RESUMO
Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor-ligand interactions have been shown to impact anti-tumour immune responses in several cancers, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour-microenvironment interactions across a spectrum of lymphoid cancers.
Assuntos
Linfoma de Células B/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Transativadores/genética , Translocação Genética/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-H1 , Sequência de Bases , Linhagem Celular Tumoral , Pontos de Quebra do Cromossomo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/genética , Humanos , Hibridização in Situ Fluorescente , Células Jurkat , Ativação Linfocitária , Dados de Sequência Molecular , Proteína 2 Ligante de Morte Celular Programada 1 , RNA Neoplásico/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Análise Serial de Tecidos , Microambiente TumoralRESUMO
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.
Assuntos
Histonas/metabolismo , Linfoma não Hodgkin/genética , Mutação/genética , Cromatina/genética , Cromatina/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genoma Humano/genética , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Perda de Heterozigosidade/genética , Linfoma Folicular/enzimologia , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/enzimologia , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Fatores de Transcrição MEF2 , Fatores de Regulação Miogênica/genética , Fatores de Regulação Miogênica/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMO
In classical Hodgkin lymphoma (cHL) the mechanisms underlying primary refractory disease and relapse remain unknown. To gain further insight into cHL pathogenesis and genomic changes linked to treatment response, we studied 53 cHL patients by array comparative genomic hybridization, including 23 patients whose primary treatment failed, using DNA from microdissected HRS cells. Copy number alterations found in more than 20% of cases included gains of 2p, 9p, 16p, 17q, 19q, 20q, and losses of 6q, 11q, and 13q. We identified at high resolution recurrent changes defining minimally gained and lost regions harboring genes involved in nuclear factor kappaB signaling, such as REL, IKBKB, CD40, and MAP3K14. Gains of chromosome 16p11.2-13.3 were significantly more frequent in pretreatment and relapse biopsies of unresponsive patients and were associated with shortened disease-specific survival (P = .028). In the therapy-resistant HL cell line KMH2, we found genomic gains and overexpression of the multidrug resistance gene ABCC1 mapping to cytoband 16p13.11. We show that doxorubicin exposure to KMH2 induces ABCC1 expression and that siRNA silencing of ABCC1 sensitizes KMH2 cells to doxorubicin toxicity in vitro, suggesting that overexpression of ABCC1 contributes to the drug resistance phenotype found in KMH2.
Assuntos
Dosagem de Genes , Doença de Hodgkin/genética , Células de Reed-Sternberg/metabolismo , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Criança , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , RNA Interferente Pequeno/genética , Células de Reed-Sternberg/patologia , Resultado do Tratamento , Adulto JovemRESUMO
BCL2 and MYC are oncogenes commonly deregulated in lymphomas. Concurrent BCL2 and MYC translocations (BCL2(+)/MYC(+)) were identified in 54 samples by karyotype and/or fluorescence in situ hybridization with the aim of correlating clinical and cytogenetic characteristics to overall survival. BCL2(+)/MYC(+) lymphomas were diagnosed as B-cell lymphoma unclassifiable (BCLU; n = 36) with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL); DLBCL (n = 17), or follicular lymphoma (n = 1). Despite the presence of a t(14;18), 5 cases were BCL2 protein-negative. Nonimmunoglobulin gene/MYC (non-IG/MYC) translocations occurred in 24 of 54 cases (44%) and were highly associated with DLBCL morphology (P < .001). Over a median follow-up of 5.3 years, 6 patients remained in remission and 32 died within 6 months of the MYC(+) rearrangement, irrespective of whether MYC(+) occurred at diagnosis (31 of 54) or transformation (23 of 54; P = .53). A non-IG/MYC translocation partner, absent BCL2 protein expression and treatment with rituximab-based chemotherapy, were associated with a more favorable outcome, but a low International Prognostic Index score and DLBCL morphology were independent predictors of overall survival. A comprehensive cytogenetic analysis of BCL2 and MYC status on all aggressive lymphomas may identify a group of high-risk patients who may benefit from chemotherapeutic regimens that include rituximab and/or BCL2-targeted therapy.
