title: Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma.
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 TRAILreceptor-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.
authors: Department of Pathology and Microbiology, Munroe Meyer Institute for Genetics and Rehabilitation, Omaha, NE, USA.
authors: Ken H
authors: KH
authors: Young
authors: Dennis D
authors: DD
authors: Weisenburger
authors: Bhavana J
authors: BJ
authors: Dave
authors: Lynette
authors: L
authors: Smith
authors: Warren
authors: W
authors: Sanger
authors: Javeed
authors: J
authors: Iqbal
authors: Elias
authors: E
authors: Campo
authors: Jan
authors: J
authors: Delabie
authors: Randy D
authors: RD
authors: Gascoyne
authors: German
authors: G
authors: Ott
authors: Lisa
authors: L
authors: Rimsza
authors: H Konrad
authors: HK
authors: Müller-Hermelink
authors: Elaine S
authors: ES
authors: Jaffe
authors: Andreas
authors: A
authors: Rosenwald
authors: Louis M
authors: LM
authors: Staudt
authors: Wing C
authors: WC
authors: Chan
authors: Timothy C
authors: TC
authors: Greiner
mesh_terms: D001665:Binding Sites; D003062:Codon; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D011379:Prognosis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D003062:Codon; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53