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
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
J Clin Oncol. 2005 Mar 1;23(7):1483-90. doi: 10.1200/JCO.2005.04.074.
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.
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.
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.
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.
TP53基因的突变与多种不同恶性肿瘤对化疗的耐药性以及不良预后相关。这是第一项关于新诊断的肢体骨肉瘤患者中体细胞TP53突变预后价值的前瞻性研究。
从七家三级医疗机构招募了196例高级别、非转移性肢体骨肉瘤患者，并对其进行前瞻性肿瘤复发观察（中位随访时间为44个月）。所有患者均接受新辅助或辅助化疗及手术。通过聚合酶链反应单链构象多态性分析和直接DNA测序分析肿瘤中TP53突变的存在情况。使用生存分析，将传统和组织学标志物作为预后因素，研究TP53基因状态与全身复发风险的关联。
患者年龄是唯一与TP53基因状态相关的因素（P = 0.05）。未发现TP53状态与全身复发之间存在关联（相对风险，1.24；P = 0.41）。基于错义或无义突变的分析得出了类似结果（P > 0.10）。在多变量分析中，肿瘤大（> 9 cm）（相对风险，1.9；P = 0.006）和化疗组织学反应差（≤ 90%坏死）（相对风险，2.14；P = 0.02）是全身结局的唯一显著独立预测因素。
我们没有发现证据表明TP53突变可预测高级别骨肉瘤患者发生转移。需要鉴定影响骨肉瘤化疗反应和临床结局的其他基因，以促进患者结局的进一步改善。
