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

被引：46

作者：

Xu-Monette, Zijun Y. ^{[1
]}

Moller, Michael B. ^{[2
]}

Tzankov, Alexander ^{[3
]}

Montes-Moreno, Santiago ^{[4
]}

Hu, Wenwei ^{[5
]}

Manyam, Ganiraju C. ^{[6
]}

Kristensen, Louise ^{[2
]}

Fan, Lei ^{[7
]}

Visco, Carlo ^{[8
]}

Dybkaer, Karen ^{[9
]}

Chiu, April ^{[10
]}

Tam, Wayne ^{[11
]}

Zu, Youli ^{[12
]}

Bhagat, Govind ^{[13
,14
]}

Richards, Kristy L. ^{[15
]}

Hsi, Eric D. ^{[16
]}

Choi, William W. L. ^{[17
]}

van Krieken, J. Han ^{[18
]}

Huang, Qin ^{[19
]}

Huh, Jooryung ^{[20
]}

Ai, Weiyun ^{[21
]}

Ponzoni, Maurilio ^{[22
]}

Ferreri, Andres J. M. ^{[22
]}

Wu, Lin ^{[23
]}

Zhao, Xiaoying ^{[24
]}

Bueso-Ramos, Carlos E. ^{[1
]}

Wang, Sa A. ^{[1
]}

Go, Ronald S. ^{[25
]}

Li, Yong ^{[26
,27
]}

Winter, Jane N. ^{[28
]}

Piris, Miguel A. ^{[4
]}

Medeiros, L. Jeffrey ^{[1
]}

Young, Ken H. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

[2] Odense Univ Hosp, DK-5000 Odense, Denmark

[3] Univ Basel Hosp, CH-4031 Basel, Switzerland

[4] Hosp Univ Marques de Valdecilla, Santander, Spain

[5] Univ Med & Dent New Jersey, Canc Inst New Jersey, New Brunswick, NJ USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Biostat & Bioinformat, Houston, TX 77030 USA

[7] Nanjing Med Univ, Jiangsu Prov Hosp, Affiliated Hosp 1, Nanjing, Jiangsu, Peoples R China

[8] San Bortolo Hosp, Vicenza, Italy

[9] Aarhus Univ Hosp, Aalborg Hosp, Aalborg, Denmark

[10] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA

[11] Cornell Univ, Weill Med Coll, New York, NY 10021 USA

[12] Methodist Hosp, Houston, TX 77030 USA

[13] Columbia Univ, Med Ctr, New York, NY USA

[14] New York Presbyterian Hosp, New York, NY USA

[15] Univ N Carolina, Sch Med, Chapel Hill, NC USA

[16] Cleveland Clin, Cleveland, OH 44106 USA

[17] Univ Hong Kong, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China

[18] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[19] City Hope Natl Med Ctr, Duarte, CA 91010 USA

[20] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea

[21] Univ Calif San Francisco, Sch Med, San Francisco, CA USA

[22] Ist Sci San Raffaele, Milan, Italy

[23] Roche Mol Syst, Pleasanton, CA USA

[24] Zhejiang Univ, Sch Med, Univ Hosp 2, Hangzhou 310003, Zhejiang, Peoples R China

[25] Mayo Clin, Rochester, MN USA

[26] Univ Louisville, Louisville, KY 40292 USA

[27] Shanghai Technol Univ, Shanghai, Peoples R China

[28] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

来源：

BLOOD | 2013年 / 122卷 / 15期

基金：

美国国家卫生研究院;

关键词：

P53-MDM2 FEEDBACK LOOP; SINGLE NUCLEOTIDE POLYMORPHISM; NON-HODGKINS-LYMPHOMA; MUTANT P53; ONCOPROTEIN MDM2; IN-VIVO; OSCILLATIONS; SURVIVAL; OVEREXPRESSION; EXPRESSION;

D O I：

10.1182/blood-2012-12-473702

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：2630 / 2640

页数：11

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