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1.
Hum Mol Genet ; 31(22): 3789-3806, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-35708486

RESUMO

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.


Assuntos
COVID-19 , Estudo de Associação Genômica Ampla , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , COVID-19/genética , Caracteres Sexuais , Loci Gênicos , Predisposição Genética para Doença
2.
J Transl Med ; 17(1): 370, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718661

RESUMO

The purpose of the present work is to underline the importance of obtaining a standardized procedure to ensure and evaluate both clinical and research usability of human tissue samples. The study, which was carried out by the Biospecimen Science Working Group of the Spanish Biobank Network, is based on a general overview of the current situation about quality assurance in human tissue biospecimens. It was conducted an exhaustive review of the analytical techniques used to evaluate the quality of human tissue samples over the past 30 years, as well as their reference values if they were published, and classified them according to the biomolecules evaluated: (i) DNA, (ii) RNA, and (iii) soluble or/and fixed proteins for immunochemistry. More than 130 publications released between 1989 and 2019 were analysed, most of them reporting results focused on the analysis of tumour and biopsy samples. A quality assessment proposal with an algorithm has been developed for both frozen tissue samples and formalin-fixed paraffin-embedded (FFPE) samples, according to the expected quality of sample based on the available pre-analytical information and the experience of the participants in the Working Group. The high heterogeneity of human tissue samples and the wide number of pre-analytic factors associated to quality of samples makes it very difficult to harmonize the quality criteria. However, the proposed method to assess human tissue sample integrity and antigenicity will not only help to evaluate whether stored human tissue samples fit for the purpose of biomarker development, but will also allow to perform further studies, such as assessing the impact of different pre-analytical factors on very well characterized samples or evaluating the readjustment of tissue sample collection, processing and storing procedures. By ensuring the quality of the samples used on research, the reproducibility of scientific results will be guaranteed.


Assuntos
Bancos de Espécimes Biológicos/normas , Pesquisa Biomédica/normas , Medicina Baseada em Evidências , Garantia da Qualidade dos Cuidados de Saúde , Humanos , Inclusão em Parafina , Espanha , Fixação de Tecidos
3.
Elife ; 132024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39361370

RESUMO

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.


Assuntos
COVID-19 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hospitalização , Humanos , COVID-19/genética , COVID-19/epidemiologia , Hospitalização/estatística & dados numéricos , SARS-CoV-2/genética , Feminino , Masculino , Loci Gênicos , Fatores de Risco , Polimorfismo de Nucleotídeo Único , Pessoa de Meia-Idade , Idoso , América Latina/epidemiologia
4.
EMBO Mol Med ; 14(3): e14552, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35174975

RESUMO

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Camundongos , Recidiva Local de Neoplasia , Proteômica
5.
J Clin Oncol ; 23(17): 3940-7, 2005 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-15867203

RESUMO

PURPOSE: Lamins support the nuclear envelope and provide anchorage sites for chromatin, but they are also involved in DNA synthesis, transcription, and apoptosis. Although the lack of expression of A-type lamins in lymphoma and leukemia has been reported, the mechanism was unknown. We investigated the possible role of CpG island hypermethylation in lamin A/C silencing and its prognostic relevance. PATIENTS AND METHODS: The promoter CpG island methylation status of the lamin A/C gene, encoding the A-type lamins, was analyzed by bisulfite genomic sequencing and methylation-specific polymerase chain reaction in human cancer cell lines (n = 74; from 17 tumor types), and primary leukemias (n = 60) and lymphomas (n = 80). Lamin A/C expression was determined by reverse-transcription polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. RESULTS: seven (50%) of 14 leukemia- and five (42%) of 13 lymphoma cell lines. The presence of hypermethylation was associated with the loss of gene expression while a demethylating agent restored expression. In primary malignancies, lamin A/C hypermethylation was present in 18% (nine of 50) of acute lymphoblastic leukemias and 34% (14 of 41) of nodal diffuse large B-cell lymphomas. The presence of lamin A/C hypermethylation in nodal diffuse large B-cell lymphomas correlated strongly with a decrease in failure-free survival (Kaplan-Meier, P = .0001) and overall survival (Kaplan-Meier, P = .0005). CONCLUSION: Epigenetic silencing of the lamin A/C gene by CpG island promoter hypermethylation is responsible for the loss of expression of A-type lamins in leukemias and lymphomas. The finding that lamin A/C hypermethylation is associated with poor outcome in diffuse large B-cell lymphomas suggests important clinical implications.


