RESUMEN
Background: Diffuse astrocytomas preferentially infiltrate eloquent areas affecting the outcome. A preoperative understanding of isocitrate dehydrogenase (IDH) status may offer opportunities for specific targeted therapies impacting treatment management. The aim of this study was to analyze clinical, topographical, radiological in WHO 2 astrocytomas with different IDH status and the long-term patient's outcome. Methods: A series of confirmed WHO 2 astrocytoma patients (between 2005 and 2015) were retrospectively analyzed. MRI sequences (FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations into the Montreal Neurological Institute (MNI) space. The Brain-Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was used as an overlay for infiltration analysis of each tumor. Long-term follow-up was used to perform a survival analysis. Results: Forty patients with confirmed IDH status (26 IDH-mutant, IDHm/14 IDH-wild type, IDHwt) according to WHO 2021 classification were included with a mean follow-up of 7.8 years. IDHm astrocytomas displayed a lower number of BG-voxels (P < 0.05) and were preferentially located in the anterior insular region. IDHwt group displayed a posterior insular and peritrigonal location. IDHwt group displayed a shorter OS compared with IDHm (P < 0.05), with the infiltration of 7 or more BG-voxels as an independent factor predicting a shorter OS. Conclusions: IDHm and IDHwt astrocytomas differed in preferential location, number of BG-voxels and OS at long follow-up time. The number of BG-voxels affected the OS in IDHwt was possibly reflecting higher tumor invasiveness. We encourage the systematic use of alternative observational tools, such as gradient maps and the Brain-Grid analysis, to better detect differences of tumor invasiveness in diffuse low-grade gliomas subtypes.
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Astrocitoma , Neoplasias Encefálicas , Isocitrato Deshidrogenasa , Imagen por Resonancia Magnética , Humanos , Isocitrato Deshidrogenasa/genética , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Astrocitoma/genética , Femenino , Masculino , Estudios Retrospectivos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Pronóstico , Persona de Mediana Edad , Adulto , Mutación , Anciano , Invasividad Neoplásica , Análisis de Supervivencia , Adulto JovenAsunto(s)
Aprobación de Drogas , Glioma , Isocitrato Deshidrogenasa , United States Food and Drug Administration , Estados Unidos , Humanos , Glioma/tratamiento farmacológico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológicoRESUMEN
BACKGROUND: Glioma is the most common brain tumor. IDH mutations occur frequently in glioma, indicating a more favorable prognosis. We aimed to explore energy metabolism-related genes in glioma to promote the research and treatment. METHODS: Datasets were obtained from TCGA and GEO databases. Candidate genes were screened by differential gene expression analysis, then functional enrichment analysis was conducted on the candidate genes. PPI was also carried out to help determine the target gene. GSEA and DO analysis were conducted in the different expression level groups of the target gene. Survival analysis and immune cell infiltrating analysis were performed as well. RESULTS: We screened 34 candidate genes and selected GLUD1 as the target gene. All candidate genes were significantly enriched in 10 KEGG pathways and 330 GO terms. GLUD1 expression was higher in IDH-mutant samples than IDH-wildtype samples, and higher in normal samples than tumor samples. Low GLUD1 expression was related to poor prognosis according to survival analysis. Most types of immune cells were negatively related to GLUD1 expression, but monocytes and activated mast cells exhibited significantly positive correlation with GLUD1 expression. GLUD1 expression was significantly related to 119 drugs and 6 immune checkpoint genes. GLUD1 was able to serve as an independent prognostic indicator of IDH-mutant glioma. CONCLUSION: In this study, we identified an energy metabolism-related gene GLUD1 potentially contributing to favorable clinical outcomes of IDH-mutant glioma. In glioma, GLUD1 related clinical outcomes and immune landscape were clearer, and more valuable information was provided for immunotherapy.
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Neoplasias Encefálicas , Metabolismo Energético , Glioma , Isocitrato Deshidrogenasa , Mutación , Glioma/genética , Glioma/metabolismo , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/fisiología , Pronóstico , Glutamato Deshidrogenasa/genética , Glutamato Deshidrogenasa/metabolismoRESUMEN
Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte function, development and plays a significant role in melanoma pathogenesis. MITF genomic amplification promotes melanoma development, and it can facilitate resistance to multiple therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state.
