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: 10.45). 07/2008; 112(8):3088-98. DOI: 10.1182/blood-2008-01-129783
Source: PubMed


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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    • "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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    ABSTRACT: There is a general agreement that most of the cancer cells switch over to aerobic glycolysis (Warburg effect) and upregulate antioxidant enzymes to prevent oxidative stress induced apoptosis. Thus, there is an evolving view to target these metabolic alterations by novel anticancer agents to restrict tumor progression in vivo. Previously we have reported that when a non toxic dose (10 mg/kg bw i.p.) of a novel anticancer ruthenium(II)-complex containing 4-carboxy N-ethylbenzamide; Ru(II)-CNEB was administered to the Dalton's lymphoma (DL) bearing mice, it regressed DL growth by inducing apoptosis in the DL cells. It also inactivated M4-LDH (M4-lactate dehydrogenase), an enzyme that drives anaerobic glycolysis in the tumor cells. In the present study we have investigated whether this compound is able to modulate regulation of glycolytic inhibition-apoptosis pathway in the DL cells in vivo. We observed that Ru(II)-CNEB could decline expression of the inducible form of 6-phosphofructo-2-kinase (iPFK2: PFKFB3), the master regulator of glycolysis in the DL cells. The complex also activated superoxide dismutase (the H2O2 producing enzyme) but declined the levels of catalase and glutathione peroxidase (the two H2O2 degrading enzymes) to impose oxidative stress in the DL cells. This was consistent with the enhanced p53 level, decline in Bcl2/Bax ratio and activation of caspase 9 in those DL cells. The findings suggest that Ru(II)-CNEB is able to activate oxidative stress-apoptosis pathway via p53 (a tumor supressor protein) mediated repression of iPFK2, a key glycolytic regulator, in the DL cells in vivo. Copyright © 2015. Published by Elsevier B.V.
    Biochimie 01/2015; 110. DOI:10.1016/j.biochi.2014.12.021 · 2.96 Impact Factor
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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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    ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy that can be divided in two major subgroups, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). Activating mutations of genes involved in the BCR and NF-κB pathways (CD79A, CD79B, MYD88, and CARD11) or in epigenetic regulation (EZH2) have been recently reported, preferentially in one of the two DLBCL subtypes. We analyzed the mutational status of these five recurrently mutated genes in a cohort of 161 untreated de novo DLBCL. Overall, 93 mutations were detected, in 61 (38%) of the patients. The L265P MYD88 mutation was the most frequent MYD88 variant (n = 18), observed exclusively in the ABC subtype. CD79A/CD79B ITAM domains were targeted in ABC DLBCL (12/77; 16%), whereas CARD11 mutations were equally distributed in the two subtypes. The EZH2 Y641 substitution was found almost exclusively in the GCB subgroup (15/62; 24%). Twenty cases (12%) displayed two activating mutations, including the most frequent CD79/MYD88 variants combination (n = 8) which is observed exclusively in the ABC subtype. When considering only ABC DLBCL patients treated by rituximab plus chemotherapy, the presence of an activating NF-κB mutation was associated with an unfavorable outcome (3-years OS 26% for mutated cases versus 67% for the cases without mutations, P = 0.0337). Our study demonstrates that activating and targetable mutations are observed at a very high frequency in DLBCL at the time of diagnosis, indicating that sequencing of a limited number of genes could help tailor an optimal treatment strategy in DLBCL. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2014; 53(2):144-53. DOI:10.1002/gcc.22126 · 4.04 Impact Factor
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    • "These genes may play an important role in the pathogenesis of DLBCL leading to disease progression and BM involvement. The MYC/8q24 rearrangement, which has been reported to be associated with a poor prognosis when detected in tissues using FISH at the time of diagnosis [46-49], was independently associated with disease progression in this study. The nonrandom nature of the observed chromosomal abnormalities and their association with prognosis suggest that investigations into the clonal evolution of DLBCL could provide useful insights into the pathogenesis of this disease. "
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    ABSTRACT: Although knowledge of the genetics of diffuse large B-cell lymphoma (DLBCL) has been increasing, little is known about the characteristics and prognostic significance of cytogenetic abnormalities and the clinical utility of cytogenetic studies performed on bone marrow (BM) specimens. To investigate the significance of isolated cytogenetic aberrations in the absence of histologic BM involvement, we assessed the implication of cytogenetic staging and prognostic stratification by a retrospective multicenter analysis of newly diagnosed DLBCL patients. We analyzed cytogenetic and clinical data from 1585 DLBCL patients whose BM aspirates had been subjected to conventional karyotyping for staging. If available, interphase fluorescence in situ hybridization (FISH) data were also collected from patients. Histologic BM involvement were found in 259/1585 (16.3%) patients and chromosomal abnormalities were detected in 192 (12.1%) patients (54 patients with single abnormalities and 138 patients with 2 or more abnormalities). Isolated cytogenetic aberrations (2 or more abnormalities) without histologic involvement were found in 21 patients (1.3%). Two or more cytogenetic abnormalities were associated with inferior overall survival (OS) compared with a normal karyotype or single abnormality in both patients with histologic BM involvement (5-year OS, 16.5% vs. 52.7%; P < 0.001) and those without BM involvement (31.8% vs. 66.5%; P < 0.001). This result demonstrated that BM cytogenetic results have a significant prognostic impact that is independent of BM histology. The following abnormalities were most frequently observed: rearrangements involving 14q32, 19q13, 19p13, 1p, 3q27, and 8q24; del(6q); dup(1q); and trisomy 18. In univariate analysis, several specific abnormalities including abnormalities at 16q22-q24, 6p21-p25, 12q22-q24, and -17 were associated with poor prognosis. Multivariate analyses performed for patients who had either chromosomal abnormalities or histologic BM involvement, revealed IPI high risk, = 2 cytogenetic abnormalities, and several specific chromosomal abnormalities, including abnormalities at 19p13, 12q22-q24, 8q24, and 19q13 were significantly associated with a worse prognosis. We suggest that isolated cytogenetic aberrations can be regarded as BM involvement and cytogenetic evaluation of BM improves staging accuracy along with prognostic information for DLBCL patients.
    Journal of Hematology & Oncology 10/2013; 6(1):76. DOI:10.1186/1756-8722-6-76 · 4.81 Impact Factor
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