Assuntos
Ilhas de CpG , Metilação de DNA , Inativação Gênica , Lamina Tipo A/genética , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Regiões Promotoras Genéticas/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
6.
Urol Oncol ; 32(8): 1327-32, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24946957

RESUMO

PURPOSE: The present study analyzed the expression by immunochemistry of the novel markers P21-activated protein kinase 6 (PAK6) and proteasome beta-4 subunit (PSMB4) in men with localized prostate cancer (PC) who were treated with dose-escalation radiotherapy (RT) and androgen deprivation therapy. MATERIALS AND METHODS: Between 1996 and 2004, a cohort of 129 patients with PC who underwent diagnostic biopsies pretreatment and 24 to 36 months following RT were enrolled in this study. Suitable archival diagnostic tissue was obtained from 89 patients. Median follow-up was 129 months (48-198). Correlation analysis was done to assess association between PAK6 and PSMB4 expression and clinical outcome. RESULTS: PAK6 and PSMB4 were expressed in the cytoplasm in 62% and 96.7% of diagnostic biopsies, respectively. Increased staining for PAK6 was significantly (P = 0.04) correlated with higher Gleason scores. In the multivariate analysis, the intensity of PSMB4 staining was an independent predictor of local relapse (hazard ratio = 8.6, P = 0.04). CONCLUSIONS: To our knowledge, this is the first description of PAK6 and PSMB4 expression in the diagnostic specimens of men with PC who were treated with RT. If confirmed by further studies, increased expression of these genes could be used to identify patients at a high risk of developing local failure following high-dose RT, thus better tailoring treatments for the individual patient.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Biomarcadores Tumorais/biossíntese , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/terapia , Complexo de Endopeptidases do Proteassoma/biossíntese , Quinases Ativadas por p21/biossíntese , Biomarcadores Tumorais/genética , Estudos de Coortes , Terapia Combinada , Humanos , Imuno-Histoquímica , Masculino , Antígeno Prostático Específico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Complexo de Endopeptidases do Proteassoma/genética , Dosagem Radioterapêutica , Estudos Retrospectivos , Análise de Sobrevida , Quinases Ativadas por p21/genética
7.
Cancer Res ; 69(9): 4052-8, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19406837

RESUMO

Current treatments of sporadic Burkitt's lymphoma (sBL) are associated with severe toxicities. A better understanding of sBL formation would facilitate development of less toxic therapies. The etiology of sBL remains, however, largely unknown, C-MYC up-regulation being the only lesion known to occur in all sBL cases. Several studies examining the role of C-MYC in the pathogenesis of BL have concluded that C-MYC translocation is not the only critical event and that additional unidentified factors are expected to be involved in the formation of this tumor. We herein report that a gene distinct from C-MYC, E2F1, is involved in the formation of all or most sBL tumors. We found that E2F1 is highly expressed in Burkitt's lymphoma cell lines and sBL lymphoma specimens. Our data indicate that its elevated expression is not merely the consequence of the presence of more cycling cells in this tumor relative to other cell lines or to other neoplasias. In fact, we show that reduction of its expression in sBL cells inhibits tumor formation and decreases their proliferation rate. We also provide data suggesting that E2F1 collaborates with C-MYC in sBL formation. E2F1 expression down-regulation did not affect, however, the proliferation of human primary diploid fibroblasts. Because E2F1 is not needed for cell proliferation of normal cells, our results reveal E2F1 as a promising therapeutic target for sBL.


Assuntos
Linfoma de Burkitt/genética , Fator de Transcrição E2F1/genética , Actinas/biossíntese , Actinas/genética , Linfócitos B/metabolismo , Linfócitos B/fisiologia , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Divisão Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Regulação para Baixo , Fator de Transcrição E2F1/biossíntese , Fase G2/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
8.
Proc Natl Acad Sci U S A ; 103(23): 8822-7, 2006 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-16723399

RESUMO

Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumor-suppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylation-dependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n = 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs.


