-
Cancer Medicine Aug 2023Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of...
BACKGROUND
Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses.
METHODS
In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence.
RESULTS
Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor.
CONCLUSION
Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression.
CLINICALTRIALS
gov, Identifier: NCT05512325.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Hedgehog Proteins; Neoplasm Recurrence, Local; Mutation; Genomics; Isocitrate Dehydrogenase; DNA-Binding Proteins; RNA-Binding Proteins
PubMed: 37533228
DOI: 10.1002/cam4.6327 -
International Journal of Molecular... Oct 2023The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2...
The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [Bi]Bi/[Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT. In two oligodendroglioma patients, TAT was applied as a second-line treatment for tumor progression, 10 years after targeted beta therapy using [Y]Y-DOTA-substance P. The radiopharmaceutical was locally injected directly into the tumor via a stereotactic insertion of a capsule-catheter system. The activity used for radiolabeling was 2-2.5 GBq of Bismuth-213 and 17 to 35 MBq of Actinium-225, mostly applied in a single fraction. The recurrence-free survival times were in the range of 2 to 16 years (median 11 years) in low-grade astrocytoma (n = 8), in which TAT was administered following a biopsy or tumor debulking. Regarding oligodendroglioma, the recurrence-free survival time was 24 years in the first case treated, and 4 and 5 years in the two second-line cases. In conclusion, TAT leads to long-term tumor control in the majority of patients with LGG, and recurrence has so far not manifested in patients with low-grade (grade 2) astrocytomas who received TAT as a first-line therapy. We conclude that targeted alpha therapy has the potential to become a new treatment paradigm in LGG.
Topics: Humans; Oligodendroglioma; Substance P; Glioma; Astrocytoma; Glioblastoma; Brain Neoplasms
PubMed: 37958683
DOI: 10.3390/ijms242115701 -
Acta Neuropathologica Feb 2022Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and...
Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
Topics: Adult; Aged; Brain Neoplasms; Female; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Oligodendroglioma; Sarcoma
PubMed: 34967922
DOI: 10.1007/s00401-021-02395-z -
CNS Oncology 2015Oligodendroglioma (WHO Grade 2) and anaplastic oligodendroglioma (WHO Grade 3) are glial tumors composed of neoplastic cellular elements that resemble oligodendrocytes.... (Review)
Review
Oligodendroglioma (WHO Grade 2) and anaplastic oligodendroglioma (WHO Grade 3) are glial tumors composed of neoplastic cellular elements that resemble oligodendrocytes. The treatment of recurrent, alkylator refractory oligodendroglial tumors is challenging given the paucity of effective treatment and lack of randomized controlled trials on which to base therapy. Notwithstanding the lack of prospective, randomized data, treatment of oligodendroglial tumors with bevacizumab can be recommended tentatively recognizing that preliminary studies suggest efficacy. Somatic mutations of the isocitrate dehydrogenase enzymes (IDH1 and IDH2) appear to play a critical role in the pathogenesis of most oligodendroglial tumors and agents that target these mutations are a potential therapeutic option. Additionally, reversal of CpG island hypermethylated phenotype status through inhibition of DNA methyltransferase with an inhibitor such as decitabine may provide a target for future studies.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Neoplasm Recurrence, Local; Oligodendroglioma; Vascular Endothelial Growth Factor A
PubMed: 26509217
DOI: 10.2217/cns.15.27 -
NeuroImage. Clinical 2019To develop a statistical method of combining multimodal MRI (mMRI) of adult glial brain tumours to generate tissue heterogeneity maps that indicate tumour grade and...
PURPOSE
To develop a statistical method of combining multimodal MRI (mMRI) of adult glial brain tumours to generate tissue heterogeneity maps that indicate tumour grade and infiltration margins.
MATERIALS AND METHODS
We performed a retrospective analysis of mMRI from patients with histological diagnosis of glioma (n = 25). H Magnetic Resonance Spectroscopic Imaging (MRSI) was used to label regions of "pure" low- or high-grade tumour across image types. Normal brain and oedema characteristics were defined from healthy controls (n = 10) and brain metastasis patients (n = 10) respectively. Probability density distributions (PDD) for each tissue type were extracted from intensity normalised proton density and T-weighted images, and p and q diffusion maps. Superpixel segmentation and Bayesian inference was used to produce whole-brain tissue-type maps.
