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1.
Anticancer Res ; 39(12): 6731-6741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810938

RESUMO

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Desacetilase 6 de Histona/antagonistas & inibidores , Proteína 2 Homóloga a MutS/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Derivados de Benzeno/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Reparo de Erro de Pareamento de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Pirimidinas/farmacologia , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
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.
Biochem Soc Trans ; 47(4): 1131-1141, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31341035

RESUMO

Phase-variation of genes is defined as the rapid and reversible switching of expression - either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of 'sense-and-respond' gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology.


Assuntos
Fenômenos Fisiológicos Bacterianos , Bactérias/genética , Metilases de Modificação do DNA/metabolismo , Epigênese Genética , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos
4.
RNA ; 25(11): 1470-1480, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31350341

RESUMO

The telomeric long noncoding RNA TERRA has been implicated in regulating telomere maintenance by telomerase and homologous recombination, and in influencing telomeric protein composition during the cell cycle and the telomeric DNA damage response. TERRA transcription starts at subtelomeric regions resembling the CpG islands of eukaryotic genes extending toward chromosome ends. TERRA contains chromosome-specific subtelomeric sequences at its 5' end and long tracts of UUAGGG-repeats toward the 3' end. Conflicting studies have been published as to whether TERRA is expressed from one or several chromosome ends. Here, we quantify TERRA species by RT-qPCR in normal and several cancerous human cell lines. By using chromosome-specific subtelomeric DNA primers, we demonstrate that TERRA is expressed from a large number of telomeres. Deficiency in DNA methyltransferases leads to TERRA up-regulation only at the subset of chromosome ends that contain CpG-island sequences, revealing differential regulation of TERRA promoters by DNA methylation. However, independently of the differences in TERRA expression, short telomeres were uniformly present in a DNA methyltransferase deficient cell line, indicating that telomere length was not dictated by TERRA expression in cis Bioinformatic analyses indicated the presence of a large number of putative transcription factors binding sites at TERRA promoters, and we identified a subset of them that repress TERRA expression. Altogether, our study confirms that TERRA corresponds to a large gene family transcribed from multiple chromosome ends where we identified two types of TERRA promoters, only one of which is regulated by DNA methylation.


Assuntos
Cromossomos Humanos , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Telômero , Fatores de Transcrição/genética , Ilhas de CpG , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Células HCT116 , Humanos , Regiões Promotoras Genéticas , Regulação para Cima
5.
Cell Mol Life Sci ; 76(15): 2899-2916, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147750

RESUMO

Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively transcribed genes, providing signals for modulating transcription fidelity, mRNA splicing and DNA damage repair; and di-methylation of H3K36 (H3K36me2) spreads out within large intragenic regions, regulating distribution of histone H3 lysine 27 trimethylation (H3K27me3) and possibly DNA methylation. These H3K36 methylation-mediated events are biologically crucial and controlled by different classes of proteins responsible for either 'writing', 'reading' or 'erasing' of H3K36 methylation marks. Deregulation of H3K36 methylation and related regulatory factors leads to pathogenesis of disease such as developmental syndrome and cancer. Additionally, recurrent mutations of H3K36 and surrounding histone residues are detected in human tumors, further highlighting the importance of H3K36 in biology and medicine. This review will elaborate on current advances in understanding H3K36 methylation and related molecular players during various chromatin-templated cellular processes, their crosstalks with other chromatin factors, as well as their deregulations in the diseased contexts.


Assuntos
Histonas/metabolismo , Neoplasias/patologia , Transtornos do Neurodesenvolvimento/patologia , Metilases de Modificação do DNA/metabolismo , Reparo do DNA , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Metilação , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Processamento de RNA
6.
Biosens Bioelectron ; 141: 111386, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220725

