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 Dybkaer, 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, S. A. Wang, Ronald S. Go, Yong Li, Jane N. Winter, Miguel A. Piris, L. Jeffrey Medeiros, Ken H. Young

Research output: Contribution to journalArticle

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
Pages (from-to)2630-2640
Number of pages11
JournalBlood
Volume122
Issue number15
Publication statusPublished - Oct 10 2013

Fingerprint

Chemotherapy
Lymphoma, Large B-Cell, Diffuse
Vincristine
Prednisone
Polymorphism
Gene expression
Cyclophosphamide
Amplification
Tumors
Assays
Nucleotides
Fluorescence
Cells
Single Nucleotide Polymorphism
Survival
Gene Amplification
Gene Expression Profiling
Fluorescence In Situ Hybridization
Immunohistochemistry
Drug Therapy

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

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

In: Blood, Vol. 122, No. 15, 10.10.2013, p. 2630-2640.

Research output: Contribution to journalArticle

Xu-Monette, ZY, Møller, MB, Tzankov, A, Montes-Moreno, S, Hu, W, Manyam, GC, Kristensen, L, Fan, L, Visco, C, Dybkaer, K, Chiu, A, Tam, W, Zu, Y, Bhagat, G, Richards, KL, Hsi, ED, Choi, WWL, van Krieken, JH, Huang, Q, Huh, J, Ai, W, Ponzoni, M, Ferreri, AJM, Wu, L, Zhao, X, Bueso-Ramos, CE, Wang, SA, Go, RS, Li, Y, Winter, JN, Piris, MA, Medeiros, LJ & Young, KH 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, vol. 122, no. 15, pp. 2630-2640.
Xu-Monette, Zijun Y. ; Møller, Michael B. ; Tzankov, Alexander ; Montes-Moreno, Santiago ; Hu, Wenwei ; Manyam, Ganiraju C. ; Kristensen, Louise ; Fan, Lei ; Visco, Carlo ; Dybkaer, Karen ; Chiu, April ; Tam, Wayne ; Zu, Youli ; Bhagat, Govind ; Richards, Kristy L. ; Hsi, Eric D. ; Choi, William W L ; van Krieken, J. Han ; Huang, Qin ; Huh, Jooryung ; Ai, Weiyun ; Ponzoni, Maurilio ; Ferreri, Andrés J M ; Wu, Lin ; Zhao, Xiaoying ; Bueso-Ramos, Carlos E. ; Wang, S. A. ; Go, Ronald S. ; Li, Yong ; Winter, Jane N. ; Piris, Miguel A. ; Medeiros, L. Jeffrey ; Young, Ken H. / 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. In: Blood. 2013 ; Vol. 122, No. 15. pp. 2630-2640.
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title = "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.",
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.",
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T1 - MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy

T2 - a report from the International DLBCL Rituximab-CHOP Consortium Program.

AU - Xu-Monette, Zijun Y.

AU - Møller, Michael B.

AU - Tzankov, Alexander

AU - Montes-Moreno, Santiago

AU - Hu, Wenwei

AU - Manyam, Ganiraju C.

AU - Kristensen, Louise

AU - Fan, Lei

AU - Visco, Carlo

AU - Dybkaer, Karen

AU - Chiu, April

AU - Tam, Wayne

AU - Zu, Youli

AU - Bhagat, Govind

AU - Richards, Kristy L.

AU - Hsi, Eric D.

AU - Choi, William W L

AU - van Krieken, J. Han

AU - Huang, Qin

AU - Huh, Jooryung

AU - Ai, Weiyun

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J M

AU - Wu, Lin

AU - Zhao, Xiaoying

AU - Bueso-Ramos, Carlos E.

AU - Wang, S. A.

AU - Go, Ronald S.

AU - Li, Yong

AU - Winter, Jane N.

AU - Piris, Miguel A.

AU - Medeiros, L. Jeffrey

AU - Young, Ken H.

PY - 2013/10/10

Y1 - 2013/10/10

N2 - 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.

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