IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation.
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ABSTRACT:
SUBMITTER: Oktay Y
PROVIDER: S-EPMC4901315 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.
| S-EPMC3652416 | biostudies-literature
Project description:Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2.
| S-EPMC5352106 | biostudies-literature
Project description: Not available
| S-EPMC9071324 | biostudies-literature
Project description:BackgroundRecurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated.MethodsIn this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort.ResultsWe found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type.ConclusionOur finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management.Implications for practicePatients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.
| S-EPMC4746092 | biostudies-literature
Project description:BackgroundIsocitrate dehydrogenase (IDH) mutant gliomas are a distinct subtype, reflected in the World Health Organization (WHO) 2016 revised diagnostic criteria. To inform IDH-targeting trial design, we sought to characterize outcomes exclusively within IDH mutant gliomas.MethodsWe retrospectively analyzed 275 IDH mutant glioma patients treated at our institution. Progression was determined using low-grade glioma criteria from Response Assessment in Neuro-Oncology. We calculated survival statistics with the Kaplan-Meier method, and survival proportions were correlated with molecular, histologic, and clinical factors.ResultsDuring a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression (PFS1) events (54.1%) were observed. Median PFS1 was 5.7 years (95% CI: 4.7-6.4) and OS was 18.7 years (95% CI: 12.2 y-not reached). Consistent with prior studies, we observed an association of grade, molecular diagnosis, and treatment with PFS1. Following the first progressive episode, 79 second progression events occurred during a median follow-up period of 4.1 years. Median PFS following an initial progressive event (PFS2) was accelerated at 3.1 years (95% CI: 2.1-4.1). PFS2 was a surrogate prognostic marker, identifying patients with poorer overall survival.ConclusionWe report outcomes in a large cohort of IDH mutant glioma, providing a well-characterized historical control population for future clinical trial design. Notably, the interval between first and second recurrence (PFS2, 3.0 y) is shorter than time from diagnosis to first recurrence (PFS1, 5.7 y), evidence that these tumors clinically degenerate from an indolent course to an accelerated malignant phase. Thus, PFS2 represents a relevant outcome for trials investigating drug efficacy at recurrence.
| S-EPMC6502499 | biostudies-literature
Project description:Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032. However, to date, early detection of response remains a challenge. In this study we used high resolution 1H magnetic resonance spectroscopy (1H-MRS) to identify early noninvasive MR (Magnetic Resonance)-detectable metabolic biomarkers of response to mutant IDH inhibition. In vivo 1H-MRS was performed on mice orthotopically-implanted with either genetically engineered (U87IDHmut) or patient-derived (BT257 and SF10417) mutant IDH1 cells. Treatment with either AG-881 or BAY-1436032 induced a significant reduction in 2-HG. Moreover, both inhibitors led to a significant early and sustained increase in glutamate and the sum of glutamate and glutamine (GLX) in all three models. A transient early increase in N-acetylaspartate (NAA) was also observed. Importantly, all models demonstrated enhanced animal survival following both treatments and the metabolic alterations were observed prior to any detectable differences in tumor volume between control and treated tumors. Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies.
| S-EPMC7917625 | biostudies-literature
Project description:Most gliomas are associated with a fatal prognosis and remain incurable because of their infiltrative growth. Consequently, the addition of immunotherapy to conventional therapy may improve patient outcomes. Here, we analyzed T-cell infiltration and, therefore, a major prerequisite for successful immunotherapy in a series of primary (n = 78) and recurrent (n = 66) isocitrate dehydrogenase (IDH)-mutant glioma and their changes following treatment with radio- and/or chemotherapy. After multicolor immunofluorescence staining, T cells were counted in entire tumor sections using a software-based setup. Newly diagnosed diffuse IDH-mutant gliomas displayed a median T-cell infiltration of 0.99 T cells/mm2 (range: 0-48.97 CD3+ T cells/mm2), which was about two-fold increased for CD3+, helper, and cytotoxic T cells in recurrent glioma. Furthermore, T-cell infiltration of recurrent tumors was associated with the type of adjuvant treatment of the primary tumor. Interestingly, only glioma patients solely receiving radiotherapy presented consistently with increased T-cell infiltration in their recurrent tumors. This was confirmed in a subset of 27 matched pairs. In conclusion, differences in the T-cell infiltration of primary and recurrent gliomas were demonstrated, and evidence was provided for a beneficial long-term effect on T-cell infiltration upon treatment with radiotherapy.
| S-EPMC7590222 | biostudies-literature
Project description:BackgroundGliomas are the most common primary brain tumors and are universally fatal. Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) define a distinct glioma subtype associated with an immunosuppressive tumor microenvironment. Mechanisms underlying systemic immunosuppression in IDH mutant (mutIDH) gliomas are largely unknown. Here, we define genotype-specific local and systemic tumor immunomodulatory functions of tumor-derived glioma small extracellular vesicles (TEX).MethodsTEX produced by human and murine wildtype and mutant IDH glioma cells (wtIDH and mutIDH, respectively) were isolated by size exclusion chromatography (SEC). TEX morphology, size, quantity, molecular profiles and biodistribution were characterized. TEX were injected into naive and tumor-bearing mice, and the local and systemic immune microenvironment composition was characterized.ResultsUsing in vitro and in vivo glioma models, we show that mutIDH TEX are more numerous, possess distinct morphological features and are more immunosuppressive than wtIDH TEX. mutIDH TEX cargo mimics their parental cells, and induces systemic immune suppression in naive and tumor-bearing mice. TEX derived from mutIDH gliomas and injected into wtIDH tumor-bearing mice reduce tumor-infiltrating effector lymphocytes, dendritic cells and macrophages, and increase circulating monocytes. Astonishingly, mutIDH TEX injected into brain tumor-bearing syngeneic mice accelerate tumor growth and increase mortality compared with wtIDH TEX.ConclusionsTargeting of mutIDH TEX represents a novel therapeutic approach in gliomas.
| S-EPMC8804898 | biostudies-literature
Project description:BackgroundIsocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the oncometabolite 2-hydroxyglutarate. Therefore, therapies targeting reversal of epigenetic dysregulation in gliomas have been suggested. However, the utility of epigenetic treatments in gliomas remains unclear. Here, we present the first clinical systematic review of epigenetic therapies in treatment of IDH-mutant gliomas and highlight their safety and efficacy.MethodsWe conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safety/tolerability of epigenetic therapies and progression-free survival/overall survival, respectively.ResultsA total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3/grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%.ConclusionIDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.
| S-EPMC9177782 | biostudies-literature
Project description:BackgroundRecent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments.ResultsTo reconcile these findings, we profile 22 human IDH-mutant gliomas using scATAC-seq and scRNA-seq. We determine the cell-type-specific differences in transcription factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knock out the chromatin remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence.ConclusionsThese studies explain how IDH-mutant gliomas from different subtypes maintain distinct phenotypes and tumor microenvironments despite a common lineage hierarchy.
| S-EPMC8588616 | biostudies-literature