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1.
Expert Rev Clin Pharmacol ; 12(11): 1059-1067, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31645159

RESUMO

Introduction: Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category consisting of different molecular subtypes relying in their biology on distinct signaling pathways.Areas covered: This article provides an overview of the molecular understanding in DLBCL and highlights potential clinical implications reviewing relevant publications and clinical trials from PubMed and clinicaltrials.gov until August 2019.Expert opinion: Based on gene expression profiling, DLBCL can be divided in two broad subtypes, the activated B-cell-like (ABC) and germinal centre derived (GCB) DLBCL. Recent comprehensive genomic analyses revealed reproducible molecular clusters within the ABC/GCB classification and suggest a more profound molecular characterization to stratify patients within clinical trials. During the last couple of years, a multitude of novel targeted therapies has been developed, but so far without improving our current therapeutic standard of immunochemotherapy. Next to the limitation of toxic side effects and a more precise selection of patients, one of the greatest challenges will be to provide molecular characterization in a more time efficient way to enable a specific and individual treatment strategy.


Assuntos
Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/terapia , Terapia de Alvo Molecular , Desenvolvimento de Medicamentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Seleção de Pacientes , Transdução de Sinais
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1515-1521, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607306

RESUMO

OBJECTIVE: To investigate the expression and significance of LncRNA RP11-513G11.1 in peripheral blood of patients with diffuse large B-cell lymphoma (DLBCL), and to analyze its correlation with clinicopathological features and prognosis of patients. METHODS: The serum samples of 93 patients with DLBCL(DLBCL group) and 62 normal persons (control group) were collected from the Department of Hematology, Southwest Medical University. The expression of RP11-513G11.1 in serum samples was detected by real-time fluorescence quantitative PCR, the relationship between the RP11-513G11.1 expression with clinicopathological characteristics and prognosis was analyzed. RESULTS: Compared with normal control group, the expression of RP11-513G11.1 significantly increased in DLBCL patients (P<0.001). The expression of RP11-513G11.1 not related with the age, sex, course of treatment and germinal center B-cell-like lymphoma(GCB) subtypes of the patients, but it related with the diameter of tumor,Ann Arbor stage,B symptoms,chemosensitivity and the international prognostic index(IPI) (P<0.05). The progression-free survival time and overall survival time of patients, whom with high expression of RP11-513G11.1 were significantly shorter than those of RP11-513G11.1 low expression(P<0.001). The median progression-free survival time and overall survival time of chemotherapy-sensitive patients were significantly longer than those of chemotherapy-resistant patients (P<0.001). Univariate analysis and multivariate Cox regression analysis showed that Ann Arbor stage, RP11-513G11.1 expression, IPI and chemosensitivity were also the independent factors affecting the prognosis of DLBCL patients(P<0.05). CONCLUSION: RP11-513G11.1 is highly expressed in patients with DLBCL, which is related with the prognosis of DLBCL patients.


Assuntos
Linfoma Difuso de Grandes Células B , Linfócitos B , Centro Germinativo , Humanos , Linfoma Difuso de Grandes Células B/genética , Prognóstico , RNA Longo não Codificante/genética
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1504-1514, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607305

