Mdm2 mRNA Level is a Prognostic Factor in Soft Tissue Sarcoma

Abstract

The oncogenic properties of murine double minute-2 (mdm2) protein over-expression, which mostly results from the interaction with the tumor suppressor p53, are well described and their negative impacts on the prognosis of affected patients is well characterized. However, clinical relevance of mdm2 mRNA expression is poorly investigated. In this study, 65 soft tissue sarcoma (STS) samples were analyzed for mdm2 mRNA expression by a quantitative reverse transcription polymerase chain reaction (RT-PCR) approach using available validated ready-to-use assays based on the TaqMan technology (PE Applied Biosystems, Weiterstadt, Germany). Mdm2 data were correlated to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression calculated from the same sample. For patients with a mdm2/GAPDH mRNA ratio below 50 zmol/amol the survival was strikingly reduced in comparison to patients with a ratio of > or =50 (p = 0.0241). Multivariate Cox analysis showed that the difference in prognosis for patients with tumor stage 2 and 3 became even more pronounced between patients with a ratio of <50 zmol/amol and patients with a ratio of > or =50 (p = 0.0041; RR = 5.6). To test if the group with an mdm2 mRNA expression > or =50 is homogenous concerning the prognosis, the group was divided into three subgroups with values of 50 to <100, 100 to <500 and > or =500. The subgroup with values of 100 to <500 showed the best prognosis (p = 0.0164); whereas, the one with values of 50 to <100 showed the worst prognosis in this group and, in between, was the one with values of > or =500. After omitting patients of stage 1 and 4, the subgroup with values of 100 to <500 showed an even more striking best prognosis (p = 0.0015); the other subgroups remained in the same sequence. The risk of tumor-related death over 5 years was most conspicuous in patients with mdm2 mRNA expression <50 than in those with ratios of 100 to <500 displaying a 13.3-fold higher risk. In a comparison between mdm2 mRNA levels and P53 protein expression or p53 mutational status, no relationship was found. In our study, the mdm2 mRNA level appears to be an independent prognostic factor for STS patients, marking its role in STS genesis and as a potential factor for gene therapeutical approaches.