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1.
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
2.
Adv Exp Med Biol ; 1190: 281-297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760651

RESUMO

Gliomas are a heterogeneous group of tumors with evolving classification based on genotype. Isocitrate dehydrogenase (IDH) mutation is an early event in the formation of some diffuse gliomas, and is the best understood mechanism of their epigenetic dysregulation. Glioblastoma may evolve from lower-grade lesions with IDH mutations, or arise independently from copy number changes in platelet-derived growth factor receptor alpha (PDGFRA) and phosphatase and tensin homolog (PTEN). Several molecular subtypes of glioblastoma arise from a common proneural precursor with a tendency toward transition to a mesenchymal subtype. Following oncogenic transformation, gliomas escape growth arrest through a distinct step of aberrant telomere reverse transcriptase (TERT) expression, or mutations in either alpha thalassemia/mental retardation syndrome (ATRX) or death-domain associated protein (DAXX) genes. Metabolic reprogramming allows gliomas to thrive in harsh microenvironments such as hypoxia, acidity, and nutrient depletion, which contribute to tumor initiation, maintenance, and treatment resistance.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Glioma/patologia , Reprogramação Celular , Humanos , Isocitrato Desidrogenase/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Telomerase/genética , Microambiente Tumoral , Proteína Nuclear Ligada ao X/genética
3.
Anal Bioanal Chem ; 411(30): 7929-7933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31754769

RESUMO

Knowledge of the isocitrate dehydrogenase (IDH) mutation status of glioma patients could provide insights for decision-making during brain surgery. However, pathology is not able to provide such information intraoperatively. Here we describe the first application of a miniature mass spectrometer (MS) to the determination of IDH mutation status in gliomas intraoperatively. The instrumentation was modified to be compatible with use in the operating room. Tandem MS was performed on the oncometabolite, 2-hydroxyglutarate, and a reference metabolite, glutamate, which is not involved in the IDH mutation. Ratios of fragment ion intensities were measured to calculate an IDH mutation score, which was used to differentiate IDH mutant and wild-type tissues. The results of analyzing 25 biopsies from 13 patients indicate that reliable determination of IDH mutation status was achieved (p = 0.0001, using the Kruskal-Wallis non-parametric test). With its small footprint and low power consumption and noise level, this application of miniature mass spectrometers represents a simple and cost-effective platform for an important intraoperative measurement. Graphical abstract.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/genética , Mutação , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Biópsia , Neoplasias Encefálicas/patologia , Estudos de Coortes , Glioma/patologia , Humanos , Período Intraoperatório
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1440-1448, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607296

RESUMO

OBJECTIVE: To explore the coexisting mutations in IDH-mutated acute myeloid leukemia(AML) and its relation with partial clinical parametrs. METHODS: The exon 4 mutation of IDH1/2 gene was screened by using genome DNA-PCR combined with sanger sequencing, 51 targeted gene mutations in the patients with IDH1/2 mutation were detected by using high throughput DNA sequencing combined with sanger sequencing. RESULTS: Among 358 patients, the IDH1/2 mutation was found in 46 cases including IDH1 mutation in 35 cases and IDH2 mutation in 11 cases, 97.87%(45/46) patients with IDH1/2 mutation simultaneously carried other gene mutations including 8(17.8%) cases with mutation of double gene, 17(37.8%) cases with mutation of 3 genes and 20(44.4%) cases with mutation of ≥ 4 genes. The mutation frequency of each patient averaged 3.52 times. In mutation of accompanied genes, the common genes were NPM1(n=29, 63.0%), next DNMT3A(n=25, 54.3%), FLT3-ITD(n=7, 15.2%), TET2(n=5, 10.9%) and NRAS(n=5, 10.9%). The average WBC level of patients with NPM1 mutation in IDH1 mutation group was higher than that of patients in wild type group(P<0.05). The complete remission (CR) rate of patients with DNMT3A mutation was significant lower than that of patients with wild type (30% vs 80%, P<0.01). The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than that in the patients with double mutations(P<0.05). CONCLUSION: More than 95% AML patients with IDH1/2 mutation commonly show additional mutations. The number and the type of IDH coexisting mutations have certain effect on the clinical features and CR rate.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda , Éxons , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Indução de Remissão
5.
Nature ; 574(7777): 273-277, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578525

RESUMO

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.


