Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.516
Filtrar
1.
Cancer Treat Rev ; 82: 101935, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31821983

RESUMO

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.


Assuntos
Neoplasias Colorretais , Temozolomida/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Supressoras de Tumor/genética
2.
Medicine (Baltimore) ; 98(50): e18194, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852075

RESUMO

OBJECTIVE: To date, there are several published studies on the value of IDH-1 (isocitrate dehydrogenase-1) mutation and MGMT (O6-Methylguanine-DNA methyltransferas) promoter methylated status on the diagnosis of pseudoprogression (PSP) and true tumor progression after or within chemo-radiotherapy of high grade glioma (HGG). We performed a meta-analysis about the significant value of these 2 molecular markers on the diagnosis of PsP in high- grade glioma. METHODS: We searched the eligible studies from PubMed, Medline, Embase, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wan Fang Database. The relevant studies published before October 2018 were identified. ORs (odds ratios) with 95%CIs (confidence intervals) were used to evaluate the value using fixed- or random-effect model. RESULTS: Thirteen studies about MGMT promoter methylated status and 4 studies about IDH-1 mutations were found eligible for this present meta-analysis. Significant value of MGMT promoter methylation status (OR = 4.02, 95%CI = 2.76-5.87, P < .001) and IDH-1 mutations (OR = 12.78, 95%CI = 3.86-42.35, P < .001) were observed. CONCLUSIONS: This meta-analysis provided evidences that MGMT promoter methylation status and IDH-1 mutations could distinguish PSP from true tumor progression.


Assuntos
Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Estadiamento de Neoplasias , Proteínas Supressoras de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/metabolismo , Progressão da Doença , Glioma/diagnóstico , Glioma/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/metabolismo
3.
World Neurosurg ; 132: e140-e161, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31505292

RESUMO

BACKGROUND: This study aimed to predict methylation status of the O6 methylguanine-DNA methyltransferase (MGMT) gene promoter status by using magnetic resonance imaging radiomics features, as well as univariate and multivariate analysis. METHODS: Eighty-two patients who had an MGMT methylation status were included in this study. Tumors were manually segmented in the 4 regions of magnetic resonance images, 1) whole tumor, 2) active/enhanced region, 3) necrotic regions, and 4) edema regions. About 7000 radiomics features were extracted for each patient. Feature selection and classifier were used to predict MGMT status through different machine learning algorithms. The area under the curve (AUC) of the receiver operating characteristic curve was used for model evaluations. RESULTS: Regarding univariate analysis, the Inverse Variance feature From Gray Level Co-occurrence Matrix in whole tumor segment with 4.5 mm Sigma of Laplacian of Gaussian filter with AUC of 0.71 (P value = 0.002) was found to be the best predictor. For multivariate analysis, the Decision Tree classifier with Select from Model feature selector and LOG (Laplacian of Gaussian) filter in edema region had the highest performance (AUC, 0.78), followed by Ada-Boost classifier with Select from Model feature selector and LOG filter in edema region (AUC, 0.74). CONCLUSIONS: This study showed that radiomics using machine learning algorithms is a feasible noninvasive approach to predict MGMT methylation status in patients with glioblastoma multiforme cancer.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Edema Encefálico/diagnóstico por imagem , Feminino , Genômica , Humanos , Avaliação de Estado de Karnofsky , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Necrose , Distribuição Normal , Valor Preditivo dos Testes , Estudos Retrospectivos
4.
Nucleic Acids Res ; 47(18): 9761-9776, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31504772

