Joanna J. PhillipsDerick ArandaDavid W. EllisonAlexander R. JudkinsSidney CroulDaniel J. BratKeith L. LigonCraig HorbinskiSriram VennetiGelareh ZadehMariarita SantiShengmei ZhouChristina AppinStefano SioleticLisa SullivanMaria Martinez‐LageAaron E. RobinsonWilliam H. YongTimothy F. CloughesyAlbert LaiHeidi PhillipsRoxanne MarshallSabine MuellerDaphne A. Haas‐KoganAnnette M. MolinaroArie Perry
90
Citation
31
Reference
10
Related Paper
Citation Trend
Abstract:
High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.Keywords:
PDGFRA
Isocitrate dehydrogenase
IDH2
Isocitrate dehydrogenase
Cite
Citations (213)
Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg132 of IDH1 and Arg172 of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy.
Isocitrate dehydrogenase
IDH2
Cite
Citations (250)
Isocitrate dehydrogenase
Cite
Citations (7)
A recent cancer genome-sequencing project revealed that that novel point mutations in isocitrate dehydrogenase 1(IDH1) in the majority of gliomas at WHO Grade Ⅱ and Ⅲ and secondary glioblastomas at grade IV.IDH1 mutations are early events in the development of gliomas,and are related with prolonged survival in gliomas at various grades.Mutated IDH1 shows an altered catalytic activity that results in the elevated levels of α-ketoglutarate and 2-hydroxyglutarate.The correlations among the gliomas pathological diagnosis,tumor genesis,the therapeutic potential for targeting mutant IDH enzymes are discussed in this review.
Isocitrate dehydrogenase
IDH2
Cite
Citations (0)
Isocitrate dehydrogenase
IDH2
Myeloid leukaemia
Cite
Citations (9)
A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes.We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
IDH2
Isocitrate dehydrogenase
Cite
Citations (5,354)
Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.
Isocitrate dehydrogenase
Cite
Citations (19)
Purpose of review Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies. Recent findings Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth. Summary As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
Isocitrate dehydrogenase
IDH2
Cite
Citations (84)
A mutation in IDH1, which encodes an isocitrate dehydrogenase, is associated with susceptibility to glioma. This mutation results in an acquired enzyme activity that points to a potential biomarker of the mutant tumor.
Isocitrate dehydrogenase
IDH2
Cite
Citations (16)
Isocitrate dehydrogenase 1 and 2 mutations are known to be early events in gliomagenesis and have a definite role in tumor progression.Isocitrate dehydrogenase1/2 mutation status is considered to be one of the most powerful independent positive predictor of outcome amongst all molecular markers described in association with gliomas. The inclusion of this parameter in the 2016 update of the World Health Organization Classification of Tumors of The Central Nervous System reinforced its importance in glioma classification and prognostication. As a result, now there is enough evidence to prove that Isocitrate dehydrogenase-mutant and Isocitrate dehydrogenase- wildtypegliomas are two biologically distinct categories of gliomas with likely different pathways of tumorigenesis, different clinical outcomes, and respond differently to similar treatment strategies. Increasing knowledge aboutthe role of IDH1/2 mutation in gliomagenesis has resulted in many novel targeting strategies being developed and evaluated forusefulness in the clinical setting. This literature review aims to highlight the diagnostic and prognostic importance of Isocitrate dehydrogenase1/2 gene mutations in adult gliomas.
Isocitrate dehydrogenase
Cite
Citations (0)