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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4396-4405.
Prepublished online as a Blood First Edition Paper on September 19, 2007October 25, 2007; DOI 10.1182/blood-2007-02-072082.
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Submitted February 6, 2007
Accepted August 11, 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
Ken H. Young, Dennis D. Weisenburger, Bhavana Dave, Lynette Smith, Warren Sanger, Javeed Iqbal, Elias Campo, Jan Delabie, Randy D. Gascoyne, German Ott, Lisa Rimsza, H. Konrad Muller-Hermelink, Elaine S. Jaffe, Andreas Rosenwald, Louis M. Staudt, Wing C. Chan, and Timothy C. Greiner*
Dept of Pathology & Microbiology, Preventive & Societal Med., Inst of Human Cytogenetics, & Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
Department of Pathology, University of Barcelona, Barcelona, Spain
Pathology Department, Norwegian Radium Hospital, Oslo, Norway
Pathology Department, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Institute of Pathology, University of Wurzburg, Wurzburg, Germany
Department of Pathology, University of Arizona, Tucson, AZ, United States
Hematopathology Section and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
* Corresponding author; email: tgreiner{at}unmc.edu.
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 of the 24 cases (50%) 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 = 0.044), but DNA-binding mutations were the most significant predictor of poor OS (P < 0.001). 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 under-expressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy towards TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.
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