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Regulación Neoplásica de la Expresión Génica , Isocitrato Deshidrogenasa , Melanoma , Factor de Transcripción Asociado a Microftalmía , Especies Reactivas de Oxígeno , Pez Cebra , Factor de Transcripción Asociado a Microftalmía/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Especies Reactivas de Oxígeno/metabolismo , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Animales , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Línea Celular Tumoral , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Daño del ADN , Transcripción GenéticaAsunto(s)
Neoplasias Encefálicas , Ácidos Nucleicos Libres de Células , Glioblastoma , Isocitrato Deshidrogenasa , Neoplasias Meníngeas , Secuenciación de Nanoporos , Humanos , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Glioblastoma/diagnóstico , Isocitrato Deshidrogenasa/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/diagnóstico , Neoplasias Meníngeas/líquido cefalorraquídeo , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/diagnóstico , Secuenciación de Nanoporos/métodos , Ácidos Nucleicos Libres de Células/líquido cefalorraquídeo , Ácidos Nucleicos Libres de Células/genética , Masculino , Persona de Mediana Edad , FemeninoRESUMEN
Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH.
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Antineoplásicos , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Isocitrato Deshidrogenasa , Mutación , Piperidinas , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Piperidinas/farmacología , Antineoplásicos/farmacología , Quinolizidinas/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
Glioblastoma (GBM) is one of the most aggressive malignant tumors of the brain. We queried PubMed for articles about molecular predictor markers in GBM. This scoping review aims to analyze the most important outcome predictors in patients with GBM and to compare these factors in terms of absolute months of survival benefit and percentages. Performing a gross total resection for patients with GBM undergoing optimal chemo- and radiotherapy provides a significant benefit in overall survival compared to those patients who received a subtotal or partial resection. However, compared to IDH-Wildtype GBMs, patients with IDH-Mutant 1/2 GBMs have an increased survival. MGMT promoter methylation status is another strong outcome predictor for patients with GBM. In the reviewed literature, patients with methylated MGMT promoter lived approximately 50% to 90% longer than those with an unmethylated MGMT gene promoter. Moreover, KPS is an important predictor of survival and quality of life, demonstrating that we should refrain from aggressive surgery in important brain areas. As new therapies (such as TTFs) emerge, we are optimistic that the overall median survival will increase, even for IDH-Wildtype GBMs. In conclusion, molecular profiles are stronger outcome predictors than the extent of neurosurgical resection for GBM.
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Neoplasias Encefálicas , Glioblastoma , Imagen por Resonancia Magnética , Humanos , Glioblastoma/genética , Glioblastoma/cirugía , Glioblastoma/diagnóstico por imagen , Glioblastoma/patología , Glioblastoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Biomarcadores de Tumor/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Pronóstico , Metilación de ADN , Isocitrato Deshidrogenasa/genética , Mutación , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown. METHODS: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified. RESULTS: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition. CONCLUSIONS: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.
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Isocitrato Deshidrogenasa , Macrófagos , Ratones Noqueados , Mitocondrias , Microambiente Tumoral , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/genética , Animales , Mitocondrias/metabolismo , Macrófagos/metabolismo , Ratones , Carcinogénesis/metabolismo , Carcinogénesis/genética , Carcinogénesis/patología , Humanos , Línea Celular Tumoral , Activación de Macrófagos , Técnicas de CocultivoRESUMEN
Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient's sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level.
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Neoplasias Encefálicas , Transformación Celular Neoplásica , Glioma , Isocitrato Deshidrogenasa , Mutación , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Glioma/genética , Glioma/patología , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , AnimalesRESUMEN
We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.
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Glutaratos , Isocitrato Deshidrogenasa , Mutación , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/química , Cristalografía por Rayos X , Humanos , Glutaratos/metabolismo , Glutaratos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Espectroscopía de Resonancia Magnética , Regulación Alostérica , Modelos MolecularesRESUMEN
PURPOSE: To investigate the application value of support vector machine (SVM) model based on diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) and amide proton transfer- weighted (APTW) imaging in predicting isocitrate dehydrogenase 1(IDH-1) mutation and Ki-67 expression in glioma. METHODS: The DWI, DCE and APTW images of 309 patients with glioma confirmed by pathology were retrospectively analyzed and divided into the IDH-1 group (IDH-1(+) group and IDH-1(-) group) and Ki-67 group (low expression group (Ki-67 ≤ 10%) and high expression group (Ki-67 > 10%)). All cases were divided into the training set, and validation set according to the ratio of 7:3. The training set was used to select features and establish machine learning models. The SVM model was established with the data after feature selection. Four single sequence models and one combined model were established in IDH-1 group and Ki-67 group. The receiver operator characteristic (ROC) curve was used to evaluate the diagnostic performance of the model. Validation set data was used for further validation. RESULTS: Both in the IDH-1 group and Ki-67 group, the combined model had better predictive efficiency than single sequence model, although the single sequence model had a better predictive efficiency. In the Ki-67 group, the combined model was built from six selected radiomics features, and the AUC were 0.965 and 0.931 in the training and validation sets, respectively. In the IDH-1 group, the combined model was built from four selected radiomics features, and the AUC were 0.997 and 0.967 in the training and validation sets, respectively. CONCLUSION: The radiomics model established by DWI, DCE and APTW images could be used to detect IDH-1 mutation and Ki-67 expression in glioma patients before surgery. The prediction performance of the radiomics model based on the combination sequence was better than that of the single sequence model.
