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.
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors: Zijun Y
authors: ZY
authors: Xu-Monette
authors: Michael B
authors: MB
authors: Møller
authors: Alexander
authors: A
authors: Tzankov
authors: Santiago
authors: S
authors: Montes-Moreno
authors: Wenwei
authors: W
authors: Hu
authors: Ganiraju C
authors: GC
authors: Manyam
authors: Louise
authors: L
authors: Kristensen
authors: Lei
authors: L
authors: Fan
authors: Carlo
authors: C
authors: Visco
authors: Karen
authors: K
authors: Dybkaer
authors: April
authors: A
authors: Chiu
authors: Wayne
authors: W
authors: Tam
authors: Youli
authors: Y
authors: Zu
authors: Govind
authors: G
authors: Bhagat
authors: Kristy L
authors: KL
authors: Richards
authors: Eric D
authors: ED
authors: Hsi
authors: William W L
authors: WW
authors: Choi
authors: J Han
authors: JH
authors: van Krieken
authors: Qin
authors: Q
authors: Huang
authors: Jooryung
authors: J
authors: Huh
authors: Weiyun
authors: W
authors: Ai
authors: Maurilio
authors: M
authors: Ponzoni
authors: Andrés J M
authors: AJ
authors: Ferreri
authors: Lin
authors: L
authors: Wu
authors: Xiaoying
authors: X
authors: Zhao
authors: Carlos E
authors: CE
authors: Bueso-Ramos
authors: Sa A
authors: SA
authors: Wang
authors: Ronald S
authors: RS
authors: Go
authors: Yong
authors: Y
authors: Li
authors: Jane N
authors: JN
authors: Winter
authors: Miguel A
authors: MA
authors: Piris
authors: L Jeffrey
authors: LJ
authors: Medeiros
authors: Ken H
authors: KH
authors: Young
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011241:Prednisone / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012307:Risk Factors; D000069283:Rituximab; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011241:Prednisone
references: Cancer Res. 2011 Dec 1;71(23):7168-75
references: 21983037
references: Carcinogenesis. 2012 Feb;33(2):442-51
references: 22114072
references: Nat Cell Biol. 2008 Sep;10(9):1098-105
references: 19160491
references: Mol Cancer Res. 2004 Jan;2(1):1-8
references: 14757840
references: Clin Cancer Res. 2008 Nov 1;14(21):6780-9
references: 18980971
references: Genes Dev. 2012 Jun 15;26(12):1268-86
references: 22713868
references: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14266-71
references: 16186499
references: Cell Death Differ. 2010 Jan;17(1):93-102
references: 19498444
references: BMC Syst Biol. 2008 Aug 18;2:75
references: 18706112
references: Blood. 2012 Apr 19;119(16):3668-83
references: 22275381
references: Cancer Cell. 2009 Mar 3;15(3):171-83
references: 19249676
references: Syst Biol (Stevenage). 2005 Sep;152(3):109-18
references: 16986275
references: Haematologica. 2007 Apr;92(4):574-5
references: 17488676
references: Mol Cell Biol. 2007 Dec;27(23):8284-95
references: 17908790
references: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11250-5
references: 11016968
references: J Theor Biol. 2008 Sep 21;254(2):452-65
references: 18577387
references: Nat Genet. 2004 Feb;36(2):147-50
references: 14730303
references: Mol Cancer Res. 2003 Dec;1(14):1009-16
references: 14707284
references: Cell Cycle. 2011 Mar 15;10(6):932-50
references: 21368573
references: Development. 2009 Jul;136(13):2277-86
references: 19502488
references: J Theor Biol. 2010 Jun 21;264(4):1177-89
references: 20346959
references: Science. 2012 Apr 13;336(6078):225-8
references: 22499945
references: Mol Cancer Res. 2008 Jun;6(6):947-54
references: 18567799
references: Oncogene. 2008 Mar 6;27(11):1590-8
references: 17828300
references: J Biol Chem. 2001 Nov 30;276(48):45255-60
references: 11572869
references: Blood. 2012 Nov 8;120(19):3986-96
references: 22955915
references: Leukemia. 2005 Sep;19(9):1663-9
references: 15990866
references: Cell. 2004 Nov 24;119(5):591-602
references: 15550242
references: Cancer Res. 2002 Feb 15;62(4):1222-30
references: 11861407
references: J Pathol. 1996 Oct;180(2):129-37
references: 8976869
references: Leukemia. 2012 Sep;26(9):2103-13
references: 22437443
references: BMC Cancer. 2008 Apr 23;8:116
references: 18433491
references: Mol Syst Biol. 2006;2:2006.0033
references: 16773083
references: Mod Pathol. 1999 Nov;12(11):1010-6
references: 10574597
references: J Pathol. 1999 Jul;188(3):322-8
references: 10419603
references: Hum Mutat. 2007 Jun;28(6):622-9
references: 17311302
references: Oncogene. 1998 Mar 26;16(12):1603-10
references: 9569028
references: Cancer Res. 2007 Mar 15;67(6):2757-65
references: 17363597
references: Haematologica. 2002 Nov;87(11):1141-50
references: 12414343
references: Hematol Oncol Clin North Am. 2007 Oct;21(5):841-54
references: 17908623
references: Cancer Res. 2006 Aug 1;66(15):7482-9
references: 16885345
references: Genes Dev. 2008 May 15;22(10):1337-44
references: 18483220
references: Cell Cycle. 2005 Mar;4(3):488-93
references: 15725723
references: Mol Cancer Res. 2003 Dec;1(14):993-1000
references: 14707282
references: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15608-12
references: 9861017
references: BMC Syst Biol. 2010 Jul 12;4:94
references: 20624280
references: Curr Biol. 2003 Aug 19;13(16):1409-13
references: 12932324
references: Cell Cycle. 2009 Nov 15;8(22):3707-16
references: 19844169
references: J Biol Chem. 2001 Mar 2;276(9):6874-8
references: 11152666
references: Histopathology. 2002 Oct;41(4):322-30
references: 12383214