RESUMO

OBJECTIVE: To investigate the effect of P53 expression on prognosis of patients with double expressor lymphoma(DEL) and the interaction between the expression of MYC, BCL2 and P53 in diffuse large B-cell lymphoma(DLBCL). METHODS: Eighty-eight patients with newly diagnosed DLBCL from 1st September 2012 to 31th May 2018 in Shanxi Dayi Hospital affiliated to Shanxi Medical University were selected. The expressions of MYC、BCL2、P53、CD10、BCL6、MUM and Ki-67 were tested by immunohistochemistry method. The overall survival of patients was analyzed by the Kaplan-Meier method and compared by the log-rank test. The prognostic effect of MYC, BCL2 and P53 expression was analyzed by univariate and multivariate analysis. RESULTS: Compared with patients without P53 expression, the patients with P53 expression had higher LDH level, higher NCCN-IPI scores, lower response to chemotherapy,poorer overall survival(OS) and a higher rate of death(P<0.05). In patients who had diffuse large B-cell lymphoma associated with MYC, BCL2 expression or MYC+/BCL2+ double expression, compared with the patients whom without P53 expression, P53 expression associated with a significant worse OS (P<0.05). The patients with concurrent MYC and P53 expression had a worse OS, compared with patients with either P53 or MYC expression(P<0.05). In patients with MYC+/P53+ co-expression, BCL2 expression did not correlate with poorer survival significantly(P>0.05). Among lymphoma patients with MYC+/P53+, MYC+/BCL2+ and BCL2+/P53+ co-expression, the patients with MYC+/P53+ co-expression had the worse OS (3 year OS rate:31.6%), followed by the subgroup of patients with MYC-/BCL2+/P53+(3 year OS rate:46.2%), patients with MYC+/BCL2+/P53- expression(3 year OS rate: 636%) showed a longer OS compared with the other two subgroups(P<0.05). Multivariate analysis demonstrated that P53 expression and NCCN-IPI were independent prognostic factors in this patient cohort. CONCLUSION: P53 and MYC expressions have a synergistically negative prognostic effect in DLBCL patients. P53 expression augments the negative prognostic effect of MYC+/BCL2+ double expression. Patients with MYC+/P53+ co-expression have a worse prognosis in comparison with the patients with MYC+/BCL2+ double expression.


Assuntos
Linfoma Difuso de Grandes Células B , Proteína Supressora de Tumor p53/genética , Humanos , Linfoma Difuso de Grandes Células B/genética , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-myc
4.
Rinsho Ketsueki ; 60(9): 1186-1192, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597842

RESUMO

Hematopoietic tumors represent a range of clinically and biologically diverse diseases, and within this, the lymphoid malignancies, especially B-cell lymphomas, are classified into many entities in the WHO classification system. It is thought that various molecular genetic abnormalities are involved in the tumorigenesis of diffuse large B-cell lymphoma (DLBCL). Due to recent developments in genetic analysis technology, novel and recurrent genetic abnormalities have been discovered. This is important knowledge for the development of new therapeutic drugs and may support indications for clinical trials, ultimately leading to the availability of more targeted therapies and precision medicine in the DLBCL arena. Here the possibility of patient stratification, based on genetic abnormality, has been described.


Assuntos
Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Humanos , Medicina de Precisão
5.
Immunity ; 51(3): 535-547.e9, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31519498

RESUMO

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.


Assuntos
Linfócitos B/fisiologia , Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Epigênese Genética/genética , Centro Germinativo/fisiologia , Linfoma Folicular/etiologia , Linfoma Difuso de Grandes Células B/genética , Acetiltransferases/genética , Animais , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Deleção de Sequência/genética , Transcrição Genética/genética
7.
Malays J Pathol ; 41(2): 101-124, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31427546

RESUMO

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non-Hodgkin lymphoma with variable clinical outcomes. The immunogenotypic features of this heterogeneous disease in Malaysia were not well characterized. MATERIALS & METHODS: In total 141 local series of DLBCL cases from UKM Medical Centre were retrospectively studied. RESULTS: Of these cases, we classified our patients into two subtypes: 32.7% (37/113) GCB and non-GCB 67.3% (76/113) by Hans algorithm and the results showed strong agreement with the results by Choi algorithm (κ = 0.828, P<0.001). Survival analysis indicated significant difference in between GCB and non-GCB subtypes (P=0.01), elevated serum LDH (P=0.016), age more than 60-year-old (P=0.021) and the presence of B symptoms (P=0.04). We observed 12% DLBCL cases were CD5 positive and 81.8% of them died of the disease (P=0.076). Analysis on the dual expression of MYC/BCL2 revealed that there is no significant difference in DE and non-DE groups (P=0.916). FISH study reported there were 9.22% (13/141) rearranged cases observed in our population at which highest frequency of BCL6 gene rearrangement (76.9%), followed by MYC (15.4%) and BCL2 (7.7%); no BCL10 and MALT-1 gene rearrangement found regardless of using TMAs or whole tissue samples. More cases of MYC protein overexpression observed compared to MYC translocation. CONCLUSION: Relatively lower frequency of GCB tumours and low gene rearrangement rates were observed in Malaysian population. A national study is therefore warranted to know better the immunogenotypic characteristics of DLBCL in Malaysia and their implications on the survival.