Assuntos
Linfoma de Burkitt/genética , Linfoma de Burkitt/mortalidade , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Antineoplásicos/administração & dosagem , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/metabolismo , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 18/metabolismo , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Estudos Retrospectivos , Rituximab , Taxa de SobrevidaRESUMO
Although the combination of lenalidomide and dexamethasone is effective therapy for patients with relapsed/refractory multiple myeloma, the influence of high-risk cytogenetic abnormalities on outcomes is unknown. This subanalysis of a large, open-label study investigated the effects of the most common unfavorable cytogenetic abnormalities detected by fluorescence in situ hybridization, del(13q), t(4;14), and del(17p13), in 130 evaluable patients treated with this regimen. Whereas patients with either del(13q) or t(4;14) experienced a median time to progression and overall survival comparable with those without these cytogenetic abnormalities, patients with del(17p13) had a significantly worse outcome, with a median time to progression of 2.22 months (hazard ratio, 2.82; P < .001) and median overall survival of 4.67 months (hazard ratio, 3.23; P < .001). Improved therapeutic strategies are required for this subgroup of patients. This study was registered at www.ClinicalTrials.gov as #NCT00179647.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos , Aberrações Cromossômicas , Intervalo Livre de Doença , Humanos , Hibridização in Situ Fluorescente , Lenalidomida , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Terapia de Salvação , Taxa de Sobrevida , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
The BCL6 transcriptional repressor is required for development of germinal center (GC) B cells and when expressed constitutively causes diffuse large B-cell lymphomas (DLBCLs). We examined genome-wide BCL6 promoter binding in GC B cells versus DLBCLs to better understand its function in these settings. BCL6 bound to both distinct and common sets of functionally related gene in normal GC cells versus DLBCL cells. Certain BCL6 target genes were preferentially repressed in GC B cells, but not DLBCL cells. Several such genes have prominent oncogenic functions, such as BCL2, MYC, BMI1, EIF4E, JUNB, and CCND1. BCL6 and BCL2 expression was negatively correlated in primary DLBCLs except in the presence of BCL2 translocations. The specific BCL6 inhibitor retro-inverso BCL6 peptidomimetic inhibitor-induced expression of BCL2 and other oncogenes, consistent with direct repression effects by BCL6. These data are consistent with a model whereby BCL6 can directly silence oncogenes in GC B cells and counterbalance its own tumorigenic potential. Finally, a BCL6 consensus sequence and binding sites for other physiologically relevant transcription factors were highly enriched among target genes and distributed in a pathway-dependent manner, suggesting that BCL6 forms specific regulatory circuits with other B-cell transcriptional factors.
Assuntos
Linfócitos B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas c-bcl-6/fisiologia , Sítios de Ligação , Técnicas de Cultura de Células , Células Cultivadas , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Proto-Oncogênicas c-bcr/fisiologia , Transcrição Gênica/fisiologiaRESUMO
Approximately 5% to 10% of diffuse large B-cell lymphomas (DLBCLs) harbor an MYC oncogene rearrangement (MYC+). The prognostic significance of MYC+ DLBCL was determined in an unselected population of patients with newly diagnosed DLBCL treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP). Using a Vysis break-apart fluorescence in situ hybridization probe, 12 of 135 (8.8%) cases of MYC+ DLBCL were identified that had no defining high-risk features. MYC+ DLBCL was associated with an inferior 5-year progression-free survival (66% vs 31%, P = .006) and overall survival (72% vs 33%, P = .016). Multivariate analysis confirmed the prognostic importance of MYC for both progression-free survival (hazard ratio = 3.28; 95% confidence interval, 1.49-7.21, P = .003) and overall survival (hazard ratio = 2.98; 95% confidence interval, 1.28-6.95, P = .011). Cases of MYC+ DLBCL also had a higher risk of central nervous system relapse (P = .023), independent of other risk factors. The diagnosis of MYC+ DLBCL is likely underappreciated; and given the lack of defining risk factors, fluorescence in situ hybridization for MYC rearrangements should be performed in all patients with DLBCL. In the R-CHOP treatment era, MYC+ DLBCLs have an inferior prognosis. Treatment regimens similar to those used in Burkitt lymphoma may be more appropriate in this patient population and need to be prospectively tested.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rearranjo Gênico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Prednisona/administração & dosagem , Prognóstico , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto JovemRESUMO
The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model-based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q-, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.
