Comprehensive Mapping of p53 Pathway Alterations Reveals an Apparent Role for Both SNP309 and MDM2 Amplification in Sarcomagenesis

Abstract

Purpose: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease.Experimental Design: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status.Results: We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification.Conclusions: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists. Clin Cancer Res; 17(3); 416-26. Ó2010 AACR.

Letter regarding Wang et al. entitled “Effects of murine double minute 2 polymorphisms on the risk and survival of osteosarcoma: a systematic review and meta-analysis”

“…According to our analyses, there is no association between MDM2 rs2279744 and osteosarcoma risk in the population used by Ito et al [3]. This contradicts the result shown by Wang et al [1] in their study.…”

“…This contradicts the result shown by Wang et al [1] in their study. When we calculate the odds ratio (OR) value of Ito et al [3] samples, using the total of benign tumors (n=37) as controls, we obtain a different OR value. This contradictory result has been observed in all hereditary models (allele model, OR=1.46, 95 % CI 0.62-3.43; codominant model, OR=1.50, 95 % 0.29-7.65; recessive model, OR 1.11, 95 % CI 0.24-5.08; dominant model, OR=1.88, 95 % 0.59-6.01).…”

“…The main problem we detect here is that Wang et al [1] specify neither the samples nor the genotype frequencies used for the meta-analyses. The only available data in the Ito et al [3] paper that can be used as controls come from the benign tumors. When we used these data (osteosarcoma, GG=3, GT=7, TT=7; benign tumors, GG=6, GT=10, TT= 21), no significant values were found.…”

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

“…4,6,7,30 The hypothesis that MDM2 Ampl and TP53 Mut both provide inactivation of the p53 response has been challenged by the occasional report that the 2 aberrations may be found in the same tumor. 31 We found such apparent double mutations in 2 samples, LS03 and MFH53 (Fig. 2).…”

A systematic review and meta-analysis of MDM2 polymorphisms in osteosarcoma susceptibility

“…MDM2 rs2279744, situated in the promoter region, was related to an increased risk of OS (GG vs. TT) in Italian population (211 OS patients and 250 controls) (5), being this association stronger in females. Moreover, a robust correlation between rs2279744 G allele enrichment and MDM2 amplification was found, suggesting the contribution of this polymorphism to OS tumorigenesis (12). However, this single nucleotide polymorphism (SNP) did not show any association in the North-American population (7).…”