Assuntos
Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Biomarcadores Tumorais/análise , Criança , Pré-Escolar , Feminino , Genótipo , Centro Germinativo/patologia , Humanos , Imuno-Histoquímica , Malásia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
8.
Blood ; 134(12): 946-950, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31366619

RESUMO

Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in Cd37-knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, CD37 mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. CD37 mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site CD37 mutations. Modeling and functional analysis of CD37 missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without CD37 mutations.


Assuntos
Antígenos de Neoplasias/genética , Privilégio Imunológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Tetraspaninas/genética , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Frequência do Gene , Inativação Gênica , Humanos , Privilégio Imunológico/genética , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Mutação , Neoplasias Testiculares/genética , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/patologia , Testículo/imunologia , Testículo/patologia , Tetraspaninas/química , Tetraspaninas/imunologia , Evasão Tumoral/genética , Evasão Tumoral/imunologia
10.
Mol Cell Biochem ; 461(1-2): 47-56, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31338678

RESUMO

Long non-coding RNAs (lncRNAs) can modulate gene expression through different mechanisms, but the fundamental molecular mechanism between lncRNAs and MET protein in diffuse large B-cell lymphoma (DLBCL) was poorly understood. The expression of lncRNA TUG1 and MET in DLBCL tissues and cell lines was determined by quantitative real-time PCR and western blotting. Cell proliferation, invasion and apoptosis were determined by cell counting kit-8 assay, transwell assay and flow cytometer. The animal xenograft model was established by the injection of DLBCL cells carrying si-TUG1. The expression of TUG1 and MET was upregulated in DLBCL tissues and cells. We demonstrated that MET was altered in the TUG1 knockdown DLBCL cells, and confirmed the interaction between TUG1 and MET by RNA pull-down and RNA immunoprecipitation. Furthermore, knockdown of TUG1 reduced MET protein level by promoting ubiquitination, and suppressed tumor growth in vitro and in vivo. Our findings demonstrated that TUG1 exerted its oncogenic function in DLBCL by inhibiting the ubiquitination and the subsequent degradation of MET. Knockdown of TUG1 through MET downregulation suppressed DLBCL cell proliferation and tumor growth.


Assuntos
Regulação para Baixo/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Longo não Codificante/genética , Ubiquitinação/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met/genética , RNA Longo não Codificante/metabolismo , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Am J Dermatopathol ; 41(8): 602-605, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31335416

RESUMO

Large B-cell lymphomas include several subtypes. Recently, anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma has been delineated as a distinct entity involving mostly lymph nodes and rarely affecting extranodal sites. We describe the first case of a primary cutaneous ALK-positive large B-cell lymphoma in a 48-year-old man with a solitary nodule on the back, and describe the histologic and phenotypic features. Accurate staging confirmed the absence of other lesions, and so surgical excision and postoperative local radiation therapy were initiated and resulted in complete remission. Two years later, extracutaneous spread with involvement of axillary lymph nodes occurred. Complete remission was achieved again by multiagent chemotherapy. Our case demonstrates that a primary cutaneous form of ALK-positive large B-cell lymphoma exists. The immunophenotypic analysis of cutaneous large B-cell lymphomas affecting the skin primarily or secondarily should include the assessment of ALK expression.


Assuntos
Quinase do Linfoma Anaplásico/análise , Biomarcadores Tumorais/análise , Linfoma Difuso de Grandes Células B/enzimologia , Neoplasias Cutâneas/enzimologia , Quinase do Linfoma Anaplásico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Biópsia , Procedimentos Cirúrgicos Dermatológicos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Resultado do Tratamento
12.
Blood ; 134(10): 802-813, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31292115

RESUMO

Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.


