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Nature Genetics Aug 2013Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically...
Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
Topics: Animals; Astrocytoma; Base Sequence; Brain Neoplasms; Cell Line; Cell Transformation, Neoplastic; Chromosome Breakpoints; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 9; Fibroblast Growth Factors; Humans; MAP Kinase Signaling System; Mice; Models, Molecular; Mutation; Oncogene Proteins, Fusion; Protein Conformation; Proto-Oncogene Proteins B-raf; Receptor, Fibroblast Growth Factor, Type 1; Receptor, trkB
PubMed: 23817572
DOI: 10.1038/ng.2682 -
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 -
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 -
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 -
BMJ Case Reports Mar 2016
Topics: Adult; Astrocytoma; Brain Neoplasms; Confusion; Female; Humans; Neoplasm Recurrence, Local; Paresis; Temporal Lobe
PubMed: 27033282
DOI: 10.1136/bcr-2015-213013 -
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 -
Child's Nervous System : ChNS :... Nov 2016The purpose of this review is to document the various types of astrocytoma that occur in the fetus and neonate, their locations, initial findings, pathology, and... (Review)
Review
INTRODUCTION
The purpose of this review is to document the various types of astrocytoma that occur in the fetus and neonate, their locations, initial findings, pathology, and outcome. Data are presented that show which patients are likely to survive or benefit from treatment compared with those who are unlikely to respond.
MATERIALS AND METHODS
One hundred one fetal and neonatal tumors were collected from the literature for study.
RESULTS
Macrocephaly and an intracranial mass were the most common initial findings. Overall, hydrocephalus and intracranial hemorrhage were next. Glioblastoma (GBM) was the most common neoplasm followed in order by subependymal giant cell astrocytoma (SEGA), low-grade astrocytoma, anaplastic astrocytoma, and desmoplastic infantile astrocytoma (DIA). Tumors were detected most often toward the end of the third trimester of pregnancy.
CONCLUSION
A number of patients were considered inoperable since their tumor occupied much of the intracranial cavity involving large areas of the brain. High-grade astrocytomas were more common than low-grade ones in this review. Fetuses and neonates with astrocytoma have a mixed prognosis ranging from as low as 20 % (GBM) to a high of 90 %. The overall survival was 47/101 or 46 %.
Topics: Astrocytoma; Brain Neoplasms; Female; Fetus; Humans; Infant, Newborn; Pregnancy
PubMed: 27568373
DOI: 10.1007/s00381-016-3215-y -
Neurology India 2022Intraventricular pilocytic astrocytomas are a rare occurrence, accounting for approximately 4% -15.6% of all pilocytic astrocytomas .The aim of the study was to describe...
BACKGROUND
Intraventricular pilocytic astrocytomas are a rare occurrence, accounting for approximately 4% -15.6% of all pilocytic astrocytomas .The aim of the study was to describe the radiology, surgical management and outcome in 15 patients with histopathologically proven intraventricular pilocytic astrocytoma(IVPA).
OBJECTIVE
To study the clinical presentation radiology and operative challenges in rare intra ventricular pilocytic astrocytomas.
MATERIALS AND METHODS
Between January 2010 and August 2018, 15 patients with histopathologically proven IVPA were identified. The radiological images were obtained from PACS. Patient and surgical details were obtained from the computerized discharge summary, OT records and operative notes, whereas follow up was obtained from the record section.
RESULTS
Headache with progressive loss of vision was the most common presentation. Duration of symptoms varied from 4 months to 2 years (mean 9. 88 months). Except one patient, all patients with preoperative CT scan revealed calcifications in the lesion, with extensive calcification in 3 patients. All the tumors were predominantly hypointense on T1WI and iso to hyperintense on T2WI. Lesion in all patients showed heterogenous contrast enhancement on post gadolinium images. Mean blood loss in the series was 1969 ml (range 250 ml- 4500 ml).There was one death in this series due to meningitis and septic shock.
CONCLUSION
IVPAs are rare tumors and are difficult to diagnose in the preoperative period based on the radiologic profile alone. These tumors can be extremely vascular with potential for massive blood loss. These tumors can be associated with extensive calcification and the calcified tumors have less bleeding as expected.
Topics: Astrocytoma; Brain Neoplasms; Calcinosis; Gadolinium; Humans; Tomography, X-Ray Computed
PubMed: 36076645
DOI: 10.4103/0028-3886.355185 -
Hematology/oncology Clinics of North... Feb 2022Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial... (Review)
Review
Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial tumors include a wide spectrum of tumors with differences in prognosis and recommended therapeutic approaches. Tumors characterized as molecular glioblastoma in the World Health Organization 2021 classification should be treated according to the glioblastoma therapeutic principles and included in glioblastoma trials. Improving on existing treatments options including targeted and immunotherapy approaches is imperative for most patients with IDH wild-type glial tumors, and enrollment in clinical trials is encouraged.
Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Oligodendroglioma
PubMed: 34756799
DOI: 10.1016/j.hoc.2021.08.007