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1.
Front Oncol ; 9: 303, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31106144

RESUMO

Background: In hormone receptor-positive (HR+)/HER2-negative breast cancer, the HER2-enriched and Basal-like intrinsic subtypes are associated with poor outcome, low response to anti-estrogen therapy and high response to chemotherapy. To date, no validated biomarker exists to identify both molecular entities other than gene expression. Methods: PAM50 subtyping and immunohistochemical data were obtained from 8 independent studies of 1,416 HR+/HER2-negative early breast tumors. A non-luminal disease score (NOLUS) from 0 to 100, based on percentage of estrogen receptor (ER), progesterone receptor (PR) and Ki67 tumor cells, was derived in a combined cohort of 5 studies (training dataset) and tested in a combined cohort of 3 studies. The performance of NOLUS was estimated using Area Under the ROC Curve (AUC). Results: In the training dataset (n = 903) and compared to luminal disease, non-luminal disease had lower percentage of ER-positive cells (median 65.2 vs. 86.2%, p < 0.01) and PR-positive cells (33.2 vs. 56.4%, p < 0.01) and higher percentage of Ki67-positive cells (18.2 vs. 13.1%, p = 0.01). A NOLUS formula was derived: -0.45*ER -0.28*PR +0.27*Ki67 + 73.02. The proportion of non-luminal tumors in NOLUS-positive (≥51.38) and NOLUS-negative (<51.38) groups was 52.6 and 8.7%, respectively. In the testing dataset (n = 514), NOLUS was found significantly associated with non-luminal disease (p < 0.01) with an AUC 0.902. The proportion of non-luminal tumors in NOLUS-positive and NOLUS-negative groups was 76.9% (56.4-91.0%) and 2.6% (1.4-4.5%), respectively. The sensitivity and specificity of the pre-specified cutoff was 59.3 and 98.7%, respectively. Conclusions: In the absence of gene expression data, NOLUS can help identify non-luminal disease within HR+/HER2-negative breast cancer.

3.
Br J Haematol ; 184(3): 373-383, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565652

RESUMO

Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Pontos de Checagem da Fase S do Ciclo Celular , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , RNA Longo não Codificante/genética , RNA Neoplásico/genética
4.
J Clin Invest ; 128(9): 4132-4147, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29990311

RESUMO

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.


Assuntos
Ciclina D1/genética , Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Código das Histonas , Humanos , Modelos Biológicos , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética
5.
Blood ; 132(4): 413-422, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29769262

RESUMO

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A/ATM deletions, but the proportion with 17p/TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53/CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.


Assuntos
Biomarcadores Tumorais/genética , Leucemia/genética , Leucemia/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Mutação , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Genômica , Humanos , Leucemia/classificação , Linfoma de Célula do Manto/classificação , Masculino , Prognóstico , Taxa de Sobrevida
6.
Blood ; 131(21): 2283-2296, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29666114

RESUMO

Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are 2 well-defined entities that diverge in their basic pathogenic mechanisms and clinical evolution but they share epidemiological characteristics, cells of origin, molecular alterations, and clinical features that differ from other lymphoid neoplasms. CLL and MCL are classically considered indolent and aggressive neoplasms, respectively. However, the clinical evolution of both tumors is very heterogeneous, with subsets of patients having stable disease for a long time whereas others require immediate intervention. Both CLL and MCL include 2 major molecular subtypes that seem to derive from antigen-experienced CD5+ B cells that retain a naive or memory-like epigenetic signature and carry a variable load of immunoglobulin heavy-chain variable region somatic mutations from truly unmutated to highly mutated, respectively. These 2 subtypes of tumors differ in their molecular pathways, genomic alterations, and clinical behavior, being more aggressive in naive-like than memory-like-derived tumors in both CLL and MCL. The pathogenesis of the 2 entities integrates the relevant influence of B-cell receptor signaling, tumor cell microenvironment interactions, genomic alterations, and epigenome modifications that configure the evolution of the tumors and offer new possibilities for therapeutic intervention. This review will focus on the similarities and differences of these 2 tumors based on recent studies that are enhancing the understanding of their pathogenesis and creating solid bases for new management strategies.