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Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Antígeno Ki-67 , Mutación , Máquina de Vectores de Soporte , Humanos , Isocitrato Deshidrogenasa/genética , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/metabolismo , Antígeno Ki-67/metabolismo , Antígeno Ki-67/genética , Persona de Mediana Edad , Femenino , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Masculino , Estudios Retrospectivos , Adulto , Anciano , Imagen de Difusión por Resonancia Magnética/métodos , Imagen Multimodal , Adulto Joven , Imagen por Resonancia Magnética/métodos , Curva ROC , Medios de ContrasteAsunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Humanos , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirugía , Persona de Mediana Edad , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patología , Astrocitoma/cirugía , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/cirugía , Glioblastoma/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Mutación , Isocitrato Deshidrogenasa/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Factor de Transcripción 2 de los Oligodendrocitos/metabolismoRESUMEN
Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.
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Acetilcoenzima A , Ácidos Grasos , Glioblastoma , Proto-Oncogenes Mas , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ácidos Grasos/metabolismo , Ácidos Grasos/biosíntesis , Línea Celular Tumoral , Fosforilación , Acetilcoenzima A/metabolismo , Animales , Proteína Tirosina Quinasa CSK/metabolismo , Proteína Tirosina Quinasa CSK/genética , Familia-src Quinasas/metabolismo , Familia-src Quinasas/genética , Progresión de la Enfermedad , Ratones , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , NADP/metabolismo , Ratones Desnudos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismoRESUMEN
Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.
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Encondromatosis , Glicina , Isocitrato Deshidrogenasa , Mutación , Piridinas , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Masculino , Mutación/genética , Piridinas/uso terapéutico , Encondromatosis/diagnóstico por imagen , Encondromatosis/tratamiento farmacológico , Encondromatosis/patología , Encondromatosis/genética , Glicina/análogos & derivados , Glicina/uso terapéutico , Condroma/diagnóstico por imagen , Condroma/tratamiento farmacológico , Condroma/patología , Adulto , RadiografíaRESUMEN
BACKGROUND: Mutations of the TP53 oncosuppressor gene are frequent events in patients with malignant tumors including IDH-wildtype GBM (GBM IDH wt). However, the effective impact of TP53 mutations on prognosis has been poorly evaluated. METHODS: We performed a retrospective study investigating the impact of TP53 mutations on patients with GBM IDH wt. Only patients with PS=0-1, treated with temozolomide concurrent with and adjuvant to radiotherapy, and younger than 70 years assessed with NGS were included in the analysis. RESULTS: 97 GBM IDH wt have been selected. The median follow-up was 34.5 months (95â¯%CI, 30.6 - NA). Overall, 20 patients (19.4â¯%) presented a TP53 mutation. There were no significant differences in terms of TERT mutation (75â¯% vs 79.2â¯%) between TP53 mutated and TP53 wild-type (wt) patients. We detected 6 TP53 mutations not previously described within GBM IDH wt patients. The overall survival (OS) did not significantly differ between TP53 mutated and wt patients (HR 0.69, 95â¯%CI 0.37-1.27, p = 0.24). Considering only patients with an OS longer than 36 months (n = 10), the presence of a TP53 mutation was significantly associated with prolonged survival (45.6 months vs Not Reached, p = 0.037). CONCLUSION: The presence of a TP53 mutation does not appear to be correlated with overall survival in this patient cohort. While there is an association with survival for patients with an OS of 36 months or longer, the number of patients is low and there is no available evidence correlating TP53 mutations to long-term survivors.
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Neoplasias Encefálicas , Glioblastoma , Isocitrato Deshidrogenasa , Mutación , Proteína p53 Supresora de Tumor , Humanos , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/mortalidad , Glioblastoma/terapia , Masculino , Femenino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Persona de Mediana Edad , Isocitrato Deshidrogenasa/genética , Proteína p53 Supresora de Tumor/genética , Estudios Retrospectivos , Adulto , Anciano , PronósticoRESUMEN
Biomarkers for classifying and grading gliomas have been extensively explored, whereas populations in public databases were mostly Western/European. Based on public databases cannot accurately represent Chinese population. To identify molecular characteristics associated with clinical outcomes of lower-grade glioma (LGG) and glioblastoma (GBM) in the Chinese population, we performed whole-exome sequencing (WES) in 16 LGG and 35 GBM tumor tissues. TP53 (36/51), TERT (31/51), ATRX (16/51), EFGLAM (14/51), and IDH1 (13/51) were the most common genes harboring mutations. IDH1 mutation (c.G395A; p.R132H) was significantly enriched in LGG, whereas PCDHGA10 mutation (c.A265G; p.I89V) in GBM. IDH1-wildtype and PCDHGA10 mutation were significantly related to poor prognosis. IDH1 is an important biomarker in gliomas, whereas PCDHGA10 mutation has not been reported to correlate with gliomas. Different copy number variations (CNVs) and oncogenic signaling pathways were identified between LGG and GBM. Differential genomic landscapes between LGG and GBM were revealed in the Chinese population, and PCDHGA10, for the first time, was identified as the prognostic factor of gliomas. Our results might provide a basis for molecular classification and identification of diagnostic biomarkers and even potential therapeutic targets for gliomas.