RESUMO

Modification dependent restriction endonucleases (MDREs) often have separate catalytic and modification dependent domains. We systematically looked for previously uncharacterized fusion proteins featuring a PUA or DUF3427 domain and HNH or PD-(D/E)XK catalytic domain. The enzymes were clustered by similarity of their putative modification sensing domains into several groups. The TspA15I (VcaM4I, CmeDI), ScoA3IV (MsiJI, VcaCI) and YenY4I groups, all featuring a PUA superfamily domain, preferentially cleaved DNA containing 5-methylcytosine or 5-hydroxymethylcytosine. ScoA3V, also featuring a PUA superfamily domain, but of a different clade, exhibited 6-methyladenine stimulated nicking activity. With few exceptions, ORFs for PUA-superfamily domain containing endonucleases were not close to DNA methyltransferase ORFs, strongly supporting modification dependent activity of the endonucleases. DUF3427 domain containing fusion proteins had very little or no endonuclease activity, despite the presence of a putative PD-(D/E)XK catalytic domain. However, their expression potently restricted phage T4gt in Escherichia coli cells. In contrast to the ORFs for PUA domain containing endonucleases, the ORFs for DUF3427 fusion proteins were frequently found in defense islands, often also featuring DNA methyltransferases.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas de Restrição do DNA/genética , Escherichia coli/enzimologia , Regulação Enzimológica da Expressão Gênica/genética , Sequência de Aminoácidos , Domínio Catalítico/genética , Clivagem do DNA , Metilases de Modificação do DNA/química , Enzimas de Restrição do DNA/química , Enzimas de Restrição do DNA/classificação , Escherichia coli/genética , Modelos Moleculares , Estrutura Terciária de Proteína/genética , Alinhamento de Sequência
5.
J Clin Neurosci ; 68: 1-8, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31416731

RESUMO

Molecular aberrations of malignancy are becoming widely recognized as important predictive and prognostic markers for treatment response and survival in oncology and have been linked to the discovery of novel treatment targets. This area of research in glioblastoma continues to evolve. The aim of this scoping review was to document the hallmark molecular characteristics of long-term survivors of glioblastoma. MEDLINE, Scopus and EMBASE were searched with core concepts: (1) glioblastoma, (2) long-term survivor and (3) molecular OR mutation. A thematic analysis was undertaken of the 18 included studies. Four main classes of characteristics were obtained: IDH mutation, MGMT methylation, other known characteristics and novel discoveries. While MGMT methylation or the combination with IDH mutation are suggested to be hallmark characteristics, there remains enough uncertainty to suggest further factors may be involved, such as CD34 expression. Further research is required to accurately describe hallmark molecular characteristics of long-term survivors to assist in defining these patients at diagnosis, preventing treatment complications and discovering novel treatments.


Assuntos
Neoplasias Encefálicas/genética , Sobreviventes de Câncer , Glioblastoma/genética , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/mortalidade , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Supressoras de Tumor/genética
6.
Cancer Imaging ; 19(1): 58, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426864

RESUMO

BACKGROUND: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has emerged as a favorable independent prognostic and predictive biomarker in glioma. This study aimed to build a radiomics signature based on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for noninvasive measurement of the MGMT promoter methylation status in glioma. METHODS: One hundred and seven pathology-confirmed primary diffuse glioma patients were retrospectively included and randomly assigned to the primary (n = 71) or validation cohort (n = 36). The MGMT promoter methylation status was measured by pyrosequencing. A total of 1561 radiomics features were extracted from the three-dimensional region of interest (ROI) on the standard uptake value (SUV) maps that were generated from the original 18F-FDG PET data. A radiomics signature, a clinical signature and a fusion signature that combined the clinical and radiomics features together were generated. The performance of the three signatures was evaluated by receiver operating characteristic (ROC) curve analysis, and the patient prognosis was stratified based on the MGMT promoter methylation status and the signature with the best performance. RESULTS: Five radiomics features were selected to construct the radiomics signature, and displayed the best performance with area under the receiver operating characteristic (ROC) curve (AUC) reaching 0.94 and 0.86 in the primary and validation cohorts, respectively, which outweigh the performances of clinical signature and fusion signature. With a median follow-up time of 32.4 months, the radiomics signature stratified the glioma patients into two risk groups with significantly different prognoses (p = 0.04). CONCLUSIONS: 18F-FDG-PET-based radiomics is a promising approach for preoperatively evaluating the MGMT promoter methylation status in glioma and predicting the prognosis of glioma patients noninvasively.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Neoplasias Encefálicas/genética , Feminino , Fluordesoxiglucose F18 , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Compostos Radiofarmacêuticos
7.
Future Oncol ; 15(22): 2595-2601, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31339049

RESUMO

Aim: European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) criteria are used to choose treatment in low-grade gliomas. However, no data exist on their concordance. Methods: Low-grade glioma patients treated at our institution from 1998 to 2015 and assessable for both RTOG and EORTC criteria were included to analyze their concordance. Surgery extension, postsurgical treatments, molecular characteristics (IDH mutation, MGMT methylation and 1p/19q codeletion) were recorded. Results: We included 99 patients. The concordance was low (50.5%; K = 0.127; p = 0.021) but for two subgroups: EORTC high-risk patients were also RTOG high-risk patients (concordance: 97.5%) and RTOG low-risk patients were also EORTC low-risk patients (concordance: 90.9%). Conclusion: The concordance between RTOG and EORTC criteria is low. Thus, clinical trials adopting different risk criteria are not comparable.


