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Brain Pathology (Zurich, Switzerland) Jul 2022Over the last decade, developments in molecular profiling have radically altered the diagnosis, classification, and management of numerous cancer types, with primary... (Review)
Review
Over the last decade, developments in molecular profiling have radically altered the diagnosis, classification, and management of numerous cancer types, with primary brain tumors being no exception. Although historically brain tumors have been classified based on their morphological characteristics, recent advances have allowed refinement of tumor classification based on molecular alterations. This shift toward molecular classification of primary brain tumors is reflected in the 2021 5 edition of the WHO classification of central nervous system tumors (WHO 2021). In this review, we will discuss the most recent updates to the classification of adult-type diffuse gliomas, a group of highly infiltrative and largely incurable CNS malignancies. It is our hope continued that refinement of molecular criteria will improve diagnosis, prognostication, and eventually treatment of these devastating tumors.
Topics: Adult; Brain Neoplasms; Central Nervous System Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; World Health Organization
PubMed: 35289001
DOI: 10.1111/bpa.13062 -
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 -
Neuro-oncology Dec 2019The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups...
BACKGROUND
The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification.
METHODS
In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas.
RESULTS
CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas.
CONCLUSIONS
Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Brain Neoplasms; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Cohort Studies; Combined Modality Therapy; Cyclin-Dependent Kinase Inhibitor p16; Female; Follow-Up Studies; Glioma; Homozygote; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Prognosis; Sequence Deletion; Survival Rate; Young Adult
PubMed: 31832685
DOI: 10.1093/neuonc/noz124 -
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 -
Current Neurology and Neuroscience... May 2020Low-grade gliomas (LGG) are a group of primary brain tumors that arise from supporting glial cells. They are characterized by a mutation in the isocitrate dehydrogenase... (Review)
Review
PURPOSE OF REVIEW
Low-grade gliomas (LGG) are a group of primary brain tumors that arise from supporting glial cells. They are characterized by a mutation in the isocitrate dehydrogenase (IDH) enzyme and include astrocytomas and oligodendrogliomas. They usually affect young adults, and their main treatment consists of surgical resection, followed by radiation and chemotherapy in selected patients. This article reviews recent research on the clinical and molecular aspects of the disease and innovative therapeutic modalities in the process.
RECENT FINDINGS
Newly identified clinical and molecular features are currently used in the classification of LGG and applied in treatment-planning decisions. Advanced studies on the cellular level have an advanced understanding of the metabolic effects induced by IDH mutations, offering opportunities for specific targeted therapies that may improve patient outcomes. Such findings may lead to a paradigm shift in the treatment of these tumors. Although LGG are sensitive to radiation and chemotherapy, these therapies are not curative, and patient survival remains limited, raising the need for more creative and effective interventions.
Topics: Astrocytoma; Brain Neoplasms; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Young Adult
PubMed: 32444979
DOI: 10.1007/s11910-020-01040-8 -
Cancers Jan 2023Diffuse infiltrating low-grade glioma (LGG) is classified as WHO grade 2 astrocytoma with isocitrate dehydrogenase (IDH) mutation and oligodendroglioma with IDH1... (Review)
Review
Diffuse infiltrating low-grade glioma (LGG) is classified as WHO grade 2 astrocytoma with isocitrate dehydrogenase (IDH) mutation and oligodendroglioma with IDH1 mutation and 1p/19q codeletion. Despite their better prognosis compared with glioblastoma, LGGs invariably recur, leading to disability and premature death. There is an unmet need to discover new therapeutics for LGG, which necessitates preclinical models that closely resemble the human disease. Basic scientific efforts in the field of neuro-oncology are mostly focused on high-grade glioma, due to the ease of maintaining rapidly growing cell cultures and highly reproducible murine tumors. Development of preclinical models of LGG, on the other hand, has been difficult due to the slow-growing nature of these tumors as well as challenges involved in recapitulating the widespread genomic and epigenomic effects of IDH mutation. The most recent WHO classification of CNS tumors emphasizes the importance of the role of IDH mutation in the classification of gliomas, yet there are relatively few IDH-mutant preclinical models available. Here, we review the in vitro and in vivo preclinical models of LGG and discuss the mechanistic challenges involved in generating such models and potential strategies to overcome these hurdles.
PubMed: 36765553
DOI: 10.3390/cancers15030596 -
Current Neurology and Neuroscience... May 2023Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct type of primary brain tumors with unique characteristics, behavior, and disease outcomes. This article... (Review)
Review
PURPOSE OF REVIEW
Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct type of primary brain tumors with unique characteristics, behavior, and disease outcomes. This article provides a review of standard of care treatment options and innovative, therapeutic approaches that are currently under investigation for these tumors.
RECENT FINDINGS
Extensive pre-clinical data and a variety of clinical studies support targeting IDH mutations in glioma using different mechanisms, which include direct inhibition and immunotherapies that target metabolic and epigenomic vulnerabilities caused by these mutations. IDH mutations have been recognized as an oncogenic driver in gliomas for more than a decade and as a positive prognostic factor influencing the research for new therapeutic methods including IDH inhibitors, DNA repair inhibitors, and immunotherapy.
Topics: Humans; Isocitrate Dehydrogenase; Brain Neoplasms; Glioma; Mutation; Immunotherapy
PubMed: 37060388
DOI: 10.1007/s11910-023-01265-3