Clinicopathologiclmplications of MDM2, p53 and K-ras gene alterations in osteosarcomas: MDM2 amplification and p53 mutations found in progressive tumors

Yokoyama, Ryohei; Schneider‐Stock, Regine; Radig, Kathrin; Wex, Thomas; Roessner, Albert

doi:10.1016/s0344-0338(98)80096-4

Cited by 48 publications

(36 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nine studies used IHC to determine TP53 status (9, 10, 12, 17-21, 24), four studies used RT-PCR (13,15,22,23), and three studies used both IHC and RT-PCR determinations (11,14,16). One study from those using both RT-PCR and IHC had clinical data only on RT-PCR determinations (14).…”

Section: Resultsmentioning

confidence: 99%

“…The most common antibody used for the detection of TP53 with IHC was DO-7, but other antibodies were also used. The cutoff of 90% necrosis to separate responders from nonresponders was used by five studies (10,16,17,21,22), whereas two studies used the Huvos grading system (9, 23) and two studies used Salzer-Kuntschik's classification (13,18). Five studies clearly stated that determination of TP53 status was blinded to outcomes (9, 17, 19 -21).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Pakos

Kyzas

Ioannidis

2004

Clinical Cancer Research

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Pakos

Kyzas

Ioannidis

2004

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Indeed, it has been clearly shown that in many of the remaining 50% of cancers, the activity of the wildtype p53 protein is greatly attenuated (8). In high-grade osteosarcoma, mutations in the p53 gene are found in only 20% of the tumors (9)(10)(11). However, the genomic region that encodes for a key negative regulator of p53, HDM2 (12,13), was found to be amplified in 10% to 35% of osteosarcomas and these amplifications were shown to be mutually exclusive to p53 mutations (9)(10)(11)14).…”

Section: Introductionmentioning

confidence: 99%

Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer

et al. 2012

View full text Add to dashboard Cite

Conventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of the p53 inhibitor HDMX (Mdmx/Mdm4) is associated with cancer risk, progression, and outcome in other tumor types, little is known about its role in osteosarcoma. High expression of the Hdmx splice variant HDMX-S relative to the full-length transcript (the HDMX-S/HDMX-FL ratio) correlates with reduced HDMX protein expression, faster progression, and poorer survival in several cancers. Here, we show that the HDMX-S/ HDMX-FL ratio positively correlates with less HDMX protein expression, faster metastatic progression, and a trend to worse overall survival in osteosarcomas. We found that the HDMX-S/HDMX-FL ratio associated with common somatic genetic lesions connected with p53 inhibition, such as p53 mutation and HDM2 overexpression in osteosarcoma cell lines. Interestingly, this finding was not limited to osteosarcomas as we observed similar associations in breast cancer and a variety of other cancer cell lines, as well as in tumors from patients with soft tissue sarcoma. The HDMX-S/HDMX-FL ratio better defined patients with sarcoma with worse survival rates than p53 mutational status. We propose a novel role for alternative splicing of HDMX, whereby it serves as a mechanism by which HDMX protein levels are reduced in cancer cells that have already inhibited p53 activity. Alternative splicing of HDMX could, therefore, serve as a more effective biomarker for p53 pathway attenuation in cancers than p53 gene mutation. Cancer Res; 72(16); 4074-84. Ó2012 AACR.

show abstract

“…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).…”

mentioning

confidence: 99%

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

Toffoli

Biason

Russo

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The germ-line polymorphisms TP53 Arg72Pro and MDM2 SNP309 T>G are risk factors for tumor development and affect response to chemotherapy and survival in several cancers, but their prognostic and predictive value in patients with high-grade osteosarcomas is not yet defined. The purpose of this study was to investigate the effect of the TP53 Arg72Pro and the MDM2 SNP309 on the risk of osteosarcoma development and survival. Experimental Design: The relative risk to develop osteosarcomas and the overall survival associated to TP53 Arg72Pro and MDM2 SNP309 polymorphisms were investigated in 201 patients. Correlations with event-free survival (EFS) were analyzed in a homogeneous subgroup of 130 patients with high-grade osteosarcomas of the limbs, nonmetastatic at diagnosis, which underwent neoadjuvant chemotherapy. Results: Multivariate analysis showed that the MDM2 polymorphism T309G was associated with an increased risk of developing osteosarcomas [GG versus TT; odds ratio, 2.09; 95% confidence interval (95% CI), 1.15-3.78]. A case/control gender approach evidenced a significant increased risk only for female osteosarcoma patients (GG versus TT; odds ratio, 4.26; 95% CI, 1.61-11.25). Subjects carrying the TP53 Arg72Pro polymorphism were found to have a significantly increased death risk (Pro/Pro versus Arg/Arg; hazard ratio, 2.90; 95% CI, 1.28-6.66). In the subgroup of 130 high-grade osteosarcomas, the TP53 Arg72Pro was an independent marker of EFS (Pro/Pro versus Arg/ Arg; hazard ratio, 2.67; 95% CI, 1.17-6.11). Conclusion:The study provides evidence supporting the association of MDM2 SNP309 with high-grade osteosarcoma risk in females and shows that TP53 Arg72Pro has a prognostic value for overall survival and EFS in osteosarcoma patients.

show abstract

Clinicopathologiclmplications of MDM2, p53 and K-ras gene alterations in osteosarcomas: MDM2 amplification and p53 mutations found in progressive tumors

Cited by 48 publications

References 18 publications

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

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

Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer

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

Contact Info

Product

Resources

About