Assuntos
Glioma/epidemiologia , Glioma/terapia , Prognóstico , Adulto , Idoso , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Intervalo Livre de Doença , Feminino , Glioma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Proteínas Supressoras de Tumor/genética
8.
Gene ; 710: 333-340, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31202904

RESUMO

Gene promoter methylation is a common epigenetic event, taking place in the early phase of tumorigenesis, which has a great potential as a diagnostic and prognostic cancer biomarker. In this umbrella review, we provide an overview on the association between gene-promoter methylation of protein-coding genes and cancer risk based on currently available meta-analyses data on gene promoter methylation. We searched MEDLINE via PubMed and the Cochrane Database of Systematic Reviews for meta-analyses that examine the association between gene-promoter methylation and cancer, published until January 2019 in English. We used AMSTAR to assess the quality of the included studies and applied a set of pre-specified criteria to evaluate the magnitude of each association. We provide a comprehensive overview of 80 unique combinations between 22 different genes and 18 cancer outcomes, all of which indicated a positive association between promoter hypermethylation and cancer. In total, the 70 meta-analyses produced significant results under a random-effects model with odds ratios that ranged from 1.94 to 26.60, with the summary effect being in favor of the unmethylated group in all cases. Three of the strong evidence associations involve RASSF1 methylation on bladder cancer risk (OR = 18.46; 95% CI: 12.69-26.85; I2 = 0%), MGMT methylation on NSCLC (OR = 4.25; 95% CI: 2.83-6.38; I2 = 22.4%) and RARB methylation on prostate cancer (OR = 6.87; 95% CI: 4.68-10.08; I2 = 0%). Meta-analyses showed a moderate quality, AMSTAR score ranging from 4 to 9 (Mdn = 8; IQR: 7.0 to 8.0). As primary studies and meta-analyses on the subject accumulate, more genetic loci may be found to be highly associated with specific cancer types and hence the biomarker sets will become wider.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Neoplasias/genética , Receptores do Ácido Retinoico/genética , Proteínas Supressoras de Tumor/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Masculino , Metanálise como Assunto , Razão de Chances , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Bexiga Urinária/genética
9.
Seizure ; 69: 283-289, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31141785

RESUMO

PURPOSE: To examine the occurrence of glioma-related preoperative seizures (GPS) and post-operative seizure control (PSC) with respect to patients characteristics including five commonly tested tumor molecular markers (TMMs). METHODS: A single-center retrospective cohort study of patients with glioma evaluated at the Mayo Clinic, Florida between 2016 and 2018. RESULTS: 68 adult patients (mean age = 51-years, 45-males) were included. 46 patients had GPS. 57 patients underwent intra-operative electrocorticography during awake craniotomy-assisted glioma resection. All patients underwent glioma resection (53, gross-total resection) with histologies of pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 4), oligodendroglioma (n = 14), anaplastic astrocytoma (n = 16), anaplastic oligodendroglioma (n = 1), and glioblastoma (n = 31). 31 (67%) patients had PSC (median follow-up = 14.5 months; IQR = 7-16.5 months). IDH1 mutation (IDH1mut) was present in 32, ARTX retention in 53, MGMT gene promotor methylation in 15, 1p/19q co-deletion in 15, and over-expression of p53 in 19 patients. Patients with IDH1mut were more likely to have GPS (p = 0.037) and PSC (p = 0.035) compared to patients with IDH1 wild-type. Patients with MGMT gene promoter methylation were also likely to have PSC (p = 0.032). GPS or PSC did not differ by age, sex, extent of surgery, glioma grade, location, and histopathological subtype, p53 expression, ARTX retention, or 1p/19q co-deletion status. CONCLUSIONS: GPS and PSC may be associated with IDH1 mutation and MGMT gene promoter methylation status but not other glioma characteristics including tumor grade, location, or histopathology. Prospective studies with larger sample size are needed to clarify the exact mechanisms of GPS and PSC by the various TMMs to identify new treatment targets.