RESUMO

DNA methylation and histone deacetylation are key epigenetic processes involved in normal cellular function and tumorigenesis. Therapeutic strategies based on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors are currently in use and under development for the treatment of cancers. Genome-wide DNA methylation profiling has been proposed for use in disease diagnosis, and histone modification profiling for disease stratification will follow suit. However, whether epigenome sequencing technologies will be feasible for rapid clinic diagnosis and patient treatment monitoring remains to be seen, and alternative detection technologies will almost certainly be needed. Here we used electrochemical impedance spectroscopy (EIS) employing a graphene-based screen-printed electrode system to directly measure global DNA methylation and histone H3 acetylation to compare non-cancer and breast cancer cell lines. We demonstrated that whilst global methylation was not useful as a differential marker in the cellular systems tested, histone H3 acetylation was effective at higher chromatin levels. Using breast and endometrial cancer cell models, EIS was then used to monitor cellular responses to the DNMT and HDAC inhibitors 5-Aza-2'-deoxycytidine and suberoylanilide hydroxamic acid in vitro, and proved very effective at detecting global cellular responses to either treatment, indicating that this approach could be useful in following treatment response to epigenetic drugs. Moreover, this work reports the first combined analysis of two epigenetic markers using a unified graphene-based biosensor platform, demonstrating the potential for multiplex analysis of both methylation and acetylation on the same sample.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Metilases de Modificação do DNA/antagonistas & inibidores , Neoplasias do Endométrio/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Técnicas Biossensoriais/métodos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Espectroscopia Dielétrica/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias do Endométrio/genética , Feminino , Humanos
7.
Nat Commun ; 10(1): 2045, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053733

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , MicroRNAs/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , RNA Longo não Codificante/metabolismo , Temozolomida/farmacologia , Adulto , Animais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Análise de Sobrevida , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
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
9.
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
10.
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
11.
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
12.
Neuropathology ; 39(2): 78-84, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937985

RESUMO

Adult thalamic glioblastomas (GBM) are uncommon tumors with limited available molecular data. One of the reported molecular alterations in these tumors is the H3K27M mutation. It has been documented that H3K27M mutation is found in a high proportion of pediatric thalamic gliomas. In this study, we have analyzed the molecular alterations exclusive to adult thalamic GBM. This is a 6 years retrospective study of adult thalamic GBM patients who underwent surgical decompression of the tumor. Clinical data were obtained from the case records. Immunohistochemistry (IHC) was performed on the tumors using antibodies directed against the gene products of R132H mutant isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), p53, H3K27M, H3K27me3, and V600E mutant BRAF. Molecular analyses were carried out to detect other IDH1 and IDH2 mutations, O6 -methylguanine-DNA-methyltransferase gene (MGMT) promoter methylation, and epidermal growth factor gene (EGFR) and telomerase reverse transcriptase gene (TERT) promoter mutations. A total of 42 cases of adult thalamic GBM were studied. The mean age of presentation was 42 years with age range of 19-58 years. Male predominance was noted. All the tumors were IDH wild-type, BRAF (V600E)-immunonegative and unmethylated for MGMT promoter. H3K27M immunopositivity was noted in 60% of tumors. Of these 33.3% were from older adults above the age of 50 years. Of the H3K27M-immunopositive cases, ATRX loss of expression was seen in 32%, p53 immunopositivity in 24% and EGFR amplification in 12%. Higher frequency of TERT promoter mutations was noted in H3K27M-immunonegative cases (58.8%) compared to immunopositive cases (20%). Ours is one of the few studies elucidating the molecular alterations exclusive to adult thalamic GBM. We show a high frequency of H3K27M immunopositivity, suggestive of its mutational status in these tumors, including in older adults.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Histonas/metabolismo , Tálamo/metabolismo , Adulto , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Telomerase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteína Nuclear Ligada ao X/metabolismo , Adulto Jovem
13.
Anticancer Res ; 39(4): 1839-1847, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952724

RESUMO

BACKGROUND/AIM: Casticin shows anti-cancer effects in many types of cancer. However, there is no information regarding its role in DNA damage in human bladder cancer. The aim of this study was to investigate the effects of casticin on TSGH-8301 cells in vitro. MATERIALS AND METHODS: Viability of cells was assayed by flow cytometry. DNA damage was assayed by DAPI staining, comet assay, and gel electrophoresis. Protein levels were examined by western blotting and confocal laser microscopy. RESULTS: Casticin decreased viability of cells and induced DNA damage. Furthermore, casticin decreased expression of p-ATM, p-ATR, MDC1 and MGMT levels after 48 h of treatment, however, it increased p-ATR and MGMT levels after 12 h. In contrast, casticin increased the levels of p-p53, p-H2A.X, and PARP after 48 h of treatment. As shown by confocal microscopy, casticin affected the translocation of DNA-PKcs and p-p53 to the nucleus of TSGH-8301 cells. CONCLUSION: Casticin decreased viability of human bladder cancer cells through DNA damage.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Flavonoides/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Transporte Ativo do Núcleo Celular , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteína Quinase Ativada por DNA/metabolismo , Histonas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Fosforilação , Poli(ADP-Ribose) Polimerases/metabolismo , Transativadores/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
14.
World Neurosurg ; 128: e21-e30, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30880199