RESULTS
Total lesion volumes derived automatically from tissue-type maps correlated with those from manual delineation (p < 0.001, r = 0.87). Large high-grade volumes were determined in all grade III & IV (n = 16) tumours, in grade II gemistocytic rich astrocytomas (n = 3) and one astrocytoma with a histological diagnosis of grade II. For patients with known outcome (n = 20), patients with survival time < 2 years (3 grade II, 2 grade III and 10 grade IV) had a high-grade volume significantly greater than zero (Wilcoxon signed rank p < 0.0001) and also significantly greater high grade volume than the 5 grade II patients with survival >2 years (Mann Witney p = 0.0001). Regions classified from mMRI as oedema had non-tumour-like H MRS characteristics.
CONCLUSIONS
H MRSI can label tumour tissue types to enable development of a mMRI tissue type mapping algorithm, with potential to aid management of patients with glial tumours.
Topics: Adult; Aged; Algorithms; Bayes Theorem; Brain; Brain Mapping; Brain Neoplasms; Female; Glioma; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neoplasm Grading; Oligodendroglioma; Retrospective Studies
PubMed: 30630760
DOI: 10.1016/j.nicl.2018.101648 -
Neuropathology : Official Journal of... Apr 2022We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after...
We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after temozolomide chemotherapy and radiotherapy. The first tumor recurrence had oligodendroglial morphology, IDH1 R132H and TERT promoter mutations, and 1p/19q codeletion detected by fluorescent in situ hybridization (FISH). Copy number analysis, assessed by next-generation sequencing, confirmed 1p/19q codeletion, and disclosed loss of heterozygosity (LOH) of chromosomes 4 and 9 and chromosome 11 gain. The second recurrence featured not only oligodendroglial morphology but also the appearance of admixed multinucleated giant cells or neoplastic cells having oval nuclei and mitoses and showing microvascular proliferation; it maintained IDH1 R132H and TERT promoter mutations, acquired TP53 mutation, and showed 19q LOH, but disomic 1p, detected by FISH. Copy number analysis depicted LOH of chromosomes 3p, 13, and 19q, 1p partial deletion (1p chr1p34.2-p11), and gain of chromosomes 2p25.3-p24.1, 8q12.2-q24.3, and 11q13.3-q25. B-allele frequency analysis of polymorphic sites disclosed copy-neutral LOH at 1p36.33-p34.2, supporting the initial deletion of 1p, followed by reduplication of 1p36.33-p34.2 alone. These findings suggest that the two tumor recurrences might have originated from an initial neoplastic clone, featuring 1p/19q codeletion and IDH1 and TERT promoter mutations, and have independently acquired other copy number alterations. The reduplication of chromosome 1p might be the result of temozolomide treatment, and gave rise to false negative 1p deletion detected by FISH. The possibility of 1p copy-neutral LOH should be considered in recurrent oligodendrogliomas with altered 1p/19q status detected by FISH.
Topics: Brain Neoplasms; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Humans; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase; Neoplasm Recurrence, Local; Oligodendroglioma; Temozolomide
PubMed: 35144313
DOI: 10.1111/neup.12789 -
Journal of Neuro-oncology May 2023Astrocytomas and oligodendrogliomas are mainly diffuse primary brain tumors harboring a diagnostic and prognostically favorable isocitrate dehydrogenase mutation. They... (Review)
Review
PURPOSE
Astrocytomas and oligodendrogliomas are mainly diffuse primary brain tumors harboring a diagnostic and prognostically favorable isocitrate dehydrogenase mutation. They are still incurable besides growing molecular knowledge and therapy options. Circumscribed astrocytomas are also discussed here, although they represent a separate entity despite similarities in the nomenclature.
METHODS
We reviewed clinical trials, preclinical approaches as well as guideline recommendations form the major scientific Neuro-Oncology organizations for astrocytomas and oligodendrogliomas according to PRISMA guidelines.
RESULTS
After histopathological diagnosis and eventually a maximal safe resection, patients with good prognostic factors may be followed by magnetic resonance imaging (MRI). If further treatment is necessary, either after diagnosis or at progression, diffuse astrocytomas and oligodendrogliomas are mainly treated with combined radiochemotherapy or maximal safe resection followed by combined radiochemotherapy according to current guidelines based on randomized trials. Circumscribed gliomas like pilocytic astrocytomas, CNS WHO grade 1, or pleomorphic xanthoastrocytomas, CNS WHO grade 2, are often treated with surgery alone. Current approaches for therapy optimization include decision of the best chemotherapy regimen. The IDH mutation presents a rational target for small molecule inhibition and immune therapy in diffuse astrocytomas and oligodendrogliomas, while the BRAF pathway is frequently mutated and treatable in circumscribed gliomas.
CONCLUSION
Despite establishment of standard treatment approaches for gliomas that include resection, radio- and chemotherapy, there is a lack of effective treatments for progressive disease. Immune- and targeted therapies are currently investigated.