Assuntos
Genômica/métodos , Linfoma Difuso de Grandes Células B/genética , Neoplasias do Mediastino/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Mutação , Integração de Sistemas , Adulto Jovem
13.
Cancer Biomark ; 25(3): 259-273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282408

RESUMO

BACKGROUND: The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated. METHODS: The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia. RESULTS: In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL). CONCLUSIONS: NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.


Assuntos
Biomarcadores Tumorais/genética , Infecções por Vírus Epstein-Barr/genética , Linfoma/genética , Neuropilina-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Humanos , Imuno-Histoquímica , Linfoma/classificação , Linfoma/patologia , Linfoma/virologia , Linfoma Extranodal de Células T-NK/genética , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
14.
Rom J Morphol Embryol ; 60(1): 41-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263826

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma, being part of mature B-cell neoplasm according to the 2016 World Health Organization (WHO) Classification of lymphoid tumors. This type of non-Hodgkin's lymphoma (NHL) can develop in the lymph nodes in most cases, or in extranodal sites (the most frequent involvement being the digestive tract, but also the thyroid, central nervous system, testes, etc.). Despite being an aggressive lymphoma, DLBCL benefits of potentially curable therapy. The addition of monoclonal antibodies to standard chemotherapy in the therapeutic approach of DLBCL leads to some net superior results to those obtained by chemotherapy alone. Despite the fact that the aggressive therapy is very efficient, 10% of patients remain refractory to it, 30-40% of them after obtaining a complete response (CR) will relapse, and 90% of refractory DLBCL have poor survival rates. Based on these findings, an explanation for the differences in clinical outcome and therapy response was attempted. The important progresses made in the understanding of DLBCL heterogeneity were based on molecular biology studies and showed differences in chromosomal alterations and in signaling pathways activation. These findings have paved the way for new therapeutic targets in order to improve therapy response. The large heterogeneity of DLBCL is acknowledged by the 2016 WHO Classification of lymphoid neoplasms, with 17 DLBCL subtypes, some of them as new varieties, compared to the 2008 Classification, and others introduced as provisional entities.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Medicina de Precisão/métodos , Organização Mundial da Saúde/organização & administração , Heterogeneidade Genética , Humanos , Linfoma Difuso de Grandes Células B/patologia
15.
Hematol Oncol ; 37(4): 360-367, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359442

RESUMO

De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is increasingly recognized as a distinct pathologic phenomenon with a specific clinical picture. However, CD5+ DLBCL has not been studied on a large scale in China. In this study, we show that CD5+ DLBCL occurs at a low frequency (9.2%). Comparison of clinical characteristics of CD5+ vs CD5- DLBCL showed that CD5+ DLBCL was more frequently elderly (>60 years) and had B symptoms, high-performance status, stage III-IV, an IPI score >2 and bone marrow involvement. Patients with CD5+ DLBCL had tumours with a higher prevalence of BCL-2 and p53 overexpression than CD5- DLBCL. Patients with CD5+ DLBCL had inferior progression-free survival (PFS) and overall survival (OS) than did patients with CD5- DLBCL. For CD5+ DLBCL, the patients who were treated with rituximab showed significantly better PFS and OS than those treated without rituximab. However, patients treated with RCHOP showed similar PFS and OS when compared with the group treated with intensive therapy. In addition, patients with p53 and CD5 co-expression had the worst PFS and OS. In conclusion, CD5+ DLBCL was associated with unfavorable clinicopathologic variables and with inferior survival. CD5+ DLBCL has a high frequency of p53 overexpression, and CD5 augments the negative effect of p53 overexpression in DLBCL.