Assuntos
Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Convulsões/genética , Convulsões/terapia , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Encéfalo/fisiopatologia , Encéfalo/cirurgia , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/cirurgia , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Glioma/fisiopatologia , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/genética , Complicações Pós-Operatórias/terapia , Período Pré-Operatório , Regiões Promotoras Genéticas , Estudos Retrospectivos , Convulsões/etiologia , Convulsões/fisiopatologia , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
10.
Biomed Res Int ; 2019: 9068314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143777

RESUMO

Background: Malar melasma has a chronic and recurrent character that may be related to epigenetic changes. Objective: To recognize the expression and DNA methylation of DNA methyltransferases (DNMTs) in malar melasma and perilesional skin, as well as the changes in DNMTs after their treatment with sunscreen in combination with 4% niacinamide, 0.05% retinoic acid, or placebo. Methods: Thirty female patients were clinically evaluated for the expression of DNMT1 and DNMT3b using real-time PCR and immunofluorescence. These initial results were compared to results after eight weeks of treatment with sunscreen in combination with niacinamide, retinoic acid, or placebo. Results: The relative expression of DNMT1 was significantly elevated in melasma compared with unaffected skin in all subjects, indicating DNA hypermethylation. After treatment, it was decreased in all groups: niacinamide (7 versus 1; p<0.01), retinoic acid (7 versus 2; p<0.05), and placebo (7 versus 3; p<0.05), which correlates with clinical improvement. DNMT3b was not overexpressed in lesional skin but reduced in all groups. Conclusions: We found DNA hypermethylation in melasma lesions. Environmental factors such as solar radiation may induce cellular changes that trigger hyperpigmentation through the activation of pathways regulated by epigenetic modifications. However, limiting or decreasing DNA methylation through sunscreen, niacinamide, and retinoic acid treatments that provide photoprotection and genetic transcription can counteract this.


Assuntos
Metilases de Modificação do DNA/metabolismo , Melanose/tratamento farmacológico , Melanose/enzimologia , Niacinamida/uso terapêutico , Protetores Solares/uso terapêutico , Tretinoína/uso terapêutico , 5-Metilcitosina/metabolismo , Adulto , Metilação de DNA , Metilases de Modificação do DNA/genética , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Fluorescência , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Placebos , Protetores Solares/farmacologia
11.
Nucl Med Commun ; 40(8): 850-856, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31135693

RESUMO

OBJECTIVE: We evaluate the O6-methylguanylmethyltransferase (MGMT) methylation status noninvasively by analyzing radiomics features of C-methionine (MET) PET images, which may reflect the detailed biological properties of gliomas. PATIENTS AND METHODS: Fifty-seven patients with histopathologically confirmed gliomas, who were initially examined with C-MET PET/MR were retrospectively enrolled. Quantitative uptake of MET was assessed using conventional, histogram and texture features. These features were compared between the two groups classified by MGMT promoter methylation status. RESULTS: The histogram features (Skewness and Kurtosis) of the MGMT methylated group were significantly higher than those of the MGMT unmethylated group (Skewness: 0.90 ± 0.71 vs. 0.49 ± 0.45; P = 0.01) (Kurtosis: 1.36 ± 2.30 vs. 0.08 ± 0.65; P = 0.003), but there were no significant differences in Skewness or Kurtosis between the groups in glioma-grade-matched subgroup analysis. Moreover, there was no significant difference in other features between the methylated group and unmethylated group. CONCLUSION: The histogram features (Skewness and Kurtosis) of MET PET/MRI may be two key indicators to detect MGMT methylation status in gliomas and valuable predictors for the clinical responses of patients scheduled to receive temozolomide chemotherapeutics.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/diagnóstico por imagem , Glioma/genética , Imagem por Ressonância Magnética , Metionina , Tomografia por Emissão de Pósitrons , Proteínas Supressoras de Tumor/genética , Adulto , Feminino , Glioma/enzimologia , Humanos , Masculino , Imagem Multimodal , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos
12.
Ann Biol Clin (Paris) ; 77(3): 307-317, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31131831

