Article

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
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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, Jul 31, 2015
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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 · 3.84 Impact Factor
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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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    ABSTRACT: The tumour suppressor TP53 (previously termed p53) mediates a pathway that is considered to be one of the most important mechanisms in the maintenance of genomic stability. The function of TP53 can be abrogated by genomic deletion, mutation, or deregulation of upstream and downstream participants in the TP53 pathway. While aberrations of TP53 are widely prevalent in non-haematological malignancies (over 60%), they are present in much lower frequency in haematological malignancies (<20%). Nevertheless, in those cases where TP53 function or expression is aberrant, correlation with inferior clinical outcome (such as overall survival and progression or transformation) has generally been strong. In this review, we focus our discussion on the relationship between TP53 and lymphoid malignancies as defined by the World Health Organization. Specifically, we examine the prevalence of TP53 aberrations and their prognostic significance in various types of lymphoid cancer. Next, we discuss the various mechanisms of TP53 inactivation. Finally, we summarize progress in the use of recent therapeutic modalities that target TP53.
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas. As DLBCL is characterized by heterogeneous clinical and biological features, its prognosis varies. To date, the International Prognostic Index has been the strongest predictor of outcome for DLBCL patients. However, no biological characters of the disease are taken into account. Gene expression profiling studies have identified two major cell-of-origin phenotypes in DLBCL with different prognoses, the favourable germinal centre B-cell-like (GCB) and the unfavourable activated B-cell-like (ABC) phenotypes. However, results of the prognostic impact of the immunohistochemically defined GCB and non-GCB distinction are controversial. Furthermore, since the addition of the CD20 antibody rituximab to chemotherapy has been established as the standard treatment of DLBCL, all molecular markers need to be evaluated in the post-rituximab era. In this study, we aimed to evaluate the predictive value of immunohistochemically defined cell-of-origin classification in DLBCL patients. The GCB and non-GCB phenotypes were defined according to the Hans algorithm (CD10, BCL6 and MUM1/IRF4) among 90 immunochemotherapy- and 104 chemotherapy-treated DLBCL patients. In the chemotherapy group, we observed a significant difference in survival between GCB and non-GCB patients, with a good and a poor prognosis, respectively. However, in the rituximab group, no prognostic value of the GCB phenotype was observed. Likewise, among 29 high-risk de novo DLBCL patients receiving high-dose chemotherapy and autologous stem cell transplantation, the survival of non-GCB patients was improved, but no difference in outcome was seen between GCB and non-GCB subgroups. Since the results suggested that the Hans algorithm was not applicable in immunochemotherapy-treated DLBCL patients, we aimed to further focus on algorithms based on ABC markers. We examined the modified activated B-cell-like algorithm based (MUM1/IRF4 and FOXP1), as well as a previously reported Muris algorithm (BCL2, CD10 and MUM1/IRF4) among 88 DLBCL patients uniformly treated with immunochemotherapy. Both algorithms distinguished the unfavourable ABC-like subgroup with a significantly inferior failure-free survival relative to the GCB-like DLBCL patients. Similarly, the results of the individual predictive molecular markers transcription factor FOXP1 and anti-apoptotic protein BCL2 have been inconsistent and should be assessed in immunochemotherapy-treated DLBCL patients. The markers were evaluated in a cohort of 117 patients treated with rituximab and chemotherapy. FOXP1 expression could not distinguish between patients, with favourable and those with poor outcomes. In contrast, BCL2-negative DLBCL patients had significantly superior survival relative to BCL2-positive patients. Our results indicate that the immunohistochemically defined cell-of-origin classification in DLBCL has a prognostic impact in the immunochemotherapy era, when the identifying algorithms are based on ABC-associated markers. We also propose that BCL2 negativity is predictive of a favourable outcome. Further investigational efforts are, however, warranted to identify the molecular features of DLBCL that could enable individualized cancer therapy in routine patient care. Diffuusi suurisoluinen B-solulymfooma (DLBCL) on yleisin imukudossyövistä, eli non-Hodgkin lymfoomista. Taudin ennuste on vaihteleva taudin heterogeenisistä piirteistä johtuen. Immunokemoterapia, eli CD20 vasta-aineen, rituksimabin, ja monisolunsalpaajien yhdistelmä on DLBCL potilaiden ensilinjan hoito. Tärkein DLBCL potilaan ennustetta määrittävä tekijä on kliinisiin parametreihin perustuva luokitus. Kuitenkin myös taudin biologisilla piirteillä on vaikutus taudin kulkuun. DLBCL on jaoteltu hyväennusteisiin itukeskusperäisiin ja huonoennusteisiin ei-itukeskusperäisiin alatyyppeihin. Näiden alatyyppien ennusteellinen merkitys on kuitenkin ollut epäselvä immunokemoterapian aikakaudella. Tämän väitöskirjan tavoitteena oli selventää immunohistokemiallisesti määriteltyjen biologisten ennustetekijöiden merkitys immunokemoterapiaa saaneilla DLBCL potilailla. Tutkimuksessa todettiin että aikaisemmin esitellyn algoritmin mukaan (CD10, BCL6 ja MUM1/IRF4) itukeskus ja ei-itukeskus alatyyppistä lymfoomaa sairastavilla potilailla ei ollut eroa taudinkulussa. Luokittelulla ei myöskään ollut ennusteellista merkitystä potilailla, joiden hoitona oli ollut korkea-annossolunsalpaajahoito ja autologinen kantasolusiirto. Sen sijaan, mikäli ei-itukeskus alatyyppi määriteltiin väitöskirjassa kuvatun uuden algoritmin mukaan (MUM1/IRF4 ja FOXP1) voitiin todeta, että tämän alatyypin omaavilla potilailla oli immunokemoterapian jälkeen huonompi ennuste kuin muilla potilailla. Väitöskirjassa tutkittiin lisäksi immunohistokemiallisesti BCL2 ja FOXP1 proteiinien ilmentyminen lymfoomakudoksessa ja niiden ennusteellista merkitystä immunokemoterapiaa saaneilla DLBCL potilailla. Tutkimuksessa todettiin, että potilailla oli huono ennuste, jos BCL2 proteiinia todettiin lymfoomakudoksessa. FOXP1 proteiinilla ei ollut ennusteellista merkitystä. Väitöskirjan tulokset osoittavat, että immunokemoterapiahoidetuilla DLBCL potilailla voidaan tunnistaa huonoennusteinen ei-itukeskusperäinen alatyyppi uudella immunohistokemiallisella algoritmilla. Lisäksi huonoennusteiseen taudinkuvaan viittaa BCL2 ilmentyminen. Taudin biologisista piirteistä tarvitaan silti täydentävää tietoa, ennen kuin nämä esitellyt tekijät voivat ohjata hoidon valintaa.
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