Topics: Humans; Oligodendroglioma; Astrocytoma; Glioma; Magnetic Resonance Imaging; Mutation
PubMed: 36566461
DOI: 10.1007/s11060-022-04216-z -
Clinical & Experimental Optometry Nov 2016Oligodendrogliomas are rare slow-growing asymptomatic glial tumours that usually present in patients in their fourth to sixth decades of life. Neurological symptoms that... (Review)
Review
Oligodendrogliomas are rare slow-growing asymptomatic glial tumours that usually present in patients in their fourth to sixth decades of life. Neurological symptoms that may present include nausea, headache, vomiting, diplopia, confusion, focal weakness, numbness and seizures. The treatment of oligodendroglioma tumours is based on functional status classification, lumbar puncture, imaging of the head, tumour biopsy and genetic testing. Grades II and IV oligodendroglial tumours, which have co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) and mutations in isocitrate dehydrogenase, have the most favourable prognosis, as they respond well to neurosurgery and chemotherapy. This report will discuss a general case of papilloedema in a young patient with oligodendroglioma and the role of the optometrist in its post-neurosurgical and chemotherapeutic care.
Topics: Adult; Brain Neoplasms; Humans; Magnetic Resonance Imaging; Male; Oligodendroglioma; Papilledema; Tomography, Optical Coherence; Visual Fields
PubMed: 27489047
DOI: 10.1111/cxo.12416 -
Neurobiology of Disease Nov 2023Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of...
Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of patients. DLGG epileptogenicity may primarily be generated by interactions between the tumor and the neocortex. Neuronal uptake of dysfunctional mitochondria from the extracellular environment can lead to abnormal neuronal discharge. Mitochondrial dysfunction is frequently observed in gliomas that can transmigrate across the plasma membranes. Here, we examined the role of the Rho GTPase-activating protein 44 (RICH2) in mitochondrial dynamics and DLGG-related epilepsy. We investigated the association between mitochondrial and RICH2 expression in human DLGG tissues using immunohistochemistry. We examined the association between RICH2 and epilepsy in nude mouse glioma models by electrophysiology. The effect of RICH2 on mitochondrial morphology and calcium motility were assessed by single cell fluorescence microscopy. Quantitative RT-PCR (qRT-PCR) and Western blot analysis were performed to characterize RICH2 induced expression changes in the genes related to mitochondrial dynamics, mitogenesis and mitochondrial function. We found that RICH2 expression was higher in oligodendroglioma than in astrocytoma and was correlated with better prognosis and higher epilepsy rate in patients. The expression of mitochondria may be associated with clinical DLGG-related epilepsy and reduced by RICH2 overexpression. And RICH2 could promote DLGG-related epilepsy in tumorigenic nude mice. RICH2 overexpression decreased calcium flow and the mitochondria released from glioma cells (SW1088 and U251) into the extracellular environment, potentially via downregulation of MFN-1/MFN-2 levels which suggests reduced mitochondrial fusion. In addition, we observed decreased mitochondrial trafficking into neurons (released from glioma cells and trafficked into neurons), which could explain the higher incidence of DLGG-related epilepsy due to reduced neuroprotection. Furthermore, RICH2 downregulated MAPK/ERK/HIF-1 pathway. In conclusion, these results suggest that RICH2 could promote epilepsy by (i) inhibiting mitochondrial fusion via MFN downregulation and Drp-1 upregulation; (ii) altering the MAPK/ERK/Hif-1 signaling axis. RICH2 may be a potential target in the treatment of DLGG-related epilepsy.
Topics: Animals; Mice; Humans; Oligodendroglioma; Calcium; Mice, Nude; Quality of Life; Glioma; Mitochondria; Astrocytoma
PubMed: 37926169
DOI: 10.1016/j.nbd.2023.106344 -
Revue Neurologique Jun 2023This paper reviews 30 years of developments in the area of low-grade gliomas. This includes the changes in diagnostics with the incorporation of 1p/19q and IDH mutations... (Review)
Review
This paper reviews 30 years of developments in the area of low-grade gliomas. This includes the changes in diagnostics with the incorporation of 1p/19q and IDH mutations in the diagnostic classifier, the improved surgical techniques, improved delivery of radiotherapy and chemotherapy. More recently, the better understanding of the altered cellular processes has lead to the development of novel drugs that may alter completely alter the management of patients early in the course of their disease.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Mutation; Glioma; Astrocytoma
PubMed: 37029057
DOI: 10.1016/j.neurol.2023.03.001