Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: An international collaborative study

Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, USA.
Blood (Impact Factor: 10.43). 07/2008; 112(8):3088-98. DOI: 10.1182/blood-2008-01-129783
Source: PubMed

ABSTRACT The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.

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Available from: Elaine S Jaffe, Aug 20, 2015
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    • "The loss of normal p53 has been reported to be critically associated with tumor progression, particularly in leukemia and lymphoma [20]. Similarly, p53 over expression has been demonstrated to have prognostic significance in lymphoma [21]. Recently, p53 has been reported to regulate tumor cell energy metabolism [22] via down regulating expression of glucose transporters GLUT1 and GLUT4 [23] and also by activating the TIGAR gene which represses iPFK2/PFKFB3 [24]. "
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    • "Functional studies have helped to identify particular anomalies in gene families or signaling pathways that could critically contribute to the pathogenesis of the two DLBCL subgroups and be new targets for therapies. GCB lymphomas generally express hundreds of genes that define germinal-center B cells with specific genetic lesions, such as deregulation of BCL2 expression through the t(14;18)(q32;q21) translocation , deregulation of MYC expression primarily through t(8;14)(q24;q32), down regulation of the tumor suppressor PTEN, amplification of REL, and mutations of TP53 (Rosenwald et al., 2002; Lenz et al., 2008b; Young et al., 2008; Pasqualucci et al., 2011). Some mutations have been identified in a number of chromatin modifying genes in the GCB subtype. "
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    • ") . The presence of mutations in the DNA binding domains could also be utilized to stratify germinal centre B - cell - like DLBCL into a subset of cases that correlated with inferior overall survival ( Young et al , 2008 ) . This was further validated by Zainuddin et al ( 2009 ) , who found that 13 of 102 patients with de novo DLBCL displayed TP53 mutations and were associated with poor lymphoma - specific survival and progression - free survival , especially those cases of germinal centre origin . "
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