Assuntos
Hibridização Genômica Comparativa , Dosagem de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/genética , Algoritmos , Biópsia , Feminino , Humanos , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Genéticos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Análise de SobrevidaRESUMO
A multiplatform approach, including conventional cytogenetic techniques, BAC array comparative genomic hybridization, and Affymetrix 500K SNP arrays, was applied to the study of the tumor genomes of 25 follicular lymphoma biopsy samples with paired normal DNA samples to characterize balanced translocations, copy number imbalances, and copy-neutral loss of heterozygosity (cnLOH). In addition to the t(14;18), eight unique balanced translocations were found. Commonly reported FL-associated copy number regions were revealed including losses of 1p32-36, 6q, and 10q, and gains of 1q, 6p, 7, 12, 18, and X. The most frequent regions affected by copy-neutral loss of heterozygosity were 1p36.33 (28%), 6p21.3 (20%), 12q21.2-q24.33 (16%), and 16p13.3 (24%). We also identified by SNP analysis, 45 aberrant regions that each affected one gene, including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways involved in tumor development. This study illustrates the power of using complementary high-resolution platforms on paired tumor/normal specimens and computational analysis to provide potential insights into the significance of single-gene somatic aberrations in FL tumorigenesis.
Assuntos
Dosagem de Genes , Genoma Humano , Perda de Heterozigosidade , Linfoma Folicular/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Cromossomos Artificiais Bacterianos , Cromossomos Humanos Par 12/genética , Biologia Computacional , Análise Citogenética , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estudos ProspectivosRESUMO
MOTIVATION: Analysis of array comparative genomic hybridization (aCGH) data for recurrent DNA copy number alterations from a cohort of patients can yield distinct sets of molecular signatures or profiles. This can be due to the presence of heterogeneous cancer subtypes within a supposedly homogeneous population. RESULTS: We propose a novel statistical method for automatically detecting such subtypes or clusters. Our approach is model based: each cluster is defined in terms of a sparse profile, which contains the locations of unusually frequent alterations. The profile is represented as a hidden Markov model. Samples are assigned to clusters based on their similarity to the cluster's profile. We simultaneously infer the cluster assignments and the cluster profiles using an expectation maximization-like algorithm. We show, using a realistic simulation study, that our method is significantly more accurate than standard clustering techniques. We then apply our method to two clinical datasets. In particular, we examine previously reported aCGH data from a cohort of 106 follicular lymphoma patients, and discover clusters that are known to correspond to clinically relevant subgroups. In addition, we examine a cohort of 92 diffuse large B-cell lymphoma patients, and discover previously unreported clusters of biological interest which have inspired followup clinical research on an independent cohort. AVAILABILITY: Software and synthetic datasets are available at http://www.cs.ubc.ca/ approximately sshah/acgh as part of the CNA-HMMer package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Hibridização Genômica Comparativa/métodos , Análise por Conglomerados , Humanos , Linfoma de Células B/genética , Linfoma Folicular/genética , Modelos Estatísticos , Análise de Sequência com Séries de Oligonucleotídeos/métodosRESUMO
Myelodysplastic syndromes (MDSs) pose an important diagnostic and treatment challenge because of the genetic heterogeneity and poorly understood biology of the disease. To investigate initiating genomic alterations and the potential prognostic significance of cryptic genomic changes in low-risk MDS, we performed whole genome tiling path array comparative genomic hybridization (aCGH) on CD34(+) cells from 44 patients with an International Prognostic Scoring System score less than or equal to 1.0. Clonal copy number differences were detected in cells from 36 of 44 patients. In contrast, cells from only 16 of the 44 patients displayed karyotypic abnormalities. Although most patients had normal karyotype, aCGH identified 21 recurring copy number alterations. Examples of frequent cryptic alterations included gains at 11q24.2-qter, 17q11.2, and 17q12 and losses at 2q33.1-q33.2, 5q13.1-q13.2, and 10q21.3. Maintenance of genomic integrity defined as less than 3 Mb total disruption of the genome correlated with better overall survival (P = .002) and was less frequently associated with transformation to acute myeloid leukemia (P = .033). This study suggests a potential role for the use of aCGH in the clinical workup of MDS patients.
