Prognostic Significance of TP53 Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma

Abstract

Purpose: Various studies examining the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. The purpose of the current study was to evaluate the relation of TP53 status with response to chemotherapy and/or clinical outcome in osteosarcoma.Experimental Design: We conducted a meta-analysis of 16 studies (n ‫؍‬ 499 patients) that evaluated the correlation between TP53 status and histologic response to chemotherapy and 2-year survival. Data were synthesized in summary receiver operating characteristic curves and with summary likelihood ratios (LRs) and risk ratios.Results: The quantitative synthesis showed that TP53 status is not a prognostic factor for the response to chemotherapy. The positive LR was 1.21 (95% confidence interval, 0.86 -1.71), and the negative LR was 0.91 (95% confidence interval, 0.77-1.07). There was no significant between-study heterogeneity. TP53-positive status tended to be associated with a worse 2-year survival, but the overall results were not formally statistically significant. The association was formally significant in studies that clearly stated that measurements were blinded to outcomes (risk ratio, 2.05; 95% confidence interval, 1.23-3.44), and in studies using reverse transcription-PCR for evaluating TP53 alterations (risk ratio, 1.76; 95% confidence interval, 1.07-2.91).Conclusions: TP53 status is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas TP53 gene alterations may be associated with decreased survival.

Effect of TP53 Arg72Pro and MDM2 SNP309 Polymorphisms on the Risk of High-Grade Osteosarcoma Development and Survival

“…Data about the effect of TP53 status on response to chemotherapy in osteosarcomas are still controversial. There is a general agreement on the detrimental effect of TP53 status on overall survival (12). In our study, osteosarcoma patients harboring the Arg allele showed a significantly longer EFS after neoadjuvant chemotherapy and a significant longer overall survival in the entire series of osteosarcomas.…”

“…Positive correlations between TP53 status and response to chemotherapy or disease progression have been reported in osteosarcomas or soft tissue sarcomas (STS) but with contradictory evidence (8)(9)(10)(11). A meta-analysis of 16 studies in human osteosarcomas evaluating the correlation between TP53 protein expression in tumor cells, histologic response to chemotherapy, and 2-year survival failed to find a relationship, whereas the TP53 gene mutations were found to be variably associated with decreased survival (12).…”

An intact ING1-p53 pathway can potentiate the cytotoxic effects of taxol

“…A recent meta-analysis has shown that there is no relationship between p53 overexpression or p53 alteration and response to chemotherapy in patients with osteosarcomas. 8 Furthermore, for patients with ovarian and breast cancers, at least two studies show p53-deficient tumors have a better response to taxol. 9 In vitro studies also demonstrate that taxol induced apoptosis can be independent of p53 or the mitochondrial pathway.…”

Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease

“…In addition, somatic mutation of p53 is frequently observed in sporadic OS (Miller et al 1990; Nishio et al 2006). Alterations of p53 correlate with markedly reduced event-free survival (Tsuchiya et al 2000;Pakos et al 2004;Wunder et al 2005). The relative importance of mutations in the p53 or pRb pathways and the degree to which they cooperate in the initiation of OS are unclear.…”