RESUMO

The study investigated the pattern of MGMT promoter methylation and the expression of MGMT, P53, EGFR, MDM2 and PTEN proteins in glioblastomas multiforme (GBM) and evaluated their prognostic significance. We carried out a retrospective study of 80 GBM. Expression of MGMT as well as of P53, EGFR, MDM2 and PTEN was investigated by immunohistochemistry. MGMT promoter methylation was investigated by methylation specific-PCR of bisulfite-treated DNA. Twenty-five GBM exhibited MGMT expression. Methylation of MGMT promoter was detected in 35.1% of cases. No significant concordance was reported between MGMT promoter methylation and protein expression (κ=-0.047, p=0.11). MGMT promoter methylation was significantly associated only with PTEN expression (p=0.001): no other significant association was identified with clinical parameters as well as with expression of P53, EGFR and MDM2 (p >0.05). Tumor recurrence was significantly associated with unmethylated MGMT promoter (p=0.01) but not with MGMT expression (p=0.51). Recurrence-free survival (RFS) was significantly better among patients with methylated MGMT promoter (log rank, p <0.0001) and PTEN expression (log rank, p=0.025) but not with MGMT expression (log rank, p=0.308). As well, using univariate analysis, MGMT promoter methylation (p=0.001) and PTEN expression (p=0.044) were significantly associated with RFS. In multivariate analysis, only MGMT promoter methylation was significantly associated with RFS (p=0.003). Together, our findings support that MGMT protein expression doesn't reflect the MGMT promoter methylation status. Furthermore, MGMT promoter methylation remains a useful prognostic marker in Tunisian patients with GBM. PTEN expression could be a potential prognostic marker of this tumor.


Assuntos
Neoplasias Encefálicas/diagnóstico , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Glioblastoma/diagnóstico , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Criança , Pré-Escolar , Metilação de DNA , Metilases de Modificação do DNA/análise , Enzimas Reparadoras do DNA/análise , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Valor Preditivo dos Testes , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estudos Retrospectivos , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/análise , Tunísia , Adulto Jovem
13.
Brain Tumor Pathol ; 36(2): 84-91, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937703

RESUMO

Adult diffuse gliomas form a heterogeneous group of tumors of the central nervous system that vary greatly in histology and prognosis. A significant advance during the last decade has been the identification of a set of genetic lesions that correlate well with histology and clinical outcome in diffuse gliomas. Most characteristic driver mutations consist of isocitrate dehydrogenase 1 (IDH1) and IDH2, and H3 histone family member 3A, which are strongly associated with DNA and histone methylation patterns. A well-characterized DNA methylation aberration is on the O6-methylguanine-DNA methyltransferase promoter. This aberration is associated with an improved response to the DNA alkylating agent, temozolomide. Methylation alterations are used for classification or treatment decisions of diffuse gliomas. This supports the importance of considering epigenomic aberrations in the pathogenesis of gliomas. Recent DNA methylation analyses revealed a small group of IDH mutant diffuse gliomas exhibiting decreased DNA hypermethylation resulting in substantial unfavorable prognosis comparable to glioblastoma. Thus, DNA methylation patterns may become a new standard that replaces the conventional grading system based on histological diagnosis. In this review, we summarize recent developments regarding the contributions of methylation patterns to the pathogenesis of adult diffuse glioma, the interactions between methylation patterns and driver mutations, and potential epigenomic targeted therapies.


