Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.41 (isocitrate dehydrogenase)
 3,101 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to identify genetic and epigenetic alterations involved in the progression of oligodendroglial tumors. We characterized 21 paired, World Health Organization (WHO) grade II and III oligodendroglial tumors from patients who received craniotomies for the partial or complete resection of primary and secondary oligodendroglial tumors. Tumor DNA was analyzed for alterations in selected genetic loci (1p36, 9p22, 10q23-24, 17p13, 19q13, 22q12), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2) and the CpG island methylation status of critical tumor-related genes (MGMT, P16, DAPK, PTEN, RASSF1A, Rb1). Alterations of these markers were common early in the tumorigenesis. In the primary tumors we identified 12 patients (57.1%) with 1p36 deletions, 17 (81.0%) with 19q13 deletions, 9 (42.9%) with 1p36/19q13 codeletions, 11 (52.3%) with 9p22 deletions, and 12 (57.1%) with IDH1 mutation. Epigenetic analysis detected promoter methylation of the MGMT, P16, DAPK, PTEN, RASSF1A, and Rb1 genes in 38.1%, 19.0%, 38.1%, 33.3%, 66.7%, and 14.3% of primary tumors, respectively. After progression, additional losses of 1p, 9p, 10q, 17p, 19q and 22q were observed in 3 (14.3%), 1 (4.8%), 3 (14.3%), 2 (9.5%), 1 (4.8%) and 3 (14.3%) cases, respectively. Additional methylations of the MGMT, P16, DAPK, PTEN, RASSF1A, and RB1 promoters was observed in 4 (19.0%), 2 (9.5%), 0 (0%), 6 (28.6%), 2(9.5%) and 3 (14.3%) cases, respectively. The status of IDH1 mutation remained unchanged in all tumors after progression. The primary tumors of three patients with subsequent progression to high-grade astrocytomas, all had 9p deletion, intact 1p, intact 10q and unmethylated MGMT. Whether this may represent a molecular signature of patients at-risk for the development of aggressive astrocytomas needs further investigation.
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PMID:Genetic and epigenetic alterations in primary-progressive paired oligodendroglial tumors. 2382 16

Promoter methylation of P15, P16, RB transcriptional corepressor 1 (RB1) and O-6-methylguanine-DNA methyltransferase (MGMT) impacts the prognosis of numerous glioma subtypes. However, whether promoter methylation of these genes also has an impact on the clinical course of pilocytic astrocytoma remains unclear. Using methylation-specific polymerase chain reaction, the methylation status of the tumor suppressor genes P15, P16, RB1, and MGMT in pilocytic astrocytomas (n=18) was analyzed. Immunohistochemical staining for the R132H mutation of the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) gene was performed. Clinical data including age, gender, localization of tumor, extent of resection, treatment modality, progression-free survival and overall survival were collected. The methylation index for P15, P16, RB1 and MGMT was 0.0, 0.0, 5.6% (1/18) and 44.5% (8/18), respectively. If the MGMT promoter was methylated, the probability of relapse and second subsequent therapy was significantly increased (P=0.019). The one patient with methylation of P15 demonstrated a poor clinical course. The pilocytic astrocytomas of all 18 patients revealed wild-type IDH1. Clinically, there was a significant correlation of subtotal resection with the occurrence of relapse (P=0.005) and of the localization of the tumor with the extent of resection (P=0.031). Gross total resection was achieved significantly more often in pediatric patients than in adult patients (P=0.003). Adult patients demonstrated more relapses following the first tumor resection (P=0.001). The present study indicates that methylation of MGMT is associated with a poor clinical course and represents an age-independent risk factor for an unfavorable outcome. Other influential factors of outcome were the age of the patient and extent of resection.
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PMID:Promoter methylation of RB1, P15, P16, and MGMT and their impact on the clinical course of pilocytic astrocytomas. 2943 55

Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH-mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations. IDH-wild-type (wt) infiltrating astrocytomas are mostly primary GBMs and are characterized by EGFR, PTEN, TP53, NF1, RB1, PDGFRA, and CDKN2A/B alterations, TERT-p mutations, and characteristic copy number alterations including gains of chromosome 7 and losses of 10. Other clinically and genetically distinct infiltrating astrocytomas include the aggressive H3K27M-mutant midline gliomas, and smaller subsets that occur in the setting of NF1 or have BRAF V600E mutations. Low-grade pediatric gliomas are both genetically and biologically distinct from their adult counterparts and often harbor a single driver event often involving BRAF, FGFR1, or MYB/MYBL1 genes. Large scale genomic and epigenomic analyses have identified distinct subgroups of ependymomas tightly linked to tumor location and clinical behavior. The diagnosis of embryonal neoplasms also integrates molecular testing: (I) 4 molecularly defined, biologically distinct subtypes of medulloblastomas are now recognized; (II) 3 histologic entities have now been reclassified under a diagnosis of "embryonal tumor with multilayered rosettes (ETMR), C19MC-altered"; and (III) atypical teratoid/rhabdoid tumors (AT/RT) now require SMARCB1 (INI1) or SMARCA4 (BRG1) alterations for their diagnosis. We discuss the practical use of contemporary biomarkers for an integrative diagnosis of central nervous system neoplasia.
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PMID:Incorporating Advances in Molecular Pathology Into Brain Tumor Diagnostics. 2952 46

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in TP53, NF1, and RB1, and CDKN2A deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.
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PMID:Molecular and clonal evolution in recurrent metastatic gliosarcoma. 3189 44

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML. Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.
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PMID:The role of autophagy in targeted therapy for acute myeloid leukemia. 3291 24