RESUMO
Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.
Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Mutação/genética , NF-kappa B/genética , Proteínas de Neoplasias/metabolismo , Adenoviridae , Proteína 3 com Repetições IAP de Baculovírus , Antígenos CD40/genética , Antígenos CD40/metabolismo , Células Cultivadas , Enzima Desubiquitinante CYLD , Ativação Enzimática , Imunofluorescência , Deleção de Genes , Perfilação da Expressão Gênica , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Hibridização de Ácido Nucleico , Plasmídeos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transfecção , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases , Quinase Induzida por NF-kappaBRESUMO
The Pap test has effectively reduced the incidence and mortality of cervical cancer. However, because of the morphological basis of this test, sensitivity and specificity are less than ideal, a situation that complicates the clinical management of women diagnosed with low-grade cervical abnormalities. In an attempt to understand the molecular basis of cervical tumorigenesis and to discover molecular markers for accurate cervical cancer screening, we used cDNA microarrays containing >30,000 Unigene clones to examine the gene expression patterns of 34 cervical tissues from different clinically defined stages. It was found that global gene expression patterns separated normal cervical tissues and low-grade squamous intraepithelial lesions from cervical cancers and most of the high-grade squamous intraepithelial lesions (HSILs). Among the top 62 genes/(expressed sequence tags) that were overexpressed in tumors and HSIL tissues, 35 were confirmed using in situ hybridization on cervical tissue micorarrays. Many of these genes were overexpressed in high-grade dysplastic and malignant cervical epithelium or in stroma adjacent to the diseased tissues, with cellular proliferation and extracellular matrix-associated genes being the most common. In general, the extent of gene overexpression increased as the lesions progressed from low-grade squamous intraepithelial lesions to HSILs and finally to cancer. It is hoped that with additional development, some of these markers will improve the interpretation of cervical screening tests and provide useful information for patient management decisions.
Assuntos
Neoplasias do Colo do Útero/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Divisão Celular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Marcadores Genéticos/genética , Humanos , Hibridização In Situ , Análise de Sequência com Séries de Oligonucleotídeos , Ativação Transcricional , Neoplasias do Colo do Útero/metabolismo , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/metabolismoRESUMO
Overexpression of the Bcl-2 family of genes results in increased transcription of anti-apoptotic proteins. In vitro data suggest that this may enhance acquired chemoresistance and correlate with extramedullary invasion. This has led to pursuing the Bcl-2 family of proteins as therapeutic targets in several malignant disorders, including multiple myeloma (MM). The impact of novel therapeutic agents such as bortezomib on these molecular markers is not known. We investigated the association between the expression of anti-apoptotic members of the Bcl-2 family and the efficacy of bortezomib in patients with relapsed/refractory MM. Gene expression data generated prospectively from large clinical trials were utilized. Hypothesis testing using a multisample test for equivalence was performed. The association between Bcl-2 expression levels and clinical response was negated in bortezomib-treated patients (p = 0.014), while not so in dexamethasone-treated patients (p = 0.92). Similar results were noted for variant 2 of the Mcl-1 gene (p = 0.003). Results for Bcl-xl did not meet the level of significance. Thus, the importance of the Bcl-2 family of proteins as prognostic markers in MM should be reassessed in the novel therapeutic agent era. Our data suggest that bortezomib may overcome the prognostic effect conferred by overexpression of some of the anti-apoptotic Bcl-2 family of genes in patients with relapsed/refractory MM.
Assuntos
Ácidos Borônicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Genes bcl-2/genética , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Ácidos Borônicos/farmacologia , Bortezomib , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise por Conglomerados , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes bcl-2/efeitos dos fármacos , Humanos , Análise em Microsséries , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Prognóstico , Pirazinas/farmacologia , Recidiva , Falha de Tratamento , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Immunohistochemical analyses of archival tumor specimens were used for pre-planned exploratory analyses of protocol-specified candidate biomarkers of bortezomib activity in 73 patients with relapsed/refractory mantle cell lymphoma in the phase 2 PINNACLE study. Consistent with other studies, elevated Ki-67 was a marker of poor prognosis, demonstrating significant associations with shorter time to progression and overall survival. Elevated NF-kappaB p65 and low PSMA5 expression demonstrated a trend for better response and were significantly associated with longer time to progression; elevated NF-kappaB p65 demonstrated a trend toward longer overall survival. This is consistent with myeloma clinical genomics research, suggesting biomarker relevance across tumor types. Elevated p27 was significantly associated with longer overall survival. Overall survival analyses by International Prognostic Index and Mantle Cell Lymphoma International Prognostic Index confirmed differential prognosis by both scores. These biomarkers data begin to illuminate bortezomib's mechanism of action in lymphoma.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Ácidos Borônicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Pirazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib , Inibidor de Quinase Dependente de Ciclina p27 , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.