Assuntos
Antígenos CD34/biossíntese , Genoma Humano , Leucemia/genética , Leucemia/terapia , Síndromes Mielodisplásicas/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/metabolismo , Intervalo Livre de Doença , Proteínas Ativadoras de GTPase/genética , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Hibridização de Ácido Nucleico , Proteínas Oncogênicas/genética , Proteínas Proto-Oncogênicas , RiscoRESUMO
BACKGROUND: BCL6 gene rearrangement is the most frequent chromosomal abnormality in diffuse large B-cell lymphoma, a malignancy characterized by genetic heterogeneity and wide variability in clinical outcome. The prognostic significance of BCL6 rearrangement has not been evaluated in the context of rituximab therapy for diffuse large B-cell lymphoma. We analyzed the effect of the BCL6 rearrangement on survival in patients with diffuse large B-cell lymphoma treated with CHOP and CHOP plus rituximab (R-CHOP). DESIGN AND METHODS: BCL6 rearrangement status was analyzed by fluorescence in situ hybridization with break-apart probes in 164 patients with diffuse large B-cell lymphoma treated with CHOP (n=65) or R-CHOP (n=99). Cell-of-origin immunophenotype including BCL6 protein expression were determined by immunohistochemistry on a tissue microarray. RESULTS: BCL6 rearrangement was detected in 19.5% of cases. The presence of the gene rearrangement was associated with a non-germinal center B-cell immunophenotype (P=0.006), and showed no correlation with BCL6 protein expression. A trend toward inferior overall survival was observed in association with the BCL6 rearrangement among patients treated with R-CHOP (P=0.08), but not among patients treated with CHOP (P=0.64). However, BCL6 rearrangement also correlated with a high International Prognostic Index score (P=0.02), and did not demonstrate independent prognostic value by multivariate analysis. CONCLUSIONS: The introduction of rituximab may have altered the prognostic impact of BCL6 gene rearrangement in patients with diffuse large B-cell lymphoma. However, prospective analysis within large randomized clinical trials will be needed to clarify the prognostic significance of this biomarker in the rituximab era.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas de Ligação a DNA/genética , Rearranjo Gênico do Linfócito B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Coortes , Ciclofosfamida , Doxorrubicina , Feminino , Seguimentos , Humanos , Imunofenotipagem , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona , Proteínas Proto-Oncogênicas c-bcl-6 , Estudos Retrospectivos , Rituximab , Taxa de Sobrevida/tendências , Resultado do Tratamento , Vincristina , Adulto JovemRESUMO
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.
Assuntos
Genes p53/genética , Linfoma/genética , Mutação/genética , Proteína Supressora de Tumor p53/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma/terapia , Prognóstico , Proteína Supressora de Tumor p53/antagonistas & inibidoresRESUMO
Follicular lymphoma (FL) is an indolent lymphoma with a long median survival. Transformation to a more aggressive histology (TLy) is a major cause of mortality. The critical events leading to TLy are unknown. We assessed the prognostic significance of secondary cytogenetic alterations on overall survival (OS) and transformation from 210 diagnostic FL biopsies. We analyzed serial and transformed karyotypes for recurrent alterations that predict transformation. Over 10 years, 31% of cases developed TLy. The only alteration in diagnostic karyotypes that correlated with an inferior OS was an additional X chromosome in males only (P = 0.005) suggesting that other mechanisms including epigenetic factors and over-expression of genes on the X chromosome may play a role in FL pathogenesis. In transformed karyotypes, 8q24 (MYC) translocations were common (14/37) and resulted in a median survival of 3 months posttransformation (P = 0.01). In serially obtained biopsies (28 pts), 43% of the later biopsies lacked the cytogenetic alterations found in the original FL karyotype, suggesting that karyotypic progression of FL is not strictly linear in all cases. Consequently, studying clonal evolution in FL using serial biopsies may not represent the full complexity of genetic alterations leading to transformation.
