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1.
Blood ; 133(15): 1664-1676, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30782609

RESUMO

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.


Assuntos
Variações do Número de Cópias de DNA , Linfoma de Células T Periférico/genética , Oncogenes , Feminino , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T Periférico/classificação , Masculino , Mutação , Proteínas com Domínio T/genética
2.
Blood ; 133(1): 81-93, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30446494

RESUMO

Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P = .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P = .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P = .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P = .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P = .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Genômica/métodos , Perda de Heterozigosidade , Linfoma Folicular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
3.
Blood ; 132(22): 2401-2405, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30257882

RESUMO

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.


Assuntos
Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Neoplasias do Mediastino/diagnóstico , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/genética , Neoplasias do Mediastino/classificação , Neoplasias do Mediastino/genética , Mediastino/patologia , Inclusão em Parafina
5.
J Clin Oncol ; 36(7): 697-703, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29356608

RESUMO

Purpose SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) with CHOP-RIT (CHOP followed by consolidation with iodine-133-tositumomab radioimmunotherapy) for previously untreated patients with follicular lymphoma. Understanding the long-term outcome of patients provides a benchmark for novel treatment regimens for FL. Patients and Methods Between 2001 and 2008, 531 previously untreated patients with FL were randomly assigned to receive either six cycles of R-CHOP or six cycles of CHOP-RIT. Patients with advanced-stage disease (bulky stage II, III, or IV) of any pathologic grade (1, 2, or 3) were eligible. Results After a median follow-up of 10.3 years, 10-year estimates of progression-free and overall survival were 49% and 78% among all patients, respectively. Patients in the CHOP-RIT arm had significantly better 10-year progression-free survival compared with patients in the R-CHOP arm (56% v 42%; P = .01), but 10-year overall survival was not different between the two arms (75% v 81%; P = .13). There was no significant difference between the CHOP-RIT and R-CHOP arms in regard to incidence of second malignancies (15.1% v 16.1%; P = .81) or myelodysplastic syndrome or acute myeloid leukemia (4.9% v 1.8%; P = .058). The estimated 10-year cumulative incidences of death resulting from second malignancies were not different (7.1% v 3.2%; P = .16), but cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia was higher in the CHOP-RIT arm compared with the R-CHOP arm (4% v 0.9%; P = .02). Conclusion Given these outstanding outcomes, immunochemotherapy should remain the standard induction approach for patients with high-risk FL until long-term follow-up of alternative approaches demonstrates superiority.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Radioimunoterapia/métodos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Causas de Morte , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prognóstico , Rituximab , Vincristina/administração & dosagem , Vincristina/uso terapêutico
6.
Leuk Lymphoma ; 59(8): 1884-1889, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29199519

RESUMO

High-grade B cell lymphoma with MYC and BCL2 rearrangements (double hit) has a poor prognosis with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). We report here a treatment algorithm of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) followed by BEAM (carmustine, etoposide, cytarabine, melphalan) autologous transplant in 36 cases of previously untreated double hit lymphoma (DHL) from 2010 to 2015. A high risk International Prognostic Index (IPI) was present in 42% of cases. At median follow-up of 38 months, the 2-year progression free survival (PFS) and overall survival (OS) were 69% (95% CI 54-84%) and 71% (95% CI 56-86%). Eight cases were refractory to induction with 1-year OS 20%, and no factors were predictive for primary refractory disease. Of 28 responders, 17 proceeded to transplant while 11 were observed, primarily due to age and co-morbidities. By 24-week landmark analysis after diagnosis, the 2-year PFS and OS were both 94% (95% CI 83-100%) vs 79% (95% CI 52-100%) for transplant vs observation (p = .59 for both PFS and OS). There was no significant benefit to consolidative transplant in our series, and primary refractory DHL needs novel approaches.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/terapia , Idoso , Carmustina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Rearranjo Gênico , Humanos , Linfoma Difuso de Grandes Células B/genética , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/administração & dosagem , Transplante Autólogo , Resultado do Tratamento , Vincristina/administração & dosagem
7.
Leuk Lymphoma ; 59(6): 1391-1398, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28868942

RESUMO

Accurate subclassification of aggressive B cell lymphomas (ABCLs) requires integration of morphologic, immunohistochemical (IHC), and cytogenetic information. Optimal strategies have not been well defined for diagnosis of high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBLwR) and double expressor lymphomas with MYC and BCL2 protein overexpression. One hundred and eighty seven ABCLs were investigated with complete IHC and FISH analysis. Morphologic and IHC analysis was insufficient to identify clinically relevant HGBLwR. Approximately, 75% of cases classified as HGBLwR showed conventional DLBCL morphologic features. Fourteen percent of MYC-rearranged cases were negative by IHC. Conversely, 60% of cases positive for MYC by IHC did not demonstrate a MYC rearrangement. Analysis by FISH without MYC and BCL2 IHC would miss 41 cases of double expressor lymphoma. Complete IHC and FISH analysis is recommended in the evaluation of all ABCLs.


