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Neuro-oncology Jun 2023IDH mutant gliomas are grouped into astrocytomas or oligodendrogliomas depending on the codeletion of chromosome arms 1p and 19q. Although the genomic alterations of IDH...
BACKGROUND
IDH mutant gliomas are grouped into astrocytomas or oligodendrogliomas depending on the codeletion of chromosome arms 1p and 19q. Although the genomic alterations of IDH mutant gliomas have been well described, transcriptional changes unique to either tumor type have not been fully understood. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas.
METHODS
We used several cell lines, including patient-derived oligodendroglioma tumorspheres, to knock down or overexpress TRIM67. We coupled high-throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS), and coimmunoprecipitation (co-IP)-MS with functional assays including immunofluorescence (IF) staining, co-IP, and western blotting (WB) to assess the in vitro phenotype associated with TRIM67. Patient-derived oligodendroglioma tumorspheres were orthotopically implanted in mice to determine the effect of TRIM67 on tumor growth and survival.
RESULTS
TRIM67 overexpression alters the abundance of cytoskeletal proteins and induces membrane bleb formation. TRIM67-associated blebbing was reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. NOGO-A/Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression, pointing to the underlying mechanism for TRIM67-induced blebbing. Phenotypically, TRIM67 expression resulted in higher cell motility and reduced cell adherence. In orthotopic implantation models of patient-derived oligodendrogliomas, TRIM67 accelerated tumor growth, reduced overall survival, and led to increased vimentin expression at the tumor margin.
CONCLUSIONS
Taken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis.
Topics: Animals; Mice; Humans; Oligodendroglioma; Nogo Proteins; Glioma; Astrocytoma; Cell Transformation, Neoplastic; Carcinogenesis; Chromosomes, Human, Pair 1; Brain Neoplasms; Chromosomes, Human, Pair 19; Isocitrate Dehydrogenase; Mutation; Tripartite Motif Proteins; Cytoskeletal Proteins
PubMed: 36215168
DOI: 10.1093/neuonc/noac233 -
The Lancet. Oncology Jun 2017The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas,... (Review)
Review
The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
Topics: Adult; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Combined Modality Therapy; Humans; Magnetic Resonance Imaging; Molecular Diagnostic Techniques; Neuroimaging; Oligodendroglioma; Positron-Emission Tomography; Radiotherapy
PubMed: 28483413
DOI: 10.1016/S1470-2045(17)30194-8 -
Cell Reports. Medicine Nov 2023The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas,...
The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas, each with unique pathological features. Here, we use single-nucleus RNA and ATAC sequencing to compare the molecular heterogeneity of these glioma subtypes. In addition to astrocyte-like, oligodendrocyte progenitor-like, and cycling tumor subpopulations, a tumor population enriched for ribosomal genes and translation elongation factors is primarily present in oligodendrogliomas. Longitudinal analysis of astrocytomas indicates that the proportion of tumor subpopulations remains stable in recurrent tumors. Analysis of tumor-associated microglia/macrophages (TAMs) reveals significant differences between oligodendrogliomas, with astrocytomas harboring inflammatory TAMs expressing phosphorylated STAT1, as confirmed by immunohistochemistry. Furthermore, inferred receptor-ligand interactions between tumor subpopulations and TAMs may contribute to TAM state diversity. Overall, our study sheds light on distinct tumor populations, TAM heterogeneity, TAM-tumor interactions in IDH-mutant glioma subtypes, and the relative stability of tumor subpopulations in recurrent astrocytomas.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Microglia; Mutation; Neoplasm Recurrence, Local; Glioma; Astrocytoma; Isocitrate Dehydrogenase
PubMed: 37883975
DOI: 10.1016/j.xcrm.2023.101249 -
Journal of Veterinary Internal Medicine Jul 2021Gliomas in dogs remain poorly understood.
BACKGROUND
Gliomas in dogs remain poorly understood.
OBJECTIVES
To characterize the clinicopathologic findings, diagnostic imaging features and survival of a large sample of dogs with glioma using the Comparative Brain Tumor Consortium diagnostic classification.
ANIMALS
Ninety-one dogs with histopathological diagnosis of glioma.
METHODS
Multicentric retrospective case series. Signalment, clinicopathologic findings, diagnostic imaging characteristics, treatment, and outcome were used. Tumors were reclassified according to the new canine glioma diagnostic scheme.