Assuntos
Processamento Alternativo/genética , Carcinogênese/genética , Epigênese Genética , Leucemia Mieloide Aguda/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mutação/genética , RNA Polimerase II/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Transcriptoma
6.
Eur J Med Chem ; 183: 111694, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561044

RESUMO

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5 exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclinical candidate to treat IDH1-mutant brain tumors.


Assuntos
Antineoplásicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas , Glioma/tratamento farmacológico , Isocitrato Desidrogenase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
7.
Eur J Pharm Sci ; 140: 105072, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518680

RESUMO

Isocitrate dehydrogenase 1 mutations have been discovered in an array of hematologic malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described the characterization of compound I-8, a novel mutant IDH1 inhibitor, both in vitro and in vivo. Compound I-8 specifically inhibited 2-HG production, reduced histone methylation levels, induced differentiation and depleted stem characteristics in engineered and endogenous IDH1 mutant cells. In addition, oral administration of I-8 also significantly suppressed 2-HG production and histone methylation with dose of 150 mg/kg. And I-8 treatment also could induce differentiation and attenuate stem characteristics in tumor tissue. Together, these studies indicated that compound I-8 has clinical potential in tumor therapies as a effective mutant IDH1 inhibitor, and provided scientific guidance for the development of mutant IDH1 inhibitor in the future.


Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Isocitrato Desidrogenase/antagonistas & inibidores , Actinas/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epigênese Genética , Glutaratos/metabolismo , Histonas/metabolismo , Humanos , Isocitrato Desidrogenase/genética , Metilação/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Conformação Proteica
8.
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
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1077-1082, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418360

RESUMO

OBJECTIVE: To analyze the prevalence, clinical characteristics and prognostic significance of the isocitrate dehydrogenase 2(IDH2) mutations in patients with acute myeloid leukemia(AML). METHODS: The bone marrow samples of 223 patients with newly diagnosed AML confirmed by MICM typing from January 2015 to October 2018 were collected. The mutation of exon 4 of IDH2 gene was detected by direct sequancing of PCR product; the incidence and types of IDH2 gene mutation in AML patients were analyzed; the clinical characteristics of AML patients with IDH2 gene mutation were analyzed and the therapeutic efficacy for these patients was evaluated. RESULTS: In a cohort of 223 AML patients, mutations were detected in 23(10.31%) patients, among them, 15 with R140Q mutations(65.22%) , 6 with R172K mutations(26.09%) and 2 with R140W mutations(8.70%). The median age in IDH2 mutated group was older than that in non.mutated group(P=0.008). The platelet level at initial diagnosis in IDH2 mutated group was higher than that in non.mutated group(P=0.010). There was no significant statistical difference between IDH2 mutated group and non.mutated group in FAB subtypes of AML(P>0.05). But the rate of IDH2 mutation in M4 and M5 was higher. The rate of IDH2 mutations was higher in AML with normal karyotype and in AML with NPM1 mutations. R140Q mutations associated with NPM1 mutations(χ2=8.481,P=0.004), but R172K mutations not associated with NPM1 mutation(P>0.05). IDH2 mutated patients had a lower complete remission rate than non.mutated patients(57.14% vs 80.46%, χ2=5.927,P=0.015). The complete remission rate of R140Q mutated patients was not significantly statistically different from non.mutated patients. The complete remission rate of R172K mutated patients was very significantly lower than non.mutated patients(χ2=7.734,P=0.005). In the patients without NPM1 mutation, the 2 years overall survival in IDH2 mutated group was lower than in non.mutated group(36.36% vs 66.40%,χ2=3.958,P=0.047), the 2 years overall survival of R172K mutated group was significantly lower than non.mutated group(although P>0.05). In all patients, the 2 years overall survival between IDH2 mutated group and non.mutated group was not statistically different(50% vs 66.88%,P>0.05), the 2 years overall survival of R172K mutated group was significantly lower than non.mutated group(although P>0.05). In the patients with normal karyotype or with mutated NPM1, the 2 years overall survival between IDH2 mutated group and non.mutated group was not statistically different(P>0.05). CONCLUSION: IDH2 gene mutations are more common in AML patients at older age, higher platelets level and normal karyotype. The rate of IDH2 mutation in M4 and M5 is higher. IDH2 gene mutations associate with NPMl gene mutations, but R172K mutations not associates with NPM1mutation. IDH2 gene mutations associate with prognosis of AML patients, R140Q mutations have no effect on prognosis of patients, but R172K mutations may be the molecular markers for poor prognosis in AML patients.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda , Genótipo , Humanos , Mutação , Prognóstico
10.
World Neurosurg ; 132: e563-e576, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442644

