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.
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.
Young
Ken H
KH
Department of Pathology and Microbiology, Munroe Meyer Institute for Genetics and Rehabilitation, Omaha, NE, USA.
Weisenburger
Dennis D
DD
Dave
Bhavana J
BJ
Smith
Lynette
L
Sanger
Warren
W
Iqbal
Javeed
J
Campo
Elias
E
Delabie
Jan
J
Gascoyne
Randy D
RD
Ott
German
G
Rimsza
Lisa
L
Müller-Hermelink
H Konrad
HK
Jaffe
Elaine S
ES
Rosenwald
Andreas
A
Staudt
Louis M
LM
Chan
Wing C
WC
Greiner
Timothy C
TC
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*
D003062:Codon; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53