Assuntos
Senilidade Prematura/genética , Neoplasias do Colo/genética , DNA Helicases/genética , Epigênese Genética/genética , Síndrome de Werner/genética , Animais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Ilhas de CpG/genética , Metilação de DNA , Exodesoxirribonucleases , Feminino , Genes Supressores de Tumor , Humanos , Irinotecano , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RecQ Helicases , Inibidores da Topoisomerase I , Helicase da Síndrome de Werner
9.
J Pathol ; 206(2): 123-34, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15880597

RESUMO

Nuclear factor kappa B (NF-kappaB) activation has been proposed as a cardinal feature of tumourigenesis, although the precise mechanism, frequency, relevance, and extent of NF-kappaB activation in lymphomas remain to be fully elucidated. In this study, expression profiling and tissue microarray studies of 209 and 323 non-Hodgkin's lymphomas (NHLs) respectively, including the most frequent sub-types of NHL, were employed to generate a hypothesis concerning the most common NF-kappaB targets in NHL. These analyses showed that NF-kappaB activation is a common phenomenon in NHL, resulting in the expression of distinct sets of NF-kappaB target genes, depending on the cell context. BCL2 and BIRC5/Survivin were identified as key NF-kappaB targets and their expression distinguished small and aggressive B-cell lymphomas, respectively. Interestingly, in the vast majority of B-cell lymphomas, the expression of these markers was mutually exclusive. A set of genes was identified whose expression correlates either with BIRC5/Survivin or with BCL2. BIRC5/Survivin expression, in contrast to BCL2, was associated with a signature of cell proliferation (overexpression of cell cycle control, DNA repair, and polymerase genes), which may contribute to the aggressive phenotype and poor prognosis of these lymphomas. Strikingly, mantle cell lymphoma and chronic lymphocytic leukaemia expressed highly elevated levels of BCL2 protein and mRNA, higher than that observed in reactive mantle zone cells or even in follicular lymphomas, where BCL2 expression is deregulated through the t(14;18) translocation. In parallel with this observation, BIRC5/Survivin expression was higher in Burkitt's lymphoma and diffuse large B-cell lymphoma than in non-tumoural germinal centre cells. In vitro studies confirmed that NF-kappaB activation contributes to the expression of both markers. In cell lines representing aggressive lymphomas, NF-kappaB inhibition resulted in a decrease in BIRC5/Survivin expression. Meanwhile, in chronic lymphocytic leukaemia (CLL)-derived lymphocytes, NF-kappaB inhibition resulted in a marked decrease in BCL2 expression.


Assuntos
Linfoma de Células B/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genes bcl-2 , Humanos , Proteínas Inibidoras de Apoptose , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Ligantes , Linfoma de Células B/genética , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/metabolismo , Proteínas Associadas aos Microtúbulos/genética , NF-kappa B/genética , Proteínas de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Receptores do Fator de Necrose Tumoral/metabolismo , Survivina
10.
Am J Pathol ; 160(4): 1371-80, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11943722

RESUMO

BCL-6 somatic mutations have been described in normal and tumoral B lymphocytes, associated with germinal center transit. We analyzed mutations in the major mutation cluster of BCL-6 in a series of 45 large B-cell lymphomas (LBCLs) and 15 Burkitt's lymphomas, and their relation to the level of BCL-6 expression and clinical outcome. Mutations in LBCL cases revealed the existence of two distinct, short mutational hot spots, spanning positions 106 to 127 and 423 to 443, in which the mutation frequency was higher than expected (P < 0.001). Mutations in the 423 to 443 subcluster were associated with an increased level of expression, although this was not the case with the 106 to 127 cluster. Additionally, LBCL cases characterized by the presence of mutations in the 423 to 443 cluster showed an increased overall survival (P < 0.05) when compared with the nonmutated LBCL cases in these positions. Burkitt's lymphoma cases showed a slightly lower frequency of mutations with a nonclustered distribution and lacked any relationship with the level of expression or any clinical characteristic. Findings from LBCLs suggest that the 423 to 443 cluster includes a regulatory region that is of importance for BCL-6 expression. Deregulation of BCL-6 expression caused by these mutations could play an important role in lymphoma genesis or progression.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Íntrons/genética , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Humanos , Família Multigênica , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-bcl-6 , Análise de Sobrevida
11.
Mod Pathol ; 15(3): 211-20, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11904338

RESUMO

Oct1 and Oct2 are transcription factors of the POU homeo-domain family that bind to the Ig gene octamer sites, regulating B-cell-specific genes. The function of these transcription factors is dependent on the activity of B-cell-restricted coactivators such as BOB.1/OBF.1. Independent studies of the expression of these proteins in non-Hodgkin's lymphoma have been restricted to single markers, and most lack data concerning immunohistochemical expression. Thus, we have investigated the expression of Oct1, Oct2, and BOB.1/OBF.1 in human reactive lymphoid tissue and in a series of 140 Hodgkin and non-Hodgkin's lymphomas. None of these proteins was found to be restricted to B cells, although only B cells expressed high levels of all three markers. Additionally, germinal center B cells showed stronger Oct2 and BOB.1/OBF.1 staining. Consequently, most B-cell lymphomas showed reactivity for all three antibodies. Oct2 expression was significantly higher in germinal center-derived lymphomas, although other B-cell lymphomas also displayed a high level of Oct2 expression. Although T-cell lymphomas and Hodgkin's lymphomas expressed some of these proteins, they commonly exhibited less reactivity than B-cell lymphomas. Despite not being entirely cell-specific, the strong nuclear expression of Oct2 and BOB.1/OBF.1 by germinal center- derived lymphomas makes these antibodies a potentially useful tool in lymphoma diagnosis.


