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TP53 Mutations and Outcome in Osteosarcoma: A Prospective, Multicenter Study

From the Samuel Lunenfeld Research Institute, and the University Musculoskeletal Oncology Unit, Mount Sinai Hospital; Departments of Surgery, Public Health Sciences, Medical Genetics and Microbiology, Pathology and Laboratory Medicine, University of Toronto; Division of Hematology-Oncology, Hospital for Sick Children, Toronto, Ontario; University of British Columbia, Vancouver, British Columbia, Canada; University of Washington Medical Center, Seattle, WA; Royal Orthopaedic Hospital, Birmingham, England; Memorial Sloan-Kettering Cancer Center, NY, New York; and Mayo Clinic, Rochester, MN

Address reprint requests to Jay S. Wunder, MD, 476E-600 University Ave, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5; e-mail: wunder{at}mshri.on.ca

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 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 ( 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.

Supported by grants from the National Cancer Institute of Canada and Canadian Institutes of Health Research (J.S.W., A.M.D., D.M., R.S.B., I.L.A.).

J.S.W. and N.G. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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