Assuntos
Transformação Celular Neoplásica/patologia , Linfoma Folicular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Transformação Celular Neoplásica/genética , Aberrações Cromossômicas , Estudos de Coortes , Análise Citogenética , Progressão da Doença , Feminino , Humanos , Cariotipagem , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Cytogenetic correlations among most types of peripheral T-cell lymphoma (PTCL) have not been very informative to date. This study aimed to identify recurrent chromosomal abnormalities in angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, unspecified (PTCL-US), and to evaluate their prognostic value. We reviewed the cytogenetic findings of 90 previously-diagnosed cases of PTCL and correlated the cytogenetic findings with the specific histological subtype. The most common abnormalities for AITL were 5q (55%), 21 (41%) and 3q (36%) gains, concurrent trisomies of 5 and 21 (41%), and loss of 6q (23%). In ALK(-) ALCL, gains of 1q (50%) and 3p (30%), and losses of 16pter (50%), 6q13q21 (30%), 15 (30%), 16qter (30%) and 17p13 (30%) were frequent findings. In PTCL-US, frequent gains involved 7q22q31 (33%), 1q (24%), 3p (20%), 5p (20%), and 8q24qter (22%), and losses of 6q22q24 (26%) and 10p13pter (26%). We did not observe any association between specific chromosomal abnormalities and overall survival (OS). However, cases with complex karyotypes, most frequently observed in ALK(-) ALCL and PTCL-US, had a significantly shorter OS. Although, genetic differences were noted in these subtypes, further studies are needed to determine the key pathogenetic events in PTCL.
Assuntos
Aberrações Cromossômicas , Linfoma de Células T Periférico/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Seguimentos , Humanos , Linfadenopatia Imunoblástica/genética , Cariotipagem , Linfoma Anaplásico de Células Grandes/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de SobrevidaRESUMO
Chromosomal translocations involving the platelet-derived growth factor receptor beta gene (PDGFRB) have been reported in a subset of patients with atypical myeloproliferative disorders (MPDs). The fusion of the PDGFRB gene, which encodes a tyrosine kinase receptor, with different partner genes results in its constitutive activation. We present the cases of two patients with atypical MPD carrying t(4;5)(q21;q33) and t(2;5)(p21;q33), respectively. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in both translocations. Further characterization of the 4q21 breakpoint using a bacterial artificial chromosome probe revealed PRKG2 as the likely gene partner to PDGFRB. Characterization of the 2p21 breakpoint identified a novel gene partner to PDGFRB, the SPTBN1 gene. Both patients achieved a complete molecular remission after introduction of imatinib mesylate therapy.
Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Espectrina/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Benzamidas , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 5 , Proteína Quinase Dependente de GMP Cíclico Tipo II , Feminino , Fusão Gênica , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologia , Translocação GenéticaRESUMO
Ewing family tumors are molecularly characterized by expression of chimeric transcripts generated by specific chromosomal translocations, most commonly involving fusion of the EWS gene to a member of the ETS family of transcription factors (including FLI1, ERG, ETV1, E1AF, and FEV). Approximately 85% of reported cases of Ewing sarcoma bear an EWS-FLI1 fusion. In rare cases, FUS can substitute for EWS, with translocation t(16;21)(p11;q24) producing a FUS-ERG fusion with no EWS rearrangement. We report a case of Ewing sarcoma, presenting as a pathological fracture of the distal clavicle in a 33-year-old male, in which cytogenetic analysis revealed a single t(2;16)(q35;p11) balanced translocation. Fluorescence in situ hybridization using a commercially available diagnostic probe was negative for an EWS gene rearrangement; instead, break-apart fluorescence in situ hybridization probes for FUS and FEV were positive for a translocation involving these genes. Cloning and sequencing of the breakpoint region demonstrated an in-frame fusion of FUS to FEV. In conclusion, this represents the first reported case of Ewing family tumors demonstrating a variant translocation involving FUS and FEV and highlights the need to consider alternative permutations of fusion partners for molecular diagnosis of sarcomas.
Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/genética , Translocação Genética/genética , Adulto , Sequência de Bases , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Metáfase , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/química , Sarcoma de Ewing/patologia , Análise de Sequência de DNARESUMO
The objectives of this study were foremost to further characterize pre-existing cell lines containing the t(11;14)(q13;q32) translocation. This translocation along with cyclin D1 overexpression is characteristic of Mantle Cell Lymphoma (MCL), an aggressive B cell neoplasm. Considerable variation in the abundance of cyclin D1 expression was observed. mRNA levels were examined by RT-PCR as differences in cyclin D1 mRNA abundance have been shown to synergize with INK4A/Arf deletions to dictate proliferation rate and survival in MCL patient samples. In this study, the cell lines, Z-138 and HBL-2, which exhibited the fastest growth rates and the shortest survival times in Rag2-M mice, had high expression of either one or both cyclin D1 mRNA isoforms and had negligible expression of p16. On the other hand, NCEB-1 and JVM-2 had low expression of both mRNA isoforms, retained p16 expression, and had slower growth rates and exhibited longer survival times in Rag2-M mice. Furthermore, JVM-2, which was found to have the lowest expression of cyclin D1, was the only cell line that expressed cyclin D2. The results of the characterization of Z-138, HBL-2, NCEB-1 and JVM-2 reveal that this group of cell lines represents both classic and variant features of MCL.
Assuntos
Cromossomos Humanos Par 11 , Linfoma de Célula do Manto/genética , Translocação Genética , Animais , Sequência de Bases , Western Blotting , Linhagem Celular Tumoral , Ciclina D1/genética , Primers do DNA , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariotipagem , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/virologia , Masculino , Camundongos , Reação em Cadeia da Polimerase , RNA Mensageiro/genéticaRESUMO
There are increasing reports of Philadelphia-negative (Ph-negative) clonal hematopoiesis developing among patients with chronic myeloid leukemia (CML) treated with imatinib mesylate (IM). To establish the incidence and significance of these chromosomal abnormalities, we analyzed data on 141 consecutive patients with CML treated with IM at the British Columbia Cancer Agency and Vancouver General Hospital from 1999 to 2004. The cumulative incidence of developing a Ph-negative clone three years from the start of IM was 8.7% at a median of 13.3 months. The Ph-negative clonal abnormalities included monosomy 7 and/or trisomy 8 (seven patients), monosomy for chromosomes X and 22 (one patient), and a (12;16) translocation (one patient). Two of the patients presented with the same chromosomal abnormality in both Ph-negative and Ph-positive cells. None of the Ph-negative clonal abnormalities was associated with myelodysplasia. In a multivariate analysis, an interval from diagnosis to initiation of IM of 1 year or less was associated with an increased risk of developing a Ph-negative clone (relative risk = 20.2; P = 0.025). There was no difference, however, in event-free survival between patients who did and did not develop Ph-negative clones. Therefore, while the development of Ph-negative clonal hematopoiesis in patients with CML treated with IM is uncommon, it appears to be more frequent than that previously seen with IFN, but it does not seem to confer a worse prognosis.
Assuntos
Antineoplásicos/uso terapêutico , Hematopoese , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Cariotipagem , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Gene expression profiling studies have reported up-regulated mRNA expression of the FOXP1 forkhead transcription factor in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to investigate the prognostic importance of FOXP1 protein expression in an independent series of DLBCL.First, the specificity of our FOXP1 monoclonal antibody was verified by confirming that it did not recognize the closely related FOXP2, FOXP3, or FOXP4 proteins. FOXP1 protein expression was then analyzed by immunohistochemistry using a DLBCL tissue microarray constructed from 101 previously untreated de novo cases from the British Columbia Cancer Agency. FOXP1 expression was scored as either positive (>30% positive nuclei) or negative (<30% positive nuclei). The overall survival curves clearly showed that patients grouped as FOXP1-positive (40%) had a significantly decreased overall survival (P = 0.0001). FOXP1-positive patients had a median overall survival of 1.6 years compared with 12.2 years in FOXP1-negative cases. In addition, FOXP1-positive patients showed a clear trend to earlier progression in comparison to the FOXP1-negative patients. The analysis of FOXP1 expression within low, medium, and high International Prognostic Index groupings found that FOXP1-negative patients had better overall survival within each group indicating that FOXP1 expression has predictive value independent of the International Prognostic Index subgrouping, a finding that was confirmed in multivariate analysis. These initial results suggest that FOXP1 expression may be important in DLBCL pathogenesis.