MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: A report from the International DLBCL Rituximab-CHOP Consortium Program

Zijun Y. Xu-Monette, Michael B. Møller, Alexander Tzankov, Santiago Montes-Moreno, Wenwei Hu, Ganiraju C. Manyam, Louise Kristensen, Lei Fan, Carlo Visco, Karen Dybkær, April Chiu, Wayne Tam, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han Van Krieken, Qin Huang, Jooryung HuhWeiyun Ai, Maurilio Ponzoni, Andrés J.M. Ferreri, Lin Wu, Xiaoying Zhao, Carlos E. Bueso-Ramos, Sa A. Wang, Ronald S. Go, Yong Li, Jane N. Winter, Miguel A. Piris, L. Jeffrey Medeiros, Ken H. Young

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically-defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n = 478), MDM2 gene amplification by fluorescence in situ hybridization (n = 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n = 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction.

Original languageEnglish (US)
Pages (from-to)2630-2640
Number of pages11
JournalBlood
Volume122
Issue number15
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Xu-Monette, Z. Y., Møller, M. B., Tzankov, A., Montes-Moreno, S., Hu, W., Manyam, G. C., Kristensen, L., Fan, L., Visco, C., Dybkær, K., Chiu, A., Tam, W., Zu, Y., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W. L., Van Krieken, J. H., Huang, Q., ... Young, K. H. (2013). MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: A report from the International DLBCL Rituximab-CHOP Consortium Program. Blood, 122(15), 2630-2640. https://doi.org/10.1182/blood-2012-12-473702