RESUMO

BACKGROUND: Recent data suggest a favorable benefit/risk ratio for insular glioma surgery. However, it remains unknown if this is also applicable in the learning period of this expertise. Moreover, little is known about the neuropsychological outcomes after resection of insular glioma. OBJECTIVE: To report an initial experience of isocitrate dehydrogenase (IDH)-mutated insular glioma resection and to contribute to our knowledge of neuropsychological outcomes after insular glioma resection. METHODS: A consecutive series of 12 patients operated on for an IDH-mutated insular glioma was retrospectively reviewed. Surgery was performed through a transopercular approach. In 10 of the 12 patients, brain mapping with electric stimulation in an awake patient guided the resection. The extent of resection was assessed by volumetric measures of postoperative fluid-attenuated inversion recovery magnetic resonance imaging. Areas of postoperative ischemia were detected by diffusion imaging. Neurologic, neuropsychological, and professional outcomes were retrieved from medical files. RESULTS: The median extent of resection was 94% (range, 80%-100%). None of the patients had permanent speech or motor deficits. Areas of ischemia were observed in 75% of patients. Neuropsychological evaluations showed slight deterioration regarding lexical abilities and verbal memory in patients with left-sided tumors. Patients' performances in cognitive flexibility also commonly declined, regardless of the tumor side. Eight of the 9 patients working at the time of the surgery were able to resume their professional activity. CONCLUSIONS: Resecting insular glioma under brain mapping techniques is a safe option, even during the learning period. Patients should be informed about the risk of mild deterioration of lexical abilities and cognitive flexibility.


Assuntos
Neoplasias Encefálicas/cirurgia , Córtex Cerebral/cirurgia , Glioma/cirurgia , Monitorização Neurofisiológica Intraoperatória/métodos , Procedimentos Neurocirúrgicos/métodos , Adulto , Idoso , Mapeamento Encefálico/métodos , Neoplasias Encefálicas/genética , Feminino , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adulto Jovem
11.
Molecules ; 24(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443404

RESUMO

Glioblastoma (GBM), the most common and malignant brain tumor, is classified according to its isocitrate dehydrogenase (IDH) mutation status in the 2016 World Health Organization (WHO) brain tumor classification scheme. The standard treatment for GBM is maximal resection, radiotherapy, and Temozolomide (TMZ). Recently, Bevacizumab (Bev) has been added to basic therapy for newly diagnosed GBM, and monotherapy for recurrent GBM. However, the effect of IDH1 mutation on the combination of Bev and TMZ is unknown. In this study, we performed transcriptomic analysis by RNA sequencing with next generation sequencing (NGS), a newly developed powerful method that enables the quantification of the expression level of genome-wide genes. Extracellular matrix and immune cell migration genes were mainly upregulated whereas cell cycle genes were downregulated in IDH1-mutant U87 cells but not in IDH1-wildtype U87 cells after adding Bev to TMZ. In vitro and in vivo studies were conducted for further investigations to verify these results, and the addition of Bev to TMZ showed a significant antitumor effect only in the IDH1-mutant GBM xenograft model. Further studies of gene expression profiling in IDH1 mutation gliomas using NGS will provide more genetic information and will lead to new treatments for this refractory disease.