Assuntos
Doença de Hodgkin/metabolismo , Linfoma não Hodgkin/metabolismo , Fator 1 de Transcrição de Octâmero/metabolismo , Fator 2 de Transcrição de Octâmero/metabolismo , Transativadores/metabolismo , Antígenos CD20/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Técnica Indireta de Fluorescência para Anticorpo , Doença de Hodgkin/patologia , Humanos , Técnicas Imunoenzimáticas , Linfoma não Hodgkin/patologia , Fatores de Transcrição
12.
Lab Invest ; 83(2): 143-52, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12594230

RESUMO

Absence of a reliable method for determining the level of c-myc expression has impeded the analysis of its biological and clinical relevance in tumors. We have standardized the conditions for a real-time reverse transcription polymerase chain reaction analysis for c-myc expression, including the selection of an endogenous reference (18S rRNA), the adequate number of measurements for each sample (2 cDNA in triplicate), and suitable controls for determining inter- and intrarun variability (standard curve and calibrator). Subsequently, in a series of 56 non-Hodgkin's lymphomas, we analyzed the expression of c-myc mRNA, using real-time reverse transcription polymerase chain reaction, and of other functionally related proteins (bcl-6, p27, cyclin D3, and p53). As expected, all eight Burkitt's lymphoma cases analyzed had high levels of c-myc mRNA expression compared with that observed in reactive lymphoid tissue. There was a wider range of expression in diffuse large B-cell lymphoma, with 30% (15 of 48) of cases overexpressing c-myc. This overexpression was largely independent of c-myc translocations (4 of 5), as demonstrated by fluorescence in situ hybridization. In this large B-cell lymphoma series, a high level of c-myc expression predicted lower survival probability, irrespectively of the International Prognostic Index risk group classification. A slightly increased frequency of p53 inactivation was observed in the cases with c-myc overexpression, which suggests a growth advantage in lymphomas with concurrent deregulation of c-myc and p53. In addition, a moderate increase in bcl-6 protein expression was observed in the c-myc-positive cases, suggesting the existence of a complex interrelationship between these two genes. These findings suggest that c-myc may play a relevant role in the pathogenesis of a subset of large B-cell lymphoma and suggest the existence of additional regulatory mechanisms of c-myc expression to c-myc rearrangements.


Assuntos
Linfócitos B/patologia , DNA de Neoplasias/análise , Genes myc/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Biomarcadores Tumorais/análise , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , DNA Complementar/análise , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Proteínas de Neoplasias/análise , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pseudolinfoma/genética , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , RNA Neoplásico/análise , RNA Ribossômico/análise , Reprodutibilidade dos Testes , Taxa de Sobrevida
13.
Am J Pathol ; 164(2): 613-22, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14742266

RESUMO

Diffuse large B-cell lymphoma (DLBCL) patients are treated using relatively homogeneous protocols, irrespective of their biological and clinical variability. Here we have developed a protein-expression-based outcome predictor for DLBCL. Using tissue microarrays (TMAs), we have analyzed the expression of 52 selected molecules in a series of 152 DLBCLs. The study yielded relevant information concerning key biological aspects of this tumor, such as cell-cycle control and apoptosis. A biological predictor was built with a training group of 103 patients, and was validated with a blind set of 49 patients. The predictive model with 8 markers can identify the probability of failure for a given patient with 78% accuracy. After stratifying patients according to the predicted response under the logistic model, 92.3% patients below the 25 percentile were accurately predicted by this biological score as "failure-free" while 96.2% of those above the 75 percentile were correctly predicted as belonging to the "fatal or refractory disease" group. Combining this biological score and the International Prognostic Index (IPI) improves the capacity for predicting failure and survival. This predictor was then validated in the independent group. The protein-expression-based score complements the information obtained from the use of the IPI, allowing patients to be assigned to different risk categories.


Assuntos
Biomarcadores Tumorais/análise , Modelos Logísticos , Linfoma de Células B/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Sensibilidade e Especificidade , Análise de Sobrevida , Resultado do Tratamento
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