Poor Survival Predicted by MDM2 Oncoprotein Expression in Diffuse Large B-Cell Lymphoma (DLBCL) with Wild-Type TP53 Gene

The p53 pathway is known to play a role in pathogenesis and prognosis of human malignancies including diffuse large B-cell lymphoma (DLBCL). The MDM2 protein has been shown to regulate p53 function and stability via a multi-factorial negative feedback loop. MDM2 is involved in transport of p53 out of the nucleus and its subsequent degradation. Additionally, MDM2 binds p53 protein and inhibits its function as a transcription factor. As an integral part of the regulation of the p53 pathway, we hypothesize MDM2 expression contributes to the pathogenesis of DLBCL and affects survival. The purpose of this study is to investigate the potential role of the MDM2 protein in DLBCL by correlating expression of MDM2 with p53 expression, TP53 mutation status and clinical outcome. Immunostains for MDM2 and TP53 gene-product proteins were performed in 133 cases from 6 medical centers. A positive immunostain was defined as nuclear staining in 10% or more of the tumor cells. The TP53 gene was analyzed for mutations with PCR-based and sequencing methods. Patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimen. The Kaplan-Meier method was used for survival analysis. MDM2 immunostains were positive in 64 of 133 cases of DLBCL (48%). There was a trend toward poor overall survival (OS) with MDM2 expression in the entire group of patient with DLBCL (p=0.32). Twelve of 24 cases (50%) with TP53 mutations demonstrated MDM2 expression. Within this TP53 mutated group, no significant difference in OS was observed between MDM2-positive and MDM2-negative cases (p=0.32). Of patients with wild-type (WT) TP53, 51 of 107 cases (48%) expressed MDM2. In this subset of patients, the MDM2-positive phenotype predicted for poor 5-year OS (38% vs 67%, p=0.002), and a significantly shorter median disease-free survival (2.3 years vs. >5.0 years; p=0.013). The complete remission rate was 57% in MDM2-positive cases compared to 73% in MDM2-negative cases in the WT-TP53 group (p=0.08). Multivariate analysis confirmed that MDM2 expression was an independent predictor of poor OS in patient with DLBCL with a WT-TP53 gene (HR 2.0, 95% CI 1.15–3.56; p=0.015). This study demonstrates the negative survival impact of MDM2 expression in patients with wild-type TP53, suggesting that MDM2 provides an alternative mechanism of p53 pathway inactivation in DLBCL cases with a WT-TP53 gene.