Assuntos
Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/etiologia , Linfoma de Célula do Manto/patologia , Microambiente Tumoral , Biomarcadores , Evolução Clonal , Suscetibilidade a Doenças , Variação Genética , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma de Célula do Manto/metabolismo , Transdução de Sinais
7.
Leuk Lymphoma ; 59(10): 2318-2326, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29115891

RESUMO

Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38high, ZAP-70high, CD49dhigh, +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = .006). Binet stage, SLL, and IGHV were independent predictive factors for TTFT. Transformation to diffuse large B-cell lymphoma was higher (10-year: 12% vs 6%; p = .003), and overall survival was shorter in SLL (10-year: 55% vs 66%; p = .004). When A0 CLL patients were excluded, only CD38 and CD49d expression, +12, and 10-year TTFT remained different between the SLL and CLL patients. In summary, SLL showed only minor clinicobiological differences when compared with CLL in similar clinical stages.


Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Tempo para o Tratamento/estatística & dados numéricos , Adulto Jovem
8.
Br J Cancer ; 117(12): 1777-1786, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29123263

RESUMO

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Núcleo Celular/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Transporte Proteico/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Curcumina/farmacologia , Dasatinibe/farmacologia , Ácidos Graxos Insaturados/farmacologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Inativação Gênica , Células HCT116 , Células HT29 , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia de Alvo Molecular , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Panitumumabe , Compostos de Fenilureia/farmacologia , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe
10.
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.
Cancer Cell ; 30(5): 806-821, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27846393

RESUMO

We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.


Assuntos
Metilação de DNA , Elementos Facilitadores Genéticos , Epigenômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma de Célula do Manto/genética , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Simulação por Computador , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição SOXC/genética
12.
Blood ; 127(17): 2122-30, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-26837699

RESUMO

Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Genes p53 , Proteínas Inibidoras de Apoptose/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Proteína 3 com Repetições IAP de Baculovírus , Células Clonais , Análise Mutacional de DNA , Progressão da Doença , Evolução Molecular , Feminino , Humanos , Proteínas Inibidoras de Apoptose/fisiologia , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/fisiologia , Células-Tronco Neoplásicas , Fosfoproteínas/fisiologia , Prognóstico , Fatores de Processamento de RNA/fisiologia , Receptor Notch1/fisiologia , Tempo para o Tratamento , Resultado do Tratamento , Proteína Supressora de Tumor p53/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Adulto Jovem
13.
Coll Antropol ; 40(3): 195-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-29139639

RESUMO

The aim of this preliminary study is to analyze genetic specificity of Kosovo Albanians comparing with neighboring populations using new genetic tool - MEDISCOPE gene chip, to investigate the feasibility of this approach. We collected 37 DNA samples (9 Croats, 17 Albanians from Croatia and 11 Albanians from Kosovo) from unrelated males born in Croatia and Kosovo. Additionally, samples were expanded with female individuals and mtDNA analysis included a total of 61 samples (15 Croats, 23 Albanians from Croatia and 23 Albanians from Kosovo). This pilot study suggests that the usage of the MEDISCOPE chip could be recognized as an efficient tool within recognition of the population genetic specificity even within extremely small sample size.


Assuntos
Variação Genética/genética , Genética Populacional/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Cromossomos Humanos Y/genética , Croácia , DNA Mitocondrial/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Marcadores Genéticos/genética , Humanos , Kosovo , Masculino , Projetos Piloto
14.
Nature ; 526(7574): 519-24, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26200345

RESUMO

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Elementos Facilitadores Genéticos/genética , Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fator de Transcrição PAX5/biossíntese , Fator de Transcrição PAX5/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fatores de Transcrição/genética
15.
Virchows Arch ; 466(4): 375-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25652585