Assuntos
Antígenos CD5/análise , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Prednisona/administração & dosagem , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Fatores de Risco , Rituximab/administração & dosagem , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Vincristina/administração & dosagem , Adulto Jovem
16.
Int J Med Sci ; 16(4): 556-566, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171907

RESUMO

Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc, BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c-Myc, BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c-Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P<0.05). IPI score was the significant determinants of median overall survival in DPL and TPL (P<0.05). CD5 protein expression and GCB/non-GCB sub-categorization did not affect treatment outcome (P>0.05). Overall, c-Myc, BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion: c-Myc, BCL2, and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict c-Myc, BCL2, and BCL6 gene rearrangements.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica/genética , Linfoma Difuso de Grandes Células B/genética , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígenos CD5/genética , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Rearranjo Gênico/genética , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Malásia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Serpinas/genética , Resultado do Tratamento , Adulto Jovem
17.
Mol Carcinog ; 58(10): 1846-1854, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31237044

RESUMO

ERG (avian v-ets erythroblastosis virus E26 oncogene homolog), an oncoprotein in prostate carcinoma and Ewing's sarcoma is associated with poor prognosis in patients with acute myeloid leukemia and T lymphoblastic leukemia. However little is known about ERG in lymphoma. Here we studied ERG in diffuse large B-cell lymphoma (DLBCL) by immunohistochemistry, fluorescence in situ hybridization (FISH), genome-wide microRNA (miRNA) expression profiling, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and whole exome sequencing (WES). Approximately 30% of de novo DLBCLs (37 of 118) expressed ERG (ERG+). ERG expression showed no significant correlation with DLBCL cell-of-origin classification, patient's age, sex, nodal, or extranodal disease status, tumor expression of p53 or p63. There was no ERG rearrangement in 10 randomly selected ERG+ DLBCLs by FISH. Forty-three miRNAs showed significant differential expression between ERG+ and ERG- DLBCLs. Downregulation of miR-4638-5p was confirmed by real-time RT-PCR. WES not only confirmed known gene mutations in DLBCLs but also revealed multiple novel gene mutations in POLA1, E2F1, PSMD8, AXIN1, GAB2, and GNB2L1, which occur more frequently in ERG+ DLBCLs. In conclusion, our studies demonstrated aberrant ERG expression in a subset of DLBCL, which is associated with downregulation of miR-4638-5p. In comparison with ERG-negative DLBCL, ERG+ DLBCL more likely harbors mutations in genes important in cell cycle control, B-cell receptor-mediated signaling and degradation of ß-catenin. Further clinicopathological correlation and functional studies of ERG-related miRNAs and pathways may provide new insight into the pathogenesis of DLBCL and reveal novel targets for better management of patients with DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prognóstico , Transdução de Sinais/genética , Regulador Transcricional ERG/genética , Sequenciamento Completo do Exoma
18.
J Clin Pathol ; 72(9): 630-635, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31189540

RESUMO

AIMS: Heightened B-cell receptor (BCR) activity in diffuse large B-cell lymphoma (DLBCL) is well established, and a subset of patients with relapsed DLBCL can benefit from BCR-targeted therapies. Universal outreach of such emerging therapies mandates forming a global landscape of BCR molecular signalling in DLBCL, including Southeast Asia. METHODS: 79 patients with DLBCL (nodal, 59% and extranodal, 41%) treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy were selected. Expression levels of BCR and linked signalling pathway molecules were inter-related with Lymph2Cx-based cell of origin (COO) types and overall survival (OS). RESULTS: Activated B-cell (ABC) type DLBCL constituted 49% (39/79) compared with germinal centre B-cell (GCB) type DLBCL (29/79; 37%) and revealed poor prognosis (p=0.013). In ABC-DLBCL, high BTK expression exerted poor response to R-CHOP, while OS in ABC-DLBCL with low BTK expression was similar to GCB-DLBCL subtype (p=0.004). High LYN expression coupled with a poor OS for ABC-DLBCL as well as GCB-DLBCL subtypes (p=0.001). Furthermore, high coexpression of BTK/LYN (BTK high/LYN high) showed poor OS (p=0.019), which linked with upregulation of several genes associated with BCR repertoire and nuclear factor-kappa B pathway (p<0.01). In multivariate analysis, high BTK and LYN expression retained prognostic significance against established clinical predictive factors such as age, International Prognostic Index and COO (p<0.05). CONCLUSIONS: Our data provide a clear association between high BCR activity in DLBCL and response to therapy in a distinct population. Molecular data provided here will pave the pathway for the provision of promising novel-targeted therapies to patients with DLBCL in Southeast Asia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/imunologia , Tomada de Decisão Clínica , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/etnologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prevalência , Receptores de Antígenos de Linfócitos B/imunologia , Sistema de Registros , Rituximab , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
19.
Int J Cancer ; 145(11): 3078-3088, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044434

