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 Huh; Weiyun 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

doi:10.1182/blood-2012-12-473702

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

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	2630-2640
Number of pages	11
Journal	Blood
Volume	122
Issue number	15
DOIs	https://doi.org/10.1182/blood-2012-12-473702
State	Published - 2013

Funding

This work was supported by Harold C. and Mary L. Daily Endowment Fellowships at The University of Texas MD Anderson Cancer Center (Z.Y.X.M.); the Stiftung zur Krebsbekaempfung Zurich Grant 269 award (A.T.); the Ministerio de Ciencia e Innovación, Spain (RETICC, SAF2008-03871) and the Spanish Association against Cancer (AECC) (M.A.P.); National Cancer Institute and National Institutes of Health grant 1R01CA160558 (W.H); a University of Texas MD Anderson Cancer Center Institutional Research Grant Award, an Anderson Lymphoma Specialized Programs of Research Excellence (SPORE) Research Development Program Award, an Anderson Myeloma SPORE Research Development Program Award, and Anderson Collaborative Research Funds with High-Throughput Molecular Diagnostics and Roche Molecular Systems (K.H.Y.). This work was also partially supported by the National Cancer Institute and National Institutes of Health grants (R01CA138688, 1RC1CA146299, P50CA136411, and P50CA142509) and by the MD Anderson Cancer Center Support Grant CA016672.

ASJC Scopus subject areas

Hematology
Biochemistry
Cell Biology
Immunology

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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., Dybkaer, 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

@article{5e9bdb53b45943b2b43794d3584fa40b,

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.",

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

note = "Publisher Copyright: {\textcopyright} 2013 by The American Society of Hematology.",

year = "2013",

doi = "10.1182/blood-2012-12-473702",

language = "English (US)",

volume = "122",

pages = "2630--2640",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "15",

}

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. https://doi.org/10.1182/blood-2012-12-473702

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 et al.
In: Blood, Vol. 122, No. 15, 2013, p. 2630-2640.

Research output: Contribution to journal › Article › peer-review

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 - 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

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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UR - http://www.scopus.com/inward/citedby.url?scp=84891606259&partnerID=8YFLogxK

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 -

Xu-Monette ZY, Møller MB, Tzankov A, Montes-Moreno S, Hu W, Manyam GC et al. 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. 2013;122(15):2630-2640. doi: 10.1182/blood-2012-12-473702

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

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