RESULTS
No associations were found between clinicopathologic findings or survival and tumor type or grade. However, definitive treatments provided significantly (P = .03) improved median survival time (84 days; 95% confidence interval [CI], 45-190) compared to palliative treatment (26 days; 95% CI, 11-54). On magnetic resonance imaging (MRI), oligodendrogliomas were associated with smooth margins and T1-weighted hypointensity compared to astrocytomas (odds ratio [OR], 42.5; 95% CI, 2.42-744.97; P = .04; OR, 45.5; 95% CI, 5.78-333.33; P < .001, respectively) and undefined gliomas (OR, 84; 95% CI, 3.43-999.99; P = .02; OR, 32.3; 95% CI, 2.51-500.00; P = .008, respectively) and were more commonly in contact with the ventricles than astrocytomas (OR, 7.47; 95% CI, 1.03-53.95; P = .049). Tumor spread to neighboring brain structures was associated with high-grade glioma (OR, 6.02; 95% CI, 1.06-34.48; P = .04).
CONCLUSIONS AND CLINICAL IMPORTANCE
Dogs with gliomas have poor outcomes, but risk factors identified in survival analysis inform prognosis and the newly identified MRI characteristics could refine diagnosis of tumor type and grade.
Topics: Animals; Brain Neoplasms; Dog Diseases; Dogs; Glioma; Magnetic Resonance Imaging; Oligodendroglioma; Retrospective Studies; Survival Analysis
PubMed: 34117807
DOI: 10.1111/jvim.16199 -
EBioMedicine Jan 2023Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy...
BACKGROUND
Human oligodendroglioma presents as a heterogeneous disease, primarily characterized by the isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion. Therapy development for this tumor is hindered by incomplete knowledge of somatic driving alterations and suboptimal disease classification. We herein aim to identify intrinsic molecular subtypes through integrated analysis of transcriptome, genome and methylome.
METHODS
137 oligodendroglioma patients from the Cancer Genome Atlas (TCGA) dataset were collected for unsupervised clustering analysis of immune gene expression profiles and comparative analysis of genome and methylome. Two independent datasets containing 218 patients were used for validation.
FINDINGS
We identified and independently validated two reproducible subtypes associated with distinct molecular characteristics and clinical outcomes. The proliferative subtype, named Oligo1, was characterized by more tumors of CNS WHO grade 3, as well as worse prognosis compared to the Oligo2 subtype. Besides the clinicopathologic features, Oligo1 exhibited enrichment of cell proliferation, regulation of cell cycle and Wnt signaling pathways, and significantly altered genes, such as EGFR, NOTCH1 and MET. In contrast, Oligo2, with favorable outcome, presented increased activation of immune response and metabolic process. Higher T cell/APC co-inhibition and inhibitory checkpoint levels were observed in Oligo2 tumors. Finally, multivariable analysis revealed our classification was an independent prognostic factor in oligodendrogliomas, and the robustness of these molecular subgroups was verified in the validation cohorts.
INTERPRETATION
This study provides further insights into patient stratification as well as presents opportunities for therapeutic development in human oligodendrogliomas.
FUNDING
The funders are listed in the Acknowledgement.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Mutation; Chromosome Aberrations; Transcriptome; Prognosis; Isocitrate Dehydrogenase; Chromosomes, Human, Pair 1
PubMed: 36525723
DOI: 10.1016/j.ebiom.2022.104410 -
The British Journal of Radiology 2016Oligodendroglioma are glial tumours, predominantly occurring in adults. Their hallmark molecular feature is codeletion of the 1p and 19q chromosome arms, which is not... (Review)
Review
Oligodendroglioma are glial tumours, predominantly occurring in adults. Their hallmark molecular feature is codeletion of the 1p and 19q chromosome arms, which is not only of diagnostic but also of prognostic and predictive relevance. On imaging, these tumours characteristically show calcification, and they have a cortical-subcortical location, most commonly in the frontal lobe. Owing to their superficial location, there may be focal thinning or remodelling of the overlying skull. In contrast to other low-grade gliomas, minimal to moderate enhancement is commonly seen and perfusion may be moderately increased. This complicates differentiation from high-grade, anaplastic oligodendroglioma, in which enhancement and increased perfusion are also common. New enhancement in a previously non-enhancing, untreated tumour, however, is suggestive of malignant transformation, as is high growth rate. MR spectroscopy may further aid in the differentiation between low- and high-grade oligodendroglioma. A relatively common feature of recurrent disease is leptomeningeal dissemination, but extraneural spread is rare. Tumours with the 1p/19q codeletion more commonly show heterogeneous signal intensity, particularly on T2 weighted imaging; calcifications; an indistinct margin; and mildly increased perfusion and metabolism than 1p/19q intact tumours. For the initial diagnosis of oligodendroglioma, MRI and CT are complementary; MRI is superior to CT in assessing tumour extent and cortical involvement, whereas CT is most sensitive to calcification. Advanced and functional imaging techniques may aid in grading and assessing the molecular genotype as well as in differentiating between tumour recurrence and radiation necrosis, but so far no unequivocal method or combination of methods is available.