Assuntos
Perfilação da Expressão Gênica , Glioblastoma/genética , Transcriptoma , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Ciclo Celular/genética , Sobrevivência Celular/genética , Biologia Computacional/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Isocitrato Desidrogenase/genética , Camundongos , Mutação , Temozolomida/administração & dosagem
12.
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
13.
Zhonghua Yi Xue Za Zhi ; 99(25): 1959-1962, 2019 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-31269600

RESUMO

Objective: To investigate the prognostic values of IDH, TERT and 1p/19q in patients with anaplastic oligodendroglioma. Methods: In the study, 66 patients with pathological diagnosis of anaplastic oligodendroglioma were enrolled (The First Affiliated Hospital of Zhengzhou University 2011 to 2016 years). Kaplan-Meier method was used to calculate the survival rates. Log-rank was used to calculate the differences in group. Chi-square testwas used tocalculate the differences in common factor group. Cox regression model was used to conduct multivariate analysis. Results: The median survival time of IDH-wt and IDH-mt subgroups were 16.10 and 42.00 months with statistical significance (P=0.001). The median survival time of 1p/19q codeleted and 1p/19q noncodeleted subgroups were 42.00 and 22.40 months with statistical significance (P=0.012). IDH-mt and 1p/19q codeleted predicted better survivals compared with IDH-wt and 1p/19q noncodeleted (P=0.001). And IDH-mt and 1p/19q noncodeleted predicted better survivals compared with IDH-wt and 1p/19q noncodeleted (P=0.041), too. Multivariate survival analysis demonstrated that Molecular groups was an independent factor to evaluate the prognosis of anaplastic oligodendroglioma (P=0.008). Conclusion: IDH-mtand (or) 1p/19q codeletedpredicted better survivals in patients with anaplastic oligodendroglioma. IDH and 1p/19q deleted might be a biomarker for predicting prognosis of patients with anaplastic oligodendroglioma.


Assuntos
Neoplasias Encefálicas , Isocitrato Desidrogenase/genética , Oligodendroglioma , Telomerase/genética , Adulto , Neoplasias Encefálicas/genética , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Humanos , Mutação , Oligodendroglioma/genética , Prognóstico
14.
Mol Med Rep ; 20(2): 1893-1900, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257503

RESUMO

Mutations of isocitrate dehydrogenase (IDH) 1 and 2 occur in low­grade gliomas, acute myeloid leukemias and other types of solid cancer. By catalyzing the reversible conversion between isocitrate and α­ketoglutarate (α­KG), IDH1 and 2 contribute to the central process of metabolism, including oxidative and reductive metabolism. IDH1 and 2 mutations result in the loss of normal catalytic function and acquire neomorphic activity, facilitating the conversion of α­KG into an oncometabolite, (R)­2­hydroxyglutarate, which can cause epigenetic modifications and tumorigenesis. Small­molecule inhibitors of mutant IDH1 and 2 have been developed, and ongoing clinical trials have shown promising results in hematological malignancies, but not in gliomas. These previous findings make it necessary to identify the mechanism and develop more effective therapies for IDH1­mutant gliomas. In the present study, it was demonstrated that under hypoxic conditions, patient­derived primary glioma cells and HCT116 cells, both of which carry a monoallelic IDH1 arginine 132 to histidine mutation (R132H), have a slower growth rate than the corresponding wild­type IDH1 cells. Western blot analysis showed that IDH1 R132H­mutant cancer cells exhibited upregulated IDH2 protein expression under hypoxic conditions. Furthermore, the silencing of IDH2 using small interfering RNA significantly inhibited the growth of IDH1­mutant cells under hypoxic conditions. Finally, [U­13C5]glutamine tracer analysis showed that IDH2 knockdown reduced the reductive carboxylation of α­KG into isocitrate in HCT116R132H/+ cells under hypoxic conditions. The present study showed for the first time, to the best of our knowledge, that IDH2 plays a compensatory role in maintaining reductive carboxylation­dependent lipogenesis and proliferation in IDH1 R132H tumor cells. Therefore, IDH2 could serve as a potential anti­tumor target for IDH1­mutant tumors, which may provide a new strategy for treatment.


Assuntos
Carcinogênese/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Sobrevivência Celular/genética , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Células HCT116 , Humanos , Isocitratos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Mutação/genética , Hipóxia Tumoral/genética
15.
Clin Nucl Med ; 44(10): e581-e582, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348085

RESUMO

A variety of neoplastic and nonneoplastic conditions involve the corpus callosum, which may result in a "butterfly" appearance on conventional MRI. Typically, that pattern shows a bilateral and heterogeneous contrast enhancement of the lesion, occasionally with central nonenhancing areas indicating intralesional necrosis. In contrast, anaplastic gliomas may show only minimal or even a lack of contrast enhancement on MRI. We here report neuroimaging findings in a 69-year-old man with a "butterfly" pattern on dynamic FET [O-(2-[F]-fluoroethyl)-L-tyrosine] PET and the diagnosis of an anaplastic astrocytoma (WHO grade III; IDH-1/-2 wildtype, no 1p/19q co-deletion) but without typical MRI contrast enhancement.