RESUMO

We studied the expression of p16(INK4a) in a series of HPV-negative laryngeal squamous cell carcinomas and assessed its association with prognosis. Forty-five patients with laryngeal carcinoma were included in the study. Clinicopathological features and prognosis were reviewed. p16(INK4a) protein expression was analysed through immunohistochemistry. We analysed messenger RNA (mRNA) in 25 cases through quantitative reverse transcription polymerase chain reaction. HPV status was assessed by PCR using three different protocols based on MY09/11 and GP5/6 primers. Four out of 45 (9 %) cases overexpressed p16(INK4a) protein and showed a tendency to worse survival that was significant for stages I-III (log-rank p value = 0.001). Expression of p16(INK4a) mRNA was high in 12 out of 25 (48 %) cases using an arbitrary cut-off level. All tumours were HPV negative with all three detection methods. A CDKN2A mutation was found in eight cases. One case with a missense and one with a frameshift mutation showed p16(INK4a) protein expression by immunohistochemistry. Six out of seven (86 %) mutated but only 6 out of 18 (33 %) non-mutated cases presented p16(INK4a) mRNA overexpression (p = 0.03). Our findings suggest that p16(INK4a) overexpression, both at protein and mRNA levels, may reflect CDKN2A genetic alterations in HPV-negative laryngeal squamous cell carcinomas.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Laríngeas/patologia , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Análise Mutacional de DNA , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Infecções por Papillomavirus , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carcinoma de Células Escamosas de Cabeça e Pescoço
16.
Blood ; 124(14): 2235-47, 2014 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-25092176

RESUMO

SOX11 is overexpressed in several solid tumors and in the vast majority of aggressive mantle cell lymphomas (MCLs). We have recently proven that SOX11 silencing reduces tumor growth in a MCL xenograft model, consistent with the indolent clinical course of the human SOX11-negative mantle cell lymphoma (MCL). However, the direct oncogenic mechanisms and downstream effector pathways implicated in SOX11-driven transformation remain poorly understood. Here, we observed that SOX11-positive xenograft and human primary MCL tumors overexpressed angiogenic gene signatures and had a higher microvascular density compared with their SOX11-negative counterparts. Conditioned media of SOX11-positive MCL cell lines induced in vitro endothelial cell proliferation, migration, tube formation, and activation of downstream angiogenic pathways. We identified PDGFA as a SOX11 direct target gene upregulated in MCL cells whose inhibition impaired SOX11-enhanced in vitro angiogenic effects on endothelial cells. In addition, platelet-derived growth factor A (PDGFA) was overexpressed in SOX11-positive but not in SOX11-negative MCL. In vivo, imatinib impaired tumor angiogenesis and lymphoma growth in SOX11-positive MCL xenograft tumors. Overall, our results demonstrate a prominent role for SOX11 as a driver of proangiogenic signals in MCL, and highlight the SOX11-PDGFA axis as a potential therapeutic target for the treatment of this aggressive disease.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição SOXC/metabolismo , Animais , Movimento Celular , Proliferação de Células , Meios de Cultivo Condicionados/química , Células Endoteliais/citologia , Perfilação da Expressão Gênica , Inativação Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Neovascularização Patológica , Proteômica , Transdução de Sinais , Ativação Transcricional
17.
Eur J Cancer ; 50(11): 1973-81, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24833563

RESUMO

INTRODUCTION: Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF(V600E) mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC. METHODS: We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy. RESULTS: KRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35-5.72; p=0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2-4.59; p=0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2-4.78; p=0.01) in KRAS/BRAF WT mCRC patients. CONCLUSIONS: RAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas rac1 de Ligação ao GTP/biossíntese , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Genótipo , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Proteínas rac1 de Ligação ao GTP/genética
18.
Blood ; 123(24): 3790-6, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24782504

RESUMO

Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.


Assuntos
Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/genética , Adulto Jovem
19.
Leuk Lymphoma ; 55(10): 2262-70, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24512319

RESUMO

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 resulting from the t(11;14) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. MCL remains a clinically challenging lymphoma subtype, as there is no proven curative therapy and no standard of care has been established for initial or subsequent lines of therapy. However, there have been considerable advances in the last several years in the treatment of MCL, leading to improved survival. Recent investigations into the biology of MCL, clinically relevant biomarkers, novel therapeutic targets and new treatment strategies were discussed at a recent workshop of the Lymphoma Research Foundation's Mantle Cell Lymphoma Consortium. The presentations are summarized in this manuscript, which is intended to highlight areas of active investigation and identify topics for future research.


Assuntos
Linfoma de Célula do Manto/etiologia , Linfoma de Célula do Manto/terapia , Humanos , Linfoma de Célula do Manto/diagnóstico
20.
Genome Res ; 24(2): 212-26, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24265505

RESUMO

Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes-most of which are not differentially expressed-exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.


Assuntos
Linfócitos B , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Sequência de Bases , Feminino , Perfilação da Expressão Gênica , Humanos , Região Variável de Imunoglobulina , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Ribossomos/genética , Spliceossomos/genética
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