

AU - Rock, Michael J.

AU - Bell, Robert S.

AU - Andrulis, Irene L.

PY - 2005

Y1 - 2005

N2 - Purpose: 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. Patients and 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 7P53 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 (≤ 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. Conclusion: 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.

AB - Purpose: 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. Patients and 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 7P53 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 (≤ 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. Conclusion: 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.

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