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Neoplasias Encefálicas , Variaciones en el Número de Copia de ADN , Glioblastoma , Glioma , Isocitrato Deshidrogenasa , Mutación , Humanos , Glioblastoma/genética , Glioblastoma/patología , Masculino , Femenino , Isocitrato Deshidrogenasa/genética , Glioma/genética , Glioma/patología , Persona de Mediana Edad , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Secuenciación del Exoma , Telomerasa/genética , Biomarcadores de Tumor/genética , Clasificación del Tumor , Cadherinas/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Pronóstico , Genómica/métodos , Protocadherinas , Adulto JovenAsunto(s)
Astrocitoma , Neoplasias Encefálicas , Isocitrato Deshidrogenasa , Imagen por Resonancia Magnética , Mutación , Humanos , Astrocitoma/genética , Astrocitoma/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Isocitrato Deshidrogenasa/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genéticaRESUMEN
Glioma represents the most common central nervous system neoplasm in adults. Current classification scheme utilizes molecular alterations, particularly IDH1.R132H, to stratify lesions into distinct prognostic groups. Identification of the single nucleotide variant through traditional tissue biopsy assessment poses procedural risks and does not fully reflect the heterogeneous and evolving tumor landscape. Here, we introduce a liquid biopsy assay, mt-IDH1dx. The blood-based test allows minimally invasive detection of tumor-derived extracellular vesicle RNA using only 2 ml plasma volume. We perform rigorous, blinded validation testing across the study population (n = 133), comprising of IDH1.R132H patients (n = 80), IDH1 wild-type gliomas (n = 44), and age matched healthy controls (n = 9). Results from our plasma testing demonstrate an overall sensitivity of 75.0% (95% CI: 64.1%-84.0%), specificity 88.7% (95% CI: 77.0%-95.7%), positive predictive value 90.9%, and negative predictive value 70.1% compared to the tissue gold standard. In addition to fundamental diagnostic applications, the study also highlights the utility of mt-IDH1dx platform for blood-based monitoring and surveillance, offering valuable prognostic information. Finally, the optimized workflow enables rapid and efficient completion of both tumor tissue and plasma testing in under 4 hours from the time of sampling.
Asunto(s)
Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Mutación , Humanos , Isocitrato Deshidrogenasa/genética , Glioma/genética , Glioma/sangre , Glioma/diagnóstico , Glioma/patología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Biopsia Líquida/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/diagnóstico , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Sensibilidad y Especificidad , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Estudios de Casos y ControlesRESUMEN
Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.
Asunto(s)
Neoplasias Encefálicas , Glioma , Metabolismo de los Lípidos , Microambiente Tumoral , Humanos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Glioma/patología , Glioma/metabolismo , Isocitrato Deshidrogenasa/genética , Femenino , Masculino , Persona de Mediana EdadRESUMEN
Changes in isocitrate dehydrogenases (IDH) lead to the production of the cancer-causing metabolite 2-hydroxyglutarate, making them a cause of cancer. However, the specific role of IDH in the progression of colon cancer is still not well understood. Our current study provides evidence that IDH2 is significantly increased in colorectal cancer (CRC) cells and actively promotes cell growth in vitro and the development of tumors in vivo. Inhibiting the activity of IDH2, either through genetic silencing or pharmacological inhibition, results in a significant increase in α-ketoglutarate (α-KG), indicating a decrease in the reductive citric acid cycle. The excessive accumulation of α-KG caused by the inactivation of IDH2 obstructs the generation of ATP in mitochondria and promotes the downregulation of HIF-1A, eventually inhibiting glycolysis. This dual metabolic impact results in a reduction in ATP levels and the suppression of tumor growth. Our study reveals a metabolic trait of colorectal cancer cells, which involves the active utilization of glutamine through reductive citric acid cycle metabolism. The data suggests that IDH2 plays a crucial role in this metabolic process and has the potential to be a valuable target for the advancement of treatments for colorectal cancer.