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Neuro-oncology Oct 2023Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic...
BACKGROUND
Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the 3 most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas.
METHODS
We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176 645 cells as a reference for an in-depth comparison to 4416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques.
RESULTS
We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study.
CONCLUSION
Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin."
Topics: Child; Humans; Animals; Mice; Medulloblastoma; Brain Neoplasms; Glioma; Astrocytoma; Ependymoma; Cerebellum; Cerebellar Neoplasms
PubMed: 37534924
DOI: 10.1093/neuonc/noad124 -
Neuro-oncology Dec 2022In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare...
In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.
Topics: Child; Adolescent; Young Adult; Humans; Glioma; Brain Neoplasms; Proto-Oncogene Proteins B-raf; Astrocytoma; Ganglioglioma
PubMed: 35908833
DOI: 10.1093/neuonc/noac188 -
Acta Neuropathologica Oct 2022Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or...
Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.
Topics: Adult; Astrocytoma; Brain Neoplasms; Glioma; Homozygote; Humans; Neurofibromatosis 1; Sequence Deletion
PubMed: 35945463
DOI: 10.1007/s00401-022-02478-5 -
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 -
Acta Neuropathologica Aug 2018Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular...
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Histones; Humans; Infant; Isocitrate Dehydrogenase; Kaplan-Meier Estimate; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Retrospective Studies; Signal Transduction; Tumor Suppressor Proteins; X-linked Nuclear Protein; Young Adult
PubMed: 29564591
DOI: 10.1007/s00401-018-1837-8 -
CNS Oncology Jul 2016Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification... (Review)
Review
Anaplastic astrocytoma (AA) is a diffusely infiltrating, malignant, astrocytic, primary brain tumor. AA is currently defined by histology although future classification schemes will include molecular alterations. AA can be separated into subgroups, which share similar molecular profiles, age at diagnosis and median survival, based on 1p/19q co-deletion status and IDH mutation status. AA with co-deletion of chromosomes 1p and 19q and IDH mutation have the best prognosis. AA with IDH mutation and no 1p/19q co-deletion have intermediate prognosis and AA with wild-type IDH have the worst prognosis and share many molecular alterations with glioblastoma. Treatment of noncodeleted AA based on preliminary results from the CATNON clinical trial consists of maximal safe resection followed by radiotherapy with post-radiotherapy temozolomide (TMZ) chemotherapy. The role of concurrent TMZ and whether IDH1 subgroups benefit from TMZ is currently being evaluated in the recently completed randomized, prospective Phase III clinical trial, CATNON.
Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Humans; Isocitrate Dehydrogenase; Mutation
PubMed: 27230974
DOI: 10.2217/cns-2016-0002 -
BMJ Case Reports Aug 2016Psychotic symptoms are rarely documented in association with cortex-sparing central nervous system (CNS) lesions limited to the midbrain. We present the case of a... (Review)
Review
Psychotic symptoms are rarely documented in association with cortex-sparing central nervous system (CNS) lesions limited to the midbrain. We present the case of a 15-year-old boy with hereditary and environmental risk factors for psychiatric illness, as well as a history of midbrain pilocytic astrocytoma treated with chemotherapy and focused radiation, who presented with non-epileptic seizures, hyper-religiosity and frank psychosis. The space-occupying midbrain lesion has been radiographically stable while the patient has decompensated psychiatrically. Differential aetiology for the patient's psychiatric decompensation is discussed, including psychosis secondary to a lesion of the midbrain. Literature linking midbrain lesions to psychotic features, such as in peduncular hallucinosis, is briefly reviewed. This case suggests that a midbrain lesion in a susceptible patient may contribute to psychosis.
Topics: Adolescent; Astrocytoma; Brain Stem Neoplasms; Humans; Male; Psychotic Disorders
PubMed: 27511753
DOI: 10.1136/bcr-2016-216165 -
Neuro-oncology Apr 2023
Topics: Humans; Senotherapeutics; Astrocytoma; Brain
PubMed: 36702510
DOI: 10.1093/neuonc/noad016 -
Acta Neuropathologica Mar 2020
Topics: Astrocytoma; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Mutation; Neoplasm Grading; Terminology as Topic; World Health Organization
PubMed: 31996992
DOI: 10.1007/s00401-020-02127-9 -
Cells Jun 2022Glioblastoma (GBM, grade IV astrocytoma), the most frequently occurring primary brain tumor, presents unique challenges to therapy due to its location, aggressive...
Glioblastoma (GBM, grade IV astrocytoma), the most frequently occurring primary brain tumor, presents unique challenges to therapy due to its location, aggressive biological behavior, and diffuse infiltrative growth, thus contributing to having disproportionately high morbidity and mortality [...].
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Humans; Molecular Biology
PubMed: 35681545
DOI: 10.3390/cells11111850