Assuntos
Biomarcadores Tumorais , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Análise Citogenética , Expressão Gênica , Variação Genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Linfoma de Células B/diagnóstico , Gradação de Tumores , Estadiamento de Neoplasias , Reprodutibilidade dos Testes
8.
Blood ; 130(16): 1819-1831, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-28801451

RESUMO

The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.


Assuntos
Linfoma de Burkitt/genética , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Imunofenotipagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Adulto Jovem
9.
J Clin Oncol ; 35(15): 1668-1677, 2017 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-28291392

RESUMO

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.


Assuntos
Biópsia/métodos , Linfoma de Célula do Manto/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/fisiologia , Feminino , Formaldeído , Perfilação da Expressão Gênica , Humanos , Linfoma de Célula do Manto/genética , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Reprodutibilidade dos Testes , Fixação de Tecidos
11.
Am J Surg Pathol ; 39(10): 1322-30, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26135560

RESUMO

Mediastinal involvement is considered essential for the diagnosis of primary mediastinal large B-cell lymphoma (PMBL). However, we have observed cases of diffuse large B-cell lymphoma (DLBCL) with features of PMBL but without detectable mediastinal involvement. The goal was to assess our previously established gene expression profiling (GEP) signature for PMBL in classifying these cases. In a large series of DLBCL cases, we identified 24 cases with a GEP signature of PMBL, including 9 cases with a submission diagnosis of DLBCL consistent with PMBL (G-PMBL-P) and 15 cases with a submission diagnosis of DLBCL. The pathology reviewers agreed with the diagnosis in the 9 G-PMBL-P cases. Among the other 15 DLBCL cases, 11 were considered to be PMBL or DLBCL consistent with PMBL, 3 were considered to be DLBCL, and 1 case was a gray-zone lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma. All 9 G-PMBL-P and 9 of the 15 DLBCL cases (G-PMBL-M) had demonstrated mediastinal involvement at presentation. Interestingly, 6 of the 15 DLBCL cases (G-PMBL-NM) had no clinical or radiologic evidence of mediastinal involvement. The 3 subgroups of PMBL had otherwise similar clinical characteristics, and there were no significant differences in overall survival. Genetic alterations of CIITA and PDL1/2 were detected in 26% and 40% of cases, respectively, including 1 G-PMBL-NM case with gain of PDL1/2. In conclusion, PMBL can present as a nonmediastinal tumor without evidence of mediastinal involvement, and GEP offers a more precise diagnosis of PMBL.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Neoplasias do Mediastino/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Cromossomos Humanos Par 9 , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Rearranjo Gênico , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/química , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fenótipo , Valor Preditivo dos Testes , Fatores de Tempo , Transativadores/genética , Translocação Genética , Adulto Jovem
12.
Blood ; 125(7): 1137-45, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25498913

RESUMO

We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.


Assuntos
Biomarcadores Tumorais/metabolismo , Linfoma de Células B/classificação , Linfoma de Células B/patologia , MicroRNAs/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Células B/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Transcriptoma , Adulto Jovem
13.
Nature ; 516(7530): 254-8, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25274307

RESUMO

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.


Assuntos
Linfócitos B/metabolismo , Linfócitos B/patologia , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Centro Germinativo/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Transdução de Sinais , Animais , Sangue/imunologia , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Humanos , Linfa/citologia , Linfoma Difuso de Grandes Células B/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/metabolismo , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/deficiência , Fatores de Troca de Nucleotídeo Guanina Rho/genética
14.
Hum Pathol ; 45(10): 2144-53, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25090918

RESUMO

Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare 2 alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in 2 independent DLBCL cohorts, E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse overall survival. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in situ hybridization as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence in situ hybridization for translocation but a higher amplification frequency, indicating that BCL2 amplification may be underreported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies.