Assuntos
Metilação de DNA/genética , Glioma/genética , Adulto , Neoplasias Encefálicas/genética , Ilhas de CpG/genética , Metilases de Modificação do DNA/genética , Epigênese Genética/genética , Glioblastoma/genética , Glioma/patologia , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Mutação , O(6)-Metilguanina-DNA Metiltransferase/genética , Prognóstico , Regiões Promotoras Genéticas/genética
14.
Ecotoxicol Environ Saf ; 178: 168-177, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31004929

RESUMO

OBJECTIVES: Among the numerous agents, genetic factors and environmental elements such as pesticides have an important role in colorectal cancer (CRC) incidence. The present study aimed to investigate the probable-role of some organochlorine pesticides (OCPs) and organophosphorous pesticides (OPPs) in patients with CRC. METHODS: In this case-control study, 42 patients with CRC and 30 healthy subjects were selected. The serum levels of some OCPs (α-HCH, ß-HCH, γ-HCH, 2,4 DDE, 4,4 DDE, 2,4DDT and 4,4DDT) were measured by gas chromatography (GC) method. Serum levels of malondialdehyde (MDA), and total antioxidant capacity (TAC) as well as the enzyme activity of acetylcholinesterase (AChE) and arylesterase activity of Paraoxonase-1 (PON-1) were evaluated in all participants. The methylation specific PCR (MSP) assay was used for determining the methylation status of CpG island of p16 and MGMT genes in CRC patients. RESULTS: The mean serum levels of each OCPs were significantly higher in the patient group compared to the control group (P < 0.001). The AChE and arylesterase activity of PON-1 in the patient group were significantly lower than the control group (P < 0.001). The mean serum levels of MDA and TAC in the serum of the patient group were significantly higher than the control group (P < 0.001 and P < 0.002, respectively). The current findings demonstrated significantly hypermethylation of p16 promoter in CRC patients. CONCLUSION: Regarding the higher levels of OCPs in CRC patients, along with hypermethylation of the p16 promoter gene, diminishing in AChE and PON-1 activity and increasing in oxidative stress factors, the role of OCPs and OPPs in the CRC progression in the South-East of Iran may be assumed.


Assuntos
Neoplasias Colorretais/sangue , Hidrocarbonetos Clorados/sangue , Compostos Organofosforados/sangue , Praguicidas/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Ilhas de CpG , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Genes p16 , Humanos , Irã (Geográfico) , Masculino , Malondialdeído/análise , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética
15.
J Neurooncol ; 143(2): 231-240, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31011934

RESUMO

INTRODUCTION: Glioblastoma remains difficult to treat and patients whose tumors express high levels of O6-methylguanine DNA methyltransferase (MGMT) usually respond poorly to standard temozolomide chemotherapy. We have previously shown that the selective AURKA inhibitor alisertib potently inhibits growth of glioblastoma cells. METHODS: We used colony formation assays, annexin V binding, and western blotting to examine the effects of alisertib on the antiproliferative capabilities of carboplatin and irinotecan in glioblastoma cells. RESULTS: In colony formation assays, alisertib potentiated the antiproliferative effects of both carboplatin and irinotecan, often synergistically, including against glioblastoma tumor stem-like cells, as demonstrated by Chou-Talalay and Bliss statistical analyses. Western blotting showed that high MGMT expression in cell lines correlated with more pronounced potentiation of carboplatin's growth inhibitory effects by alisertib, while low MGMT expression correlated with stronger potentiation of irinotecan by alisertib. This pattern was also observed when these drug combinations were tested for their ability to induce apoptosis via annexin V binding assays. MGMT knockdown increased apoptosis caused by combined alisertib and irinotecan, while exogenous MGMT overexpression increased apoptosis from alisertib and carboplatin combination treatment. CONCLUSIONS: These results suggest that tumor MGMT expression levels may be predictive of patient response to these drug combinations, and importantly that the combination of alisertib and carboplatin may be selectively effective in glioblastoma patients with high tumor MGMT who are resistant to standard therapy. Since clinical experience with alisertib, carboplatin and irinotecan as single agents already exists, these findings may provide rationale for the design of clinical trials for their use in combination treatment regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Sinergismo Farmacológico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Proteínas Supressoras de Tumor/metabolismo , Azepinas/administração & dosagem , Carboplatina/administração & dosagem , Metilases de Modificação do DNA/antagonistas & inibidores , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/genética , Glioblastoma/metabolismo , Humanos , Irinotecano/administração & dosagem , Pirimidinas/administração & dosagem , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
16.
Chemosphere ; 227: 323-328, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30999172