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is up to 17-fold more likely to occur, follows a more aggressive clinical course and frequently presents at advanced stages in HIV infected (+) individuals compared to HIV negative (-) individuals. However, the molecular pathology underpinning the clinical features of DLBCL in HIV(+) patients relative to the general population is poorly understood. We performed a retrospective study examining the transcriptional, genomic and protein expression differences between HIV(+) and HIV(-) germinal center B-cell (GCB) DLBCL cases using digital gene expression analysis, array comparative genomic hybridization (CGH) and immunohistochemistry (IHC). Genes associated with cell cycle progression (CCNA2, CCNB1, CDC25A, E2F1), DNA replication (MCM2, MCM4, MCM7) and DNA damage repair, including eight Fanconi anemia genes (FANCA, FANCD1/BRCA2, FANCE, FANCG, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCV/MAD2L2), were significantly increased in HIV(+) GCB-DLBCL tumors compared to HIV(-) tumors. In contrast, genes associated with cell cycle inhibition (CDKN1A, CDKN1B) as well as apoptosis regulating BCL2 family members (BCL2, BAX, BIM, BMF, PUMA) were significantly decreased in the HIV(+) cohort. BCL2 IHC confirmed this expression. Array CGH data revealed that HIV(+) GCB-DLBCL tumors have fewer copy number variations than their HIV(-) counterparts, indicating enhanced genomic stability. Together, the results show that HIV(+) GCB-DLBCL is a distinct molecular malignancy from HIV(-) GCB-DLBCL; with an increased proliferative capacity, confirmed by Ki67 IHC staining, and enhanced genomic stability, the latter of which is likely related to the enhanced expression of DNA repair genes.


Assuntos
Reparo do DNA , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica , Infecções por HIV/genética , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Hibridização Genômica Comparativa , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Oncol Rep ; 42(1): 321-327, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059102

RESUMO

The molecular and clinical heterogeneity in diffuse large B­cell lymphoma (DLBCL) has raised a need for the investigation of potential therapeutic biomarkers. MicroRNA­320 (miR­320) and CDK6 are both involved in the regulation of cell proliferation in various types of cancer. To investigate the clinical role of CDK6 in DLBCL, CDK6 expression was assessed using immunohistochemistry on formalin­fixed, paraffin­embedded sections. Furthermore, to investigate the relationship between CDK6 and miR­320d, as well as their roles in cell proliferation, a series of experimentally functional validations was performed in DLBCL cell lines. Bioinformatics software and Dual­Luciferase reporter assay were used to predict and validate the potential target of miR­320d. In DLBCL cells transfected with miR­320d lentiviral vector, CDK6 expression at the protein and mRNA levels was detected using western blotting and qRT­PCR, respectively. Overexpression and small­hairpin RNA knockdown of CDK6 were performed by lentiviral transduction. The results of these experiments revealed that CDK6 was overexpressed and predictive of poor prognosis in DLBCL patients. Moreover, CDK6 was revealed to be directly targeted by miR­320d and either overexpression of miR­320d or knockdown of CDK6 inhibited proliferation. In conclusion, CDK6 overexpression in DLBCL may result from miRNA­320d downregulation and subsequent loss of inhibition of cell proliferation, suggesting that miRNA­320d may be a potential therapeutic target for the treatment of DLBCL with high CDK6 expression.


Assuntos
Quinase 6 Dependente de Ciclina/genética , Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , Regulação para Cima , Regiões 3' não Traduzidas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Proliferação de Células , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
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