Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression-free survival and overall survival. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58/79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression-free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma.
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PMID:IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. 2203 64

Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.
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PMID:Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. 2228 88

The tumors of the central nervous system are classified according to the last international classification published by World Health Organization. The Classification of Tumors of the Central Nervous System was done on 2007, based on morphological features, growth pattern and molecular profile of neoplastic cells, defining malignancy grade. The neuropathological diagnosis and the grading of each histotype are based on identification of histopathological criteria and immunohistochemical data. The histopathology, also consisting of findings with prognostic or predictive relevance, plays a critical role in the diagnosis and treatment of brain tumors. The recent progresses on radiological, pathological, immunohistochemical, molecular and genetic diagnosis improved the characterization of brain tumors. Molecular and genetic profiles may identify different tumor subtypes varying in biological and clinical behavior. To investigate new therapeutic approaches is important to study the molecular pathways that lead the processes of proliferation, invasion, angiogenesis, anaplastic transformation. Different molecular biomarkers were identified by genetic studies and some of these are used in neuro-oncology for the evaluation of glioma patients, in particular combined deletions of the chromosome arms 1p and 19q in oligodendroglial tumors, methylation status of the O-6 methylguanine- DNA methyltransferase gene promoter and alterations in the epidermal growth factor receptor pathway in adult malignant gliomas, isocitrate dehydrogenase 1 (IDH1) and IDH2 gene mutations in diffuse gliomas, as well as BRAF status in pilocytic astrocytomas. The prognostic evaluation and the therapeutic strategies for patients depend on synthesis of clinical, pathological and biological data: histological diagnosis, malignancy grade, gene-molecular profile, radiological pictures, surgical resection and clinical findings (age, tumor location, "performance status").
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PMID:Pathological classification of brain tumors. 2261 34

Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.
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PMID:The role of mutations in epigenetic regulators in myeloid malignancies. 2289 39

Aberrant changes in the epigenome are now recognized to be important in driving the development of multiple human cancers including acute myeloid leukemia. Recent advances in sequencing technologies have led to the identification of recurrent mutations in genes that regulate DNA methylation including DNA methyltransferase 3A (DNMT3A), ten-eleven translocation 2 (TET2), and isocitrate dehydrogenase 1 (IDH1) and IDH2. These mutations have been shown to promote self-renewal and block differentiation of hematopoietic stem/progenitor cells. Acquisition of these mutations in hematopoietic stem cells can lead to their clonal expansion resulting in a pre-leukemic stem cell (pre-LSC) population. Pre-LSCs retain the ability to differentiate into the full spectrum of mature daughter cells but can become fully transformed with the acquisition of additional driver mutations. Here, we review the effects of mutations in DNMT3A, TET2, and IDH1/2 on mouse and human hematopoiesis, the current understanding of their role in pre-LSCs, and therapeutic strategies to eliminate this population which may serve as a cellular reservoir for relapse.
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PMID:Role of DNMT3A, TET2, and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. 2394 14

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.
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PMID:Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling. 2461 57

Oligodendrogliomas are uncommon tumors in neurooncology that represent about 5% of primary brain malignancies. Their high sensitivity to radiotherapy and chemotherapy was observed a long time ago. Nonetheless, the evidence-based proof of the significantly longer survival in patients with oligodendrogliomas treated with combined chemotherapy and radiotherapy in comparison to radiotherapy-alone did not exist. The long-term follow-up of two landmark phase III clinical trials: RTOG 9402 and EORTC 26951, recently demonstrated favorable effects of combined radiotherapy and chemotherapy (procarbazine, lomustine and vincristine) in patients with anaplastic oligodendrogliomas and anaplastic oligoastrocytomas carrying the chromosomal mutation of co-deletion of 1p/19q. There is also an increasing role of other molecular biomarkers, such as mutations in the metabolic enzyme isocitrate dehydrogenase 1/2, O6-methylguanine DNA methyltransferase gene promoter methylation, or glioma genome cytosine-phosphate-guanine islands methylator phenotype. The analysis of molecular genetics in oligodendrogliomas is now recommended as an important part of the management of these tumors and together with the novel chemotherapeutic regimens means a paradigm shift in current clinical practice in neurooncology.
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PMID:New treatment paradigm for patients with anaplastic oligodendroglial tumors. 2469 86

The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. There are a number of reasons for this, but key among them is the considerable heterogeneity of this disease and the paucity of molecular markers that can be used to predict clinical outcomes and responsiveness to different therapies. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of DNMT3A, IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents. Therefore, the clinical experience with decitabine and azacitidine in the treatment of patients harboring these mutations will be reviewed. Overall, we propose that understanding the role of these mutations in AML biology will lead to more rational therapeutic approaches targeting molecularly defined subtypes of the disease.
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PMID:DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. 2469 5

Tumor grade and molecular variants influence the survival of patients with glioma. The apparent diffusion coefficient (ADC) map is a non-invasive tool for evaluating the outcomes and response to therapy in glioma. In this study, we investigated the correlation between the tumor grade and prognostic biomarkers with the ADC in glioma patients. Eighty-two patients with supratentorial glioma were identified via analysis of surgical specimens and neuroradiological data. Using the World Health Organization grade, histological subtype, and molecular variants (1p/19q codeletion, isocitrate dehydrogenase 1/2 mutation, Ki-67 index, O6-methylguanine DNA methyltransferase, P53, and vascular endothelial growth factor immunoactivity) as prognostic biomarkers, we performed receiver operating characteristic analysis and multiple linear regression to assess the association between the magnetic resonance diffusion parameter and mean ADC and the prognostic factors of glioma pathology. Univariate analysis and multiple linear regression revealed inverse correlations between the ADC values and the tumor grade, oligodendrocytoma histology, and 1p/19q codeletion. A threshold mean ADC value could predict the 1p/19q chromosomal status in WHO II gliomas with 72 % sensitivity and 88 % specificity (area under the curve 0.82, 95 % confidence interval 0.68-0.97) and could distinguish low-grade glioma with low-risk factors from the high-risk group (P < 0.01). The mean ADC value could be used as a non-invasive tool to evaluate the prognosis of supratentorial glioma patients. A threshold mean ADC value could be used to predict the 1p/19q codeletion and to identify low-risk low-grade gliomas (LGGs). Lower ADC values are indicative of a favorable prognosis in LGGs.
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PMID:Lower apparent diffusion coefficients indicate distinct prognosis in low-grade and high-grade glioma. 2487 69

Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p < 0.001), but not 1p/19q loss (p = 0.834), occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response. Isocitrate dehydrogenase 1 mutation was highly associated with O 6-methylguanine DNA methyltransferase promoter methylation and TP53 mutation.
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PMID:Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas. 2611 94


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