RESUMO

In the present study, we investigated the association between methylation of DNA damage response-related genes such as cyclin-dependent kinase inhibitor (CDKN)2A, Ras association (RalGDS/AF-6) domain family member (RASSF)1A, O6-methylguanine DNA methyltransferase (MGMT), Kirsten rat sarcoma viral oncogene homolog (KRAS), and spleen-associated tyrosine kinase (SYK) and DNA damage in hepatocytes of rats following subchronic exposure to vinyl chloride (VC). Sixty-four healthy rats were randomly divided into three VC exposure groups (5, 25, and 125 mg/kg) and an untreated negative control group (n = 16 each). VC was administered by intraperitoneal injection every other day for a total of three times a week. Eight randomly selected rats from each group were sacrificed at the end of 6 and 12 weeks, and liver tissue was harvested for the comet assay and for assessment of DNA methylation level and mRNA expression of related genes by PCR. Overall methylation levels in the genome of hepatocytes in VC-exposed rats were higher than those in the control group at 6 and 12 weeks (P < 0.05), although no differences were observed with regarding to dose (P > 0.05). After 12 weeks of exposure, differences in the methylation of RASSF1A and MGMT promoter regions were observed between the high-dose group and other groups (P < 0.05), whereas no differences were observed for the KRAS, SYK, and CDKN2A promoters (P > 0.05). These results suggest that DNA damage and increased genome-wide methylation are biomarkers for VC exposure and that RASSF1A and MGMT promoter methylation is related to the carcinogenic mechanism of VC.


Assuntos
Dano ao DNA/genética , Metilação de DNA , Hepatócitos/efeitos dos fármacos , Cloreto de Vinil/toxicidade , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Ratos , Proteínas Supressoras de Tumor/genética
17.
Dig Liver Dis ; 51(4): 595-599, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30824408

RESUMO

INTRODUCTION: Neuroendocrine tumors (NETs) are rare, but their incidence is rising. Alkylating agents (ALKY), temozolomide and streptozotocin, are the main chemotherapies used for advanced pancreatic NETs. According to retrospective data, O6-methylguanine-DNA methyltransferase (MGMT) status appears to be a predictive factor of the response to ALKY. AIMS: The main objective is to evaluate the value of tumor MGMT promoter (pMGMT) methylation in the prediction of the objective response (OR) at 3 months in patients treated with ALKY. Secondly, we will evaluate the value of MGMT immunohistochemistry and the efficacy of treatment with ALKY vs. oxaliplatin-based chemotherapy (Ox). MATERIALS AND METHODS: A national, prospective, open-label, randomized, controlled and multicenter trial was designed. Main inclusion criteria are: adult patients with well-differentiated advanced duodeno-pancreatic, lung, or unknown primitive NETs with a validated indication for chemotherapy. pMGMT methylation will be assessed by pyrosequencing, but an ancillary study will compare this technique with others ones including MGMT immunohistochemistry. RESULTS: A total of 104 patients will be randomly assigned (1:1 for unmethylated or 2:1 for methylated pMGMT NETs) to either the ALKY arm or to the Ox arm. CONCLUSION: Recruitment started on October 16, 2018 (NCT03217097) and will be open in 21 centers in France.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Ensaios Clínicos Fase II como Assunto , Metilação de DNA , Feminino , França , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Valor Preditivo dos Testes , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estreptozocina/uso terapêutico , Temozolomida/uso terapêutico , Resultado do Tratamento
18.
Zhonghua Bing Li Xue Za Zhi ; 48(3): 186-191, 2019 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-30831643