Assuntos
Astrocitoma/diagnóstico por imagem , Astrocitoma/enzimologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/enzimologia , Isocitrato Desidrogenase/metabolismo , Tomografia por Emissão de Pósitrons , Tirosina/análogos & derivados , Idoso , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Humanos , Isocitrato Desidrogenase/genética , Imagem por Ressonância Magnética , Masculino
16.
Cancer Sci ; 110(10): 3306-3314, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31361380

RESUMO

Isocitrate dehydrogenase 2 (IDH2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. AG-221, an inhibitor primarily targeting the IDH2-R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, AG-221 has weak inhibitory activity toward IDH2-R172K, a mutant form of IDH2 with more severe clinical manifestations. Herein, we report TQ05310 as the first mutant IDH2 inhibitor that potently targets both IDH2-R140Q and IDH2-R172K mutants. TQ05310 inhibited mutant IDH2 enzymatic activity, suppressed (R)-2-hydroxyglutarate (2-HG) production and induced differentiation in cells expressing IDH2-R140Q and IDH2-R172K, but not in cells expressing wild-type IDH1/2 or mutant IDH1. TQ05310 bound to both IDH2-R140Q and IDH2-R172K, with Q316 being the critical residue mediating the binding of TQ05310 with IDH2-R140Q, but not with IDH2-R172K. TQ05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2-HG production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of TQ05310, and provide new insight into the development of novel mutant IDH2 inhibitors.


Assuntos
Substituição de Aminoácidos , Inibidores Enzimáticos/administração & dosagem , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Neoplasias/tratamento farmacológico , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Células HEK293 , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/química , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
World Neurosurg ; 131: 90-94, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356980

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is a rapid-growing central nervous system neoplasm. We report a case of GBM with extensive intramedullary lumbar drop metastasis and highly unusual osseous spine metastasis from a primary infratentorial GBM occurring 10 years after the initial diagnosis, which to our knowledge has not been described previously. CASE DESCRIPTION: This 37-year-old man presented with new-onset headaches of increasing severity. Brain magnetic resonance imaging (MRI) demonstrated a heterogeneously enhancing mass in the left superior temporal lobe with adjacent edema. The lesion was initially biopsied in December 2006 and diagnosed as GBM (World Health Organization grade IV) with characteristic features of a highly cellular infiltrating glial neoplasm with nuclear pleomorphism, abundant microvascular proliferation, and abundant necrosis with pseudopalisading nuclei. Ki-67 immunostaining revealed that 15%-20% tumor cell nuclei were positive, indicating a high proliferative index. Histologically, this neoplasm demonstrated characteristic "cell wrapping." Immunoreactivity was variably but strongly positive for glial fibrillary acidic protein in neoplastic cells. In 2018, additional MRI revealed disease throughout the spine and bone biopsy of the thoracic spine showed the same glial neoplasm with primitive neuroectodermal tumor-like components (GBM-PNET). CONCLUSIONS: This case is meant to highlight that, although rare, infratentorial GBM-PNET has a higher frequency of isocitrate dehydrogenase 1 (IDH1) mutation and may metastasize to the spine years after the initial diagnosis despite the likely better prognosis.


Assuntos
Neoplasias Ósseas/secundário , Glioblastoma/secundário , Neoplasias Infratentoriais/patologia , Tumores Neuroectodérmicos Primitivos Periféricos/secundário , Neoplasias da Coluna Vertebral/secundário , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Neoplasias Infratentoriais/diagnóstico por imagem , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/terapia , Isocitrato Desidrogenase/genética , Imagem por Ressonância Magnética , Masculino , Tumores Neuroectodérmicos Primitivos Periféricos/diagnóstico por imagem , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem
18.
Crit Rev Oncol Hematol ; 140: 8-16, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31158800