RESUMO

OBJECTIVE: To explore related factors that influence time to recurrence and prognosis of gliomas. METHODS: A retrospective analysis of pathologic and clinical data of patients with glioma who underwent surgery for the first time and had a recurrence between 2009 and 2018 in West China Hospital was performed. Clinical characteristics of patients were reviewed, and survival analysis was performed to identify prognostic factors for the recurrent time. Molecules with differential changes in the paired samples were included in the survival analysis. RESULTS: A total of 84 patients met our inclusion requirements and were included in the study; other related factors were also considered in detail in the integrated analysis. Significant differences among O6-methylguanine-DNA methyltransferase (positive/negative), isocitrate dehydrogenase 1 (positive/negative), and Ki-67 were determined by statistical analysis of paired samples (P = 0.013, P = 0.014, P = 0.017). Univariate analysis demonstrated that Ki-67 (low expression, medium expression, high expression), initial World Health Organization grade (low or high), tumor side (left, right, middle), age (≥50 years, <50 years), and extent of resection were significantly correlated with time to recurrence (log-rank P = 0.008, P < 0.001, P = 0.015, P < 0.001, P = 0.001). Multivariate analysis results showed that Ki-67 lower expression (hazard ratio [HR] = 0.585, 95% confidence interval [CI] = 0.146-2.336, P = 0.448), medium expression (HR = 0.256, 95% CI = 0.084-0.784, P = 0.017), and high expression (HR = 1 as a reference) together with the initial World Health Organization grade (HR = 0.148, 95% CI = 0.029-0.749, P = 0.021) were independent predictive factors for glioma recurrence. CONCLUSIONS: This comprehensive analysis revealed that initial World Health Organization grade and Ki-67 proliferative index were independent prognostic factors that predict the time to recurrence of glioma in patients after first surgery.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , China/epidemiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Glioma/metabolismo , Glioma/patologia , Humanos , Isocitrato Desidrogenase/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Carga Tumoral , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteína Nuclear Ligada ao X/metabolismo , Adulto Jovem
15.
Clin Transl Oncol ; 21(10): 1413-1423, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30877636

RESUMO

BACKGROUND: Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. METHODS: We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. RESULTS: In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. CONCLUSION: Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/química , Neoplasias Encefálicas/diagnóstico por imagem , Circulação Cerebrovascular , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Amplificação de Genes , Genes erbB-1 , Glioblastoma/irrigação sanguínea , Glioblastoma/química , Glioblastoma/diagnóstico por imagem , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Masculino , Metilação , Microvasos/patologia , Pessoa de Meia-Idade , Índice Mitótico , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/química , Recidiva Local de Neoplasia/diagnóstico por imagem , Estudos Retrospectivos , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/metabolismo
16.
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
17.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871110

RESUMO

We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene methylation status is closely associated with aging-associated conditions and polyamine metabolism is closely associated with regulation of gene methylation, we investigated the effects of extracellular spermine supplementation on substrate concentrations and enzyme activities involved in gene methylation. Jurkat cells and human mammary epithelial cells were cultured with spermine and/or D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Spermine supplementation inhibited enzymatic activities of adenosylmethionine decarboxylase in both cells. The ratio of decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine increased by DFMO and decreased by spermine. In Jurkat cells cultured with DFMO, the protein levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were not changed, however the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine, DNMT 3A and especially 3B were activated. We show that changes in polyamine metabolism dramatically affect substrate concentrations and activities of enzymes involved in gene methylation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Espermina/metabolismo , Adenosilmetionina Descarboxilase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Eflornitina/metabolismo , Células Epiteliais/metabolismo , Humanos , Células Jurkat , Glândulas Mamárias Humanas/metabolismo , Ornitina Descarboxilase/metabolismo , Poliaminas/metabolismo , Putrescina/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Espermidina/metabolismo
18.
Clin Transl Oncol ; 21(10): 1364-1373, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30798512