RESUMO

Objective: To investigate the prognostic impact of alterations of epidermal growth factor receptor(EGFR) and MGMT in glioblastoma. Methods: The retrospective study included 161 supratentorial glioblastomas diagnosed in the Department of Pathology, Xuanwu Hospital, Capital Medical University from 2009 to 2015. EGFR and EGFRvⅢ protein expression was detected by immunohistochemistry; EGFR amplification was detected by fluorescence in situ hybridization; MGMT promoter methylation was detected by pyrosequencing. The change of molecular genetics EGFR and MGMT and outcome were assessed statistically. Results: There were 161 patients, including 85 (52.8%) males and 76 (47.2%) females. The mean age was 53 years, and the median overall survival was 13 months. The integrated classification of glioblastoma included 16 IDH-mutant, 134 wild type, and 11 NOS. The rate of overexpression of EGFR protein was 32.9%(53/161), and that of EGFR amplification was 37.5%(18/48). There was high concordance between immunohistochemistry and FISH(85.4%, Kappa=0.475, P<0.01) and between the level of EGFR protein and EGFR amplification (P<0.01). Twelve cases showed EGFRvⅢ expression, and all also showed EGFR protein overexpression; 149 cases were EGFRv Ⅲ wild type, and EGFR protein overexpression was seen in 27.5%(41/149) of cases. There was no correlation between EGFR and EGFRv Ⅲ expression. Of all cases, 70.2%(106/151) showed MGMT promoter methylation by pyrosequencing. The changes of molecular genetics of EGFR and MGMT were not related. EGFR amplification and protein overexpression had no significant relationship with prognosis. Patients with EGFRv Ⅲ-mutant had shorter survival time than the EGFRv Ⅲ-wild type(P=0.014); patients with MGMT promoter methylation had better prognosis than without (PFS:P=0.002,OS:P=0.006),and MGMT promoter methylation was an independent predictor for overall survival (HR=0.269, 95%CI 0.124-0.583, P=0.001). Conclusions: EGFR protein expression by immunohistochemistry correlates with the status of EGFR amplification. Patients with EGFRv Ⅲ-mutant tumors have poorer prognosis than that with EGFRv Ⅲ-wild type tumors. MGMT promoter methylation is closely associated with prognosis and an independent predictor for overall survival.


Assuntos
Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Neoplasias Supratentoriais/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Receptores ErbB/genética , Feminino , Amplificação de Genes , Glioblastoma/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Metilação , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Proteínas Supressoras de Tumor/genética
19.
Int J Oncol ; 54(5): 1864-1874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864696

RESUMO

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)­α2b and interleukin­2 have been approved for adjuvant immuno­chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN­ß has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN­ß in malignant melanoma. We evaluated the efficacy of TMZ and IFN­ß by comparing O6­methylguanine­DNA transferase (MGMT)­proficient and ­deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN­ß suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN­ß enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN­ß in combination with TMZ.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Interferon beta/farmacologia , Melanoma/genética , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Autofagia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo
20.
Microbiol Spectr ; 7(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30737916

RESUMO

Streptococcus pneumoniae undergoes phase variation or spontaneous, reversible phenotypic variation in colony opacity, encapsulation, and pilus expression. The variation in colony opacity appears to occur in all strains, whereas the switches in the production of the capsule and pilus have been observed in several strains. This chapter elaborates on the variation in colony opacity since this phenomenon has been extensively characterized. S. pneumoniae produces opaque and transparent colonies on the translucent agar medium. The different colony phases are fundamentally distinct phenotypes in their metabolism and multiple characteristics, as exemplified by cell surface features and phenotypes in colonization and virulence. Opaque variants, which express more capsular polysaccharides and fewer teichoic acids, are more virulent in animal models of sepsis but colonize the nasopharynx poorly. In contrast, transparent variants, with fewer capsular polysaccharides and more teichoic acid, colonize the nasopharynx in animal models more efficiently but are relatively avirulent. Lastly, pneumococcal opacity variants are generated by differential methylation of the genome DNA variation. The reversible switch in the methylation pattern is caused by DNA inversions in three homologous hsdS genes of the colony opacity determinant (cod) or SpnD39III locus, a conserved type I restriction-modification (RM) system. The hsdS gene encodes the sequence recognition subunit of the type I RM DNA methyltransferase. The combination of DNA inversion and differential methylation, a complex mechanism of phase variation, generates a mixed population that may allow for the selection of organisms in vivo with characteristics permissive for either carriage or systemic infection.


Assuntos
Cápsulas Bacterianas/metabolismo , Metilação de DNA/genética , Fenótipo , Polissacarídeos Bacterianos/metabolismo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/fisiologia , Proteínas de Bactérias/genética , Metilases de Modificação do DNA/genética , Enzimas de Restrição-Modificação do DNA/genética , DNA Bacteriano/genética , Fímbrias Bacterianas/fisiologia , Streptococcus pneumoniae/crescimento & desenvolvimento , Ácidos Teicoicos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA