TY - JOUR
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 - Dybkær, 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, Sa A.
AU - Go, Ronald S.
AU - Li, Yong
AU - Winter, Jane N.
AU - Piris, Miguel A.
AU - Medeiros, L. Jeffrey
AU - Young, Ken H.
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013
Y1 - 2013
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.
AB - 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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U2 - 10.1182/blood-2012-12-473702
DO - 10.1182/blood-2012-12-473702
M3 - Article
C2 - 23982177
AN - SCOPUS:84891606259
SN - 0006-4971
VL - 122
SP - 2630
EP - 2640
JO - Blood
JF - Blood
IS - 15
ER -