Topics: Adult; Brain Neoplasms; Calcinosis; Diagnosis, Differential; Frontal Lobe; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Neoplasm Metastasis; Oligodendroglioma; Positron-Emission Tomography; Tomography, X-Ray Computed
PubMed: 26849038
DOI: 10.1259/bjr.20150857 -
Nature Nov 2016Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and...
Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.
Topics: Cell Differentiation; Cell Proliferation; DNA Copy Number Variations; Humans; Isocitrate Dehydrogenase; Neoplastic Stem Cells; Neural Stem Cells; Neuroglia; Oligodendroglioma; Phylogeny; Point Mutation; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 27806376
DOI: 10.1038/nature20123 -
Neuro-oncology Mar 2021We report the analysis involving patients treated on the initial CODEL design. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We report the analysis involving patients treated on the initial CODEL design.
METHODS
Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.
RESULTS
Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months.
CONCLUSIONS
TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.
Topics: Adult; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Oligodendroglioma; Progression-Free Survival; Temozolomide
PubMed: 32678879
DOI: 10.1093/neuonc/noaa168 -
Journal of Clinical Oncology : Official... Jan 2013Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Anaplastic oligodendrogliomas, pure (AO) and mixed (anaplastic oligoastrocytoma [AOA]), are chemosensitive, especially if codeleted for 1p/19q, but whether patients live longer after chemoradiotherapy is unknown.
PATIENTS AND METHODS
Eligible patients with AO/AOA were randomly assigned to procarbazine, lomustine, and vincristine (PCV) plus radiotherapy (RT) versus RT alone. The primary end point was overall survival (OS).
RESULTS
Two hundred ninety-one eligible patients were randomly assigned: 148 to PCV plus RT and 143 to RT. For the entire cohort, there was no difference in median survival by treatment (4.6 years for PCV plus RT v 4.7 years for RT; hazard ratio [HR] = 0.79; 95% CI, 0.60 to 1.04; P = .1). Patients with codeleted tumors lived longer than those with noncodeleted tumors (PCV plus RT: 14.7 v 2.6 years, HR = 0.36, 95% CI, 0.23 to 0.57, P < .001; RT: 7.3 v 2.7 years, HR = 0.40, 95% CI, 0.27 to 0.60, P < .001), and the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03). For those with noncodeleted tumors, there was no difference in median survival by treatment arm (2.6 v 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = .39). In Cox models that included codeletion status, the adjusted OS for all patients was prolonged by PCV plus RT (HR = 0.67; 95% CI, 0.50 to 0.91; P = .01).
CONCLUSION
For the subset of patients with 1p/19q codeleted AO/AOA, PCV plus RT may be an especially effective treatment, although this observation was derived from an unplanned analysis.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Disease-Free Survival; Gene Deletion; Humans; Kaplan-Meier Estimate; Lomustine; Oligodendroglioma; Procarbazine; Proportional Hazards Models; Radiotherapy; Time; Vincristine
PubMed: 23071247
DOI: 10.1200/JCO.2012.43.2674 -
Acta Neuropathologica Jun 2015For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first... (Review)
Review
For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for the diagnosis of 'canonical oligodendroglioma'. This transition to an integrated morphological and molecular diagnosis may result in the disappearance of oligoastrocytoma as an entity, but brings new challenges as well. For instance it needs to be sorted out how (histopathological) criteria for grading of 'canonical oligodendrogliomas' should be adapted, how pediatric oligodendrogliomas (known to lack codeletions) should be defined, which platforms and cut-off levels should ideally be used for demonstration of particular molecular aberrations, and how the diagnosis of oligodendroglioma should be made in centers/countries where molecular diagnostics is not available. Meanwhile, smart integration of morphological and molecular information will lead to recognition of biologically much more uniform groups within the spectrum of diffuse gliomas and thereby facilitate tailored treatments for individual patients.
Topics: Biomarkers, Tumor; Brain Neoplasms; Humans; Oligodendroglioma
PubMed: 25943885
DOI: 10.1007/s00401-015-1424-1