Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAIL receptor-2, predict for poor survival in diffuse large B-cell lymphoma

Ken H. Young, Dennis D. Weisenburger, Bhavana J Dave, Lynette M Smith, Warren Sanger, Javeed Iqbal, Elias Campo, Jan Delabie, Randy D. Gascoyne, German Ott, Lisa Rimsza, H. Konrad Müller-Hermelink, Elaine S. Jaffe, Andreas Rosenwald, Louis M. Staudt, Wing C. Chan, Timothy Charles Greiner

Research output: Contribution to journalArticle

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Abstract

Mutations of the TP53 tumor suppressor gene have been associated with poor survival in some series of diffuse large B-cell lymphoma (DLBCL) but not in other studies. The purpose of this study was to identify the frequency of TP53 alterations (mutations or deletions), characterize the gene expression of mutant/deleted cases, and determine the effects of mutations on survival. In a series of DLBCL that had previous gene expression profiling, we identified 24 mutations in 113 cases (21%). There was no difference in the frequency of mutations in the molecular subgroups of DLBCL. Twelve (50%) of the 24 cases had mutations localized to the DNA-binding codons in the core domain of TP53. The presence of any TP53 mutation correlated with poor overall survival (OS; P = .044), but DNA-binding mutations were the most significant predictor of poor OS (P < .001). Multivariate analysis confirmed that the International Prognostic Index, tumor size, and TP53 DNA-binding mutations were independent predictors of OS. Gene expression analysis showed that TRAIL receptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy toward TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.

Original languageEnglish (US)
Pages (from-to)4396-4405
Number of pages10
JournalBlood
Volume110
Issue number13
DOIs
StatePublished - Dec 15 2007

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TNF-Related Apoptosis-Inducing Ligand Receptors
Lymphoma, Large B-Cell, Diffuse
Gene expression
Codon
Cells
Mutation
Tumors
DNA
Genes
Gene Expression
Sequence Deletion
p53 Genes
Gene Expression Profiling
Mutation Rate
Tumor Suppressor Genes
Multivariate Analysis

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAIL receptor-2, predict for poor survival in diffuse large B-cell lymphoma. / Young, Ken H.; Weisenburger, Dennis D.; Dave, Bhavana J; Smith, Lynette M; Sanger, Warren; Iqbal, Javeed; Campo, Elias; Delabie, Jan; Gascoyne, Randy D.; Ott, German; Rimsza, Lisa; Müller-Hermelink, H. Konrad; Jaffe, Elaine S.; Rosenwald, Andreas; Staudt, Louis M.; Chan, Wing C.; Greiner, Timothy Charles.

In: Blood, Vol. 110, No. 13, 15.12.2007, p. 4396-4405.

Research output: Contribution to journalArticle

Young, KH, Weisenburger, DD, Dave, BJ, Smith, LM, Sanger, W, Iqbal, J, Campo, E, Delabie, J, Gascoyne, RD, Ott, G, Rimsza, L, Müller-Hermelink, HK, Jaffe, ES, Rosenwald, A, Staudt, LM, Chan, WC & Greiner, TC 2007, 'Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAIL receptor-2, predict for poor survival in diffuse large B-cell lymphoma', Blood, vol. 110, no. 13, pp. 4396-4405. https://doi.org/10.1182/blood-2007-02-072082
Young, Ken H. ; Weisenburger, Dennis D. ; Dave, Bhavana J ; Smith, Lynette M ; Sanger, Warren ; Iqbal, Javeed ; Campo, Elias ; Delabie, Jan ; Gascoyne, Randy D. ; Ott, German ; Rimsza, Lisa ; Müller-Hermelink, H. Konrad ; Jaffe, Elaine S. ; Rosenwald, Andreas ; Staudt, Louis M. ; Chan, Wing C. ; Greiner, Timothy Charles. / Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAIL receptor-2, predict for poor survival in diffuse large B-cell lymphoma. In: Blood. 2007 ; Vol. 110, No. 13. pp. 4396-4405.
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abstract = "Mutations of the TP53 tumor suppressor gene have been associated with poor survival in some series of diffuse large B-cell lymphoma (DLBCL) but not in other studies. The purpose of this study was to identify the frequency of TP53 alterations (mutations or deletions), characterize the gene expression of mutant/deleted cases, and determine the effects of mutations on survival. In a series of DLBCL that had previous gene expression profiling, we identified 24 mutations in 113 cases (21{\%}). There was no difference in the frequency of mutations in the molecular subgroups of DLBCL. Twelve (50{\%}) of the 24 cases had mutations localized to the DNA-binding codons in the core domain of TP53. The presence of any TP53 mutation correlated with poor overall survival (OS; P = .044), but DNA-binding mutations were the most significant predictor of poor OS (P < .001). Multivariate analysis confirmed that the International Prognostic Index, tumor size, and TP53 DNA-binding mutations were independent predictors of OS. Gene expression analysis showed that TRAIL receptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy toward TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.",
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AU - Young, Ken H.

AU - Weisenburger, Dennis D.

AU - Dave, Bhavana J

AU - Smith, Lynette M

AU - Sanger, Warren

AU - Iqbal, Javeed

AU - Campo, Elias

AU - Delabie, Jan

AU - Gascoyne, Randy D.

AU - Ott, German

AU - Rimsza, Lisa

AU - Müller-Hermelink, H. Konrad

AU - Jaffe, Elaine S.

AU - Rosenwald, Andreas

AU - Staudt, Louis M.

AU - Chan, Wing C.

AU - Greiner, Timothy Charles

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N2 - Mutations of the TP53 tumor suppressor gene have been associated with poor survival in some series of diffuse large B-cell lymphoma (DLBCL) but not in other studies. The purpose of this study was to identify the frequency of TP53 alterations (mutations or deletions), characterize the gene expression of mutant/deleted cases, and determine the effects of mutations on survival. In a series of DLBCL that had previous gene expression profiling, we identified 24 mutations in 113 cases (21%). There was no difference in the frequency of mutations in the molecular subgroups of DLBCL. Twelve (50%) of the 24 cases had mutations localized to the DNA-binding codons in the core domain of TP53. The presence of any TP53 mutation correlated with poor overall survival (OS; P = .044), but DNA-binding mutations were the most significant predictor of poor OS (P < .001). Multivariate analysis confirmed that the International Prognostic Index, tumor size, and TP53 DNA-binding mutations were independent predictors of OS. Gene expression analysis showed that TRAIL receptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy toward TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.

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