RESUMO

Biliary tract carcinoma (BTC) comprises gallbladder and intra-/extrahepatic cholangiocarcinoma (GBC, ICC, EHC), which are currently classified by anatomical origin. Better understanding of the mutational profile of BTCs might refine classification and improve treatment. We performed a systematic review of studies reporting on mutational profiling of BTC. We included articles reporting on whole-exome/whole-genome-sequencing (WES/WGS) and targeted sequencing (TS) of BTC, published between 2000-2017. Pooled mutation proportions were calculated, stratified by anatomical region and sequencing technique. A total of 25 studies with 1806 patients were included. Overall, TP53 was the most commonly mutated gene in BTC. GBC was associated with mutations in PFKFB3, PLXN2 and PGAP1. Mutations in IDH1, IDH2 and FGFR fusions almost exclusively occurred in ICC patients. Mutations in APC, GNAS and TGFBR2 occurred exclusively in EHC patients. In conclusion, subtypes of BTCs exhibit minor differences in mutational profile, which is likely influenced by the cell of origin.


Assuntos
Neoplasias do Sistema Biliar/genética , Mutação , Proteínas de Neoplasias/genética , Proteína da Polipose Adenomatosa do Colo/genética , Neoplasias do Sistema Biliar/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Isocitrato Desidrogenase/genética , Proteínas de Membrana/genética , Fosfofrutoquinase-2/genética , Monoéster Fosfórico Hidrolases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética
19.
Eur J Radiol ; 116: 174-179, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153561

RESUMO

PURPOSE: To evaluate any possible correlation between the presence of Isocitrate DeHydrogenase 1 mutation (IDH1m) and specific DTI (Diffusion Tensor Imaging) metrics, such as Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD). METHODS: We retrospectively analyzed 47 patients who underwent an advanced-MR study with DTI followed by surgical intervention with a subsequent histologic diagnosis of High-Grade Glioma (HGG) and immunohistochemical evaluation of IDH1 (Isocitrate DeHydrogenase) mutation status. For each DTI metrics we measured the ratio between tumor and normal tissue and we evaluated the correlation with IDH1 mutation. RESULTS: We observed a positive correlation with IDH1 status and RD and MD data. No correlation was demonstrated between IDH1 status and FA and AD. DISCUSSION: Our results support the hypothesis that the number of residual axonal fibers, extracellular matrix composition and the presence of colliquated tissue, may together contribute to a global RD increase in HGG, with a relatively higher increase in IDH1m tumors. CONCLUSIONS: Our data are in favor of a need for multimodal advance evaluation of HGG. DTI metrics help to analyze IDH1 mutation status, in order to better characterize the lesions and to tailor treatment and follow up.


Assuntos
Glioma/patologia , Isocitrato Desidrogenase/genética , Mutação/genética , Adulto , Idoso , Anisotropia , Imagem de Tensor de Difusão/métodos , Feminino , Glioma/genética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estudos Retrospectivos
20.
Int J Mol Sci ; 20(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151327

RESUMO

The R132H mutation in isocitrate dehydrogenase 1 (IDH1R132H) is commonly observed and associated with better survival in glioblastoma multiforme (GBM), a malignant brain tumor. However, the functional role of IDH1R132H as a molecular target for GBM treatment is not completely understood. In this study, we found that the overexpression of IDH1R132H suppresses cell growth, cell cycle progression and motility in U87MG glioblastoma cells. Based on cell viability and apoptosis assays, we found that IDH1R132H-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Octyl-(R)-2-hydroxyglutarate (Octyl-2HG), which is a membrane-permeable precursor form of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1-mutant tumor cells, significantly increased HDACi resistance in glioblastoma cells. Mechanistically, IDH1R132H and Octyl-2HG enhanced the promoter activation of NANOG via increased H3K4-3Me, consequently increasing NANOG mRNA and protein expression. Indeed, HDACi resistance was attenuated in IDH1R132H-expressing glioblastoma cells by the suppression of NANOG using small interfering RNAs. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1R132H, significantly attenuates HDACi resistance and NANOG expression IDH1R132H-expressing glioblastoma cells. These results suggested that IDH1R132H is a potential molecular target for HDACi-based therapy for GBM.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Isocitrato Desidrogenase/genética , Proteína Homeobox Nanog/genética , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/genética , Humanos , Mutação Puntual , Regulação para Cima
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