RESUMO

PURPOSE: Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40 weeks. Antiangiogenic agents are widely used, showing a variable response. In this study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM. METHODS/PATIENTS: In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including CD133 mRNA expression, MGMT methylation (pMGMT), PDGFR amplification, YKL40 mRNA expression, IDH1/2 condition, p53 and EGFRvIII mutation status. RESULTS: Median follow-up was 18.6 months, overall RR to the combination was 56.3%, and median PFS was 9.0 months (95% CI 8.0-9.9). OS from time of diagnosis was 21.0 months (95% CI 13.2-28.7) and from starting BCNU/Bev it was 10.7 months (95% CI 9.5-11.8). IDH1/2 mutations were found in 30.5% of the patients, pMGMT in 55.9% and high CD133 mRNA expression in 57.6%. Factors which positively affected PFS included performance status (p = 0.015), IDH+ (p = 0.05), CD133 mRNA expression (p = 0.009) and pMGMT+ (p = 0.007). OS was positively affected by pMGMT+ (p = 0.05). Meanwhile, YKL40 negatively affected PFS (p = 0.01) and OS (p = 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%). CONCLUSIONS: BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with MGMT+/IDH+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high YKL40 expression discourages the use of antiangiogenic therapy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Carmustina/uso terapêutico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Antígeno AC133/genética , Antígeno AC133/metabolismo , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bevacizumab/efeitos adversos , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Carmustina/efeitos adversos , Proteína 1 Semelhante à Quitinase-3/genética , Colômbia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Esquema de Medicação , Feminino , Genes erbB-1 , Genes p53 , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Isocitrato Desidrogenase/genética , Masculino , Metilação , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/irrigação sanguínea , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Intervalo Livre de Progressão , RNA Mensageiro/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Análise de Sobrevida , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
19.
Int J Cancer ; 145(1): 242-253, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30549269

RESUMO

TG02 is a novel cyclin-dependent kinase (CDK) inhibitor and thought to act mainly via CDK-9 inhibition-dependent depletion of short-lived oncoproteins such as MCL-1 or c-MYC. We studied the activity of TG02 in 9 human long-term glioma cell lines (LTC) and 5 glioma-initiating cell lines (GIC) using various cell death assays in vitro and in the LN-229 LTC and ZH-161 GIC models in vivo. TG02 exhibits strong anti-tumor cell activity with EC50 concentrations in the nanomolar range. Median survival in the LN-229 and ZH-161 models was moderately prolonged by TG02. Neither constitutive CDK levels nor those of MCL-1 or c-MYC correlated with sensitivity to TG02. Cdk-9 or cdk-5 gene silencing alone did not fully reproduce the effects of TG02. C-myc gene silencing inhibited cell growth, but did not modulate TG02 activity. Electron microscopy revealed cell death to be essentially apoptotic. High concentrations of TG02 induced annexin V binding and minor caspase 3 cleavage, but the pan-caspase inhibitor, zVAD-fmk, or BCL-2 or MCL-1 gene transfer only moderately attenuated TG02-induced cell death, and caspase inhibition did not prevent loss of MCL-1 or c-MYC. TG02 activity was independent of O6 -methylguanine DNA methyltransferase expression. Repetitive exposure to TG02 did not generate an acquired TG02 resistance phenotype, but accumulation of MCL-1, loss of c-MYC, or senescence. TG02 is a highly potent apoptosis-inducing agent in glioma cells in vitro. Caspase inhibition does not rescue TG02-treated cells and repetitive exposure fails to confer acquired resistance, supporting the clinical evaluation of TG02 in glioblastoma.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Tecidual , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Cancer ; 144(12): 3023-3030, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30536544

RESUMO

Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in the DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)-induced mutagenesis. In our study, we have identified a rare subset of treatment-naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment-induced hypermutagenesis. We conducted Whole-Exome Sequencing (WES), Whole-Transcriptome Sequencing (WTS), and Single-Cell Sequencing (SCS) of TMZ-naïve and post-TMZ-treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ-naïve hypermutated tumors were marked by absence of IDH1 somatic mutation and MGMT promoter (pMGMT) methylation, two genomic traits that were significantly associated with the TMZ-induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ-naive hypermutated glioma patients were also previous diagnosed with cancer development history, suggesting that germline dysfunction of the MMR pathway could potentially pose hereditary risk to genetic predisposition of carcinogenesis in gliomas. Lastly, both TMZ-naïve and post-TMZ-treated hypermutated tumors exhibited a significant accumulation of neoantigen loads, suggesting immunotherapeutic alternatives. Our results present new and unique understanding of hypermutagenic process in adult gliomas and an important step towards clinical implication of immunotherapy in glioma treatment.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Reparo de Erro de Pareamento de DNA , Mutação em Linhagem Germinativa , Glioblastoma/genética , Adulto , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Transformação Celular Neoplásica/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Temozolomida/uso terapêutico , Transcriptoma , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
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