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Gene ; 536(1): 79-83, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24325908


BACKGROUND: Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite several factors such as ionizing radiation exposure or rare genetic syndromes have been associated with the development of glioblastoma, no underlying cause has been identified for the majority of cases. We thus aimed to investigate the role of DNA repair polymorphisms in modulating glioblastoma risk. METHODS: Genotypic and allelic frequencies of seven common polymorphisms in DNA repair genes involved in nucleotide excision repair (ERCC1 rs11615, ERCC2 rs13181, ERCC6 rs4253079), base excision repair (APEX1 rs1130409, XRCC1 rs25487), double-strand break repair (XRCC3 rs861539) and mismatch repair (MLH1 rs1800734) pathways were analyzed in 115 glioblastoma patients and 200 healthy controls. Haplotype analysis was also performed for ERCC1 rs11615 and ERCC2 rs13181 polymorphisms, located on the same chromosomal region (19q13.32). RESULTS: Our results indicated that carriers of the ERCC2 Gln/Gln genotype were associated with a lower glioblastoma risk (OR=0.32, 95% CI 0.12-0.89; P=0.028), whereas carriers of the MLH1 AA genotype were associated with an increased risk of glioblastoma (OR=3.14, 95% CI 1.09-9.06; P=0.034). Furthermore, the haplotype containing the C allele of ERCC2 rs13181 polymorphism and the T allele of ERCC1 rs11615 polymorphism was significantly associated with a protective effect of developing glioblastoma (OR=0.34, 95% CI 0.16-0.71; P=0.004). CONCLUSIONS: These results pointed out that MLH1 rs1800734 and ERCC2 rs13181 polymorphisms might constitute glioblastoma susceptibility factors, and also suggested that the chromosomal region 19q could be important in glioblastoma pathogenesis.

Neoplasias Encefálicas/genética , Reparo do DNA/genética , Glioblastoma/genética , Polimorfismo Genético , Idoso , Neoplasias Encefálicas/epidemiologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Glioblastoma/epidemiologia , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
PLoS One ; 8(9): e76401, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24073290


Malignant astrocytomas are the most aggressive primary brain tumors with a poor prognosis despite optimal treatment. Dysfunction of mismatch repair (MMR) system accelerates the accumulation of mutations throughout the genome causing uncontrolled cell growth. The aim of this study was to characterize the MMR system defects that could be involved in malignant astrocytoma pathogenesis. We analyzed protein expression and promoter methylation of MLH1, MSH2 and MSH6 as well as microsatellite instability (MSI) and MMR gene mutations in a set of 96 low- and high-grade astrocytomas. Forty-one astrocytomas failed to express at least one MMR protein. Loss of MSH2 expression was more frequent in low-grade astrocytomas. Loss of MLH1 expression was associated with MLH1 promoter hypermethylation and MLH1-93G>A promoter polymorphism. However, MSI was not related with MMR protein expression and only 5% of tumors were MSI-High. Furthermore, the incidence of tumors carrying germline mutations in MMR genes was low and only one glioblastoma was associated with Lynch syndrome. Interestingly, survival analysis identified that tumors lacking MSH6 expression presented longer overall survival in high-grade astrocytoma patients treated only with radiotherapy while MSH6 expression did not modify the prognosis of those patients treated with both radiotherapy and chemotherapy. Our findings suggest that MMR system alterations are a frequent event in malignant astrocytomas and might help to define a subgroup of patients with different outcome.

Astrocitoma/genética , Biomarcadores Tumorais/análise , Metilação de DNA , Reparo de Erro de Pareamento de DNA/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Mutação/genética , Adulto , Idoso , Astrocitoma/metabolismo , Astrocitoma/mortalidade , Astrocitoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Regiões Promotoras Genéticas/genética , Taxa de Sobrevida , Análise Serial de Tecidos
J Neurooncol ; 110(1): 69-77, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22864683


Even though much progress has been made towards understanding the molecular nature of glioma, the survival rates of patients affected by this tumour have not changed significantly over recent years. Better knowledge of this malignancy is still needed in order to predict its outcome and improve patient treatment. VAV1 is an GDP/GTP exchange factor for Rho/Rac proteins with oncogenic potential that is involved in the regulation of cytoskeletal dynamics and cell migration. Here we report its overexpression in 59 patients diagnosed with high-grade glioma, and the associated upregulation of a number of genes coding for proteins also involved in cell invasion- and migration-related processes. Unexpectedly, immunohistochemical experiments revealed that VAV1 is not expressed in glioma cells. Instead, VAV1 is found in non-tumoural astrocyte-like cells that are located either peritumouraly or perivascularly. We propose that the expression of VAV1 is linked to synergistic signalling cross-talk between cancer and infiltrating cells. Interestingly, we show that the pattern of expression of VAV1 could have a role in the neoplastic process in glioblastoma tumours.

Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Proto-Oncogênicas c-vav/biossíntese , Microambiente Tumoral/fisiologia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Análise por Conglomerados , Hibridização Genômica Comparativa , Intervalo Livre de Doença , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-vav/análise , Receptor Cross-Talk/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
J Clin Oncol ; 21(17): 3285-95, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12947064


PURPOSE: Meningiomas are usually considered benign tumors. However, relapses occur in 10% to 20% of all patients, including both histopathologically aggressive and benign tumors. This study explored the value of numerical abnormalities for 10 different chromosomes in meningiomas for predicting relapse-free survival (RFS). PATIENTS AND METHODS: This study prospectively analyzed the frequency of numerical abnormalities of chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y in 70 meningioma patients by fluorescence in situ hybridization and their relationship with disease characteristics at diagnosis and patients' outcome. RESULTS: Results showed the presence of numerical abnormalities for one or more chromosomes in most patients (77%). Chromosome 22 in the whole series and chromosome Y in males were those more frequently altered, followed by chromosomes 1, 14, and X in females. Patients with abnormalities of chromosomes 1, 9, 10, 11, 14, 15, 17, the sex chromosomes, and gains of chromosome 22 were associated with adverse prognostic features, more frequent relapses, and shorter RFS. Multivariate analysis showed that tumor grade together with chromosome 14 status and age were the best combination of independent variables for predicting RFS. According to these variables, all patients with a score of two or more than two adverse prognostic factors had experienced relapse at 5 years, whereas none of those with a score of zero had experienced relapse 10 years after surgery. CONCLUSION: In addition to age and histologic grade, abnormalities of chromosome 14 contribute to a better prognostic stratification of meningioma patients at diagnosis. Additional prospective studies in larger series of patients, also including larger numbers of patients who experienced relapse, are necessary to confirm the utility of the proposed predictive model.

Aberrações Cromossômicas , Cromossomos Humanos Par 14/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Aberrações Cromossômicas/classificação , Aberrações Cromossômicas/estatística & dados numéricos , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Recidiva , Análise de Regressão , Estatísticas não Paramétricas