Assuntos
Anticorpos Monoclonais , Biomarcadores Tumorais/análise , Amplificação de Genes , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/análise , Animais , Epitopos de Linfócito B/análise , Humanos , Imuno-Histoquímica , Hibridização In Situ/métodos , Coelhos , Análise Serial de Tecidos
15.
Blood ; 123(19): 2915-23, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24632715

RESUMO

Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfoma de Células T Periférico/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Análise de Sobrevida , Adulto Jovem
16.
Cancer Discov ; 4(4): 480-93, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24491438

RESUMO

UNLABELLED: Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (∼1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target. SIGNIFICANCE: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis.


Assuntos
Mutação em Linhagem Germinativa , Linfoma Difuso de Grandes Células B/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Dicroísmo Circular , Variação Genética , Humanos , Linfoma Difuso de Grandes Células B/patologia , Modelos Moleculares , Peptídeos/síntese química , Peptídeos/farmacologia , Polimorfismo de Nucleotídeo Único , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo
17.
Blood ; 123(8): 1214-7, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24398326

RESUMO

The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell-like or activated B cell-like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)-based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.


Assuntos
Linhagem da Célula/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Fixadores , Formaldeído , Humanos , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Bancos de Tecidos , Transcriptoma , Adulto Jovem
18.
Blood ; 123(11): 1681-90, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24037725

RESUMO

Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-κB pathway, and deregulate p53 and B-cell transcription factors.


Assuntos
Transformação Celular Neoplásica/patologia , Aberrações Cromossômicas , Cromossomos Humanos/genética , Variações do Número de Cópias de DNA/genética , Genoma Humano , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Biomarcadores Tumorais/genética , DNA de Neoplasias/genética , Perfilação da Expressão Gênica , Humanos , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Taxa de Sobrevida , Translocação Genética/genética
19.
J Clin Oncol ; 31(36): 4520-8, 2013 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-24220563

RESUMO

PURPOSE: We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. PATIENTS AND METHODS: By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. RESULTS: PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025). CONCLUSION: STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto , Idoso , Análise de Variância , Anticorpos Monoclonais Murinos/administração & dosagem , Antígenos CD20/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prednisona/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Rituximab , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Análise Serial de Tecidos , Resultado do Tratamento , Vincristina/administração & dosagem
20.
Clin Cancer Res ; 19(23): 6624-32, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24130072

RESUMO

PURPOSE: There is currently no consensus on optimal frontline therapy for patients with follicular lymphoma. We analyzed a phase III randomized intergroup trial comparing six cycles of CHOP-R (cyclophosphamide-Adriamycin-vincristine-prednisone (Oncovin)-rituximab) with six cycles of CHOP followed by iodine-131 tositumomab radioimmunotherapy (RIT) to assess whether any subsets benefited more from one treatment or the other, and to compare three prognostic models. EXPERIMENTAL DESIGN: We conducted univariate and multivariate Cox regression analyses of 532 patients enrolled on this trial and compared the prognostic value of the FLIPI (follicular lymphoma international prognostic index), FLIPI2, and LDH + ß2M (lactate dehydrogenase + ß2-microglobulin) models. RESULTS: Outcomes were excellent, but not statistically different between the two study arms [5-year progression-free survival (PFS) of 60% with CHOP-R and 66% with CHOP-RIT (P = 0.11); 5-year overall survival (OS) of 92% with CHOP-R and 86% with CHOP-RIT (P = 0.08); overall response rate of 84% for both arms]. The only factor found to potentially predict the impact of treatment was serum ß2M; among patients with normal ß2M, CHOP-RIT patients had better PFS compared with CHOP-R patients, whereas among patients with high serum ß2M, PFS by arm was similar (interaction P value = 0.02). CONCLUSIONS: All three prognostic models (FLIPI, FLIPI2, and LDH + ß2M) predicted both PFS and OS well, though the LDH + ß2M model is easiest to apply and identified an especially poor risk subset. In an exploratory analysis using the latter model, there was a statistically significant trend suggesting that low-risk patients had superior observed PFS if treated with CHOP-RIT, whereas high-risk patients had a better PFS with CHOP-R.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/mortalidade , Adulto , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Hemoglobinas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Linfonodos/patologia , Linfoma Folicular/sangue , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Prednisona/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , Rituximab , Vincristina/administração & dosagem , Adulto Jovem , Microglobulina beta-2/sangue
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