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International Journal of Molecular... Nov 2020Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard... (Review)
Review
Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women's brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas.
Topics: Animals; Astrocytoma; Disease Progression; Female; Hormones; Humans; Male; Models, Biological; Receptors, Steroid; Sex Characteristics
PubMed: 33266110
DOI: 10.3390/ijms21239114 -
Neuro-oncology Apr 2023
Topics: Humans; Senotherapeutics; Astrocytoma; Brain
PubMed: 36702510
DOI: 10.1093/neuonc/noad016 -
Neuro-oncology Apr 2023Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of...
BACKGROUND
Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment.
METHODS
We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC).
RESULTS
The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function.
CONCLUSIONS
We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication.
Topics: Humans; Male; Child, Preschool; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Tumor Suppressor Protein p53; Astrocytoma; TOR Serine-Threonine Kinases; Brain Neoplasms; Proto-Oncogene Proteins B-raf
PubMed: 36260562
DOI: 10.1093/neuonc/noac241 -
CNS Oncology Mar 2021Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the... (Review)
Review
Adult pilocytic astrocytoma (PA) is less prevalent than pediatric PA and is associated with a worse prognosis. In a literature review, we found that 88.3% of the molecular alterations in adult PA are associated with MAPK pathway dysregulation. The most common alterations are fusions of . Understanding of the mechanisms underlying this pathway has evolved substantially, heralding advancements in specific targeted therapy. Here, we review clinical and molecular features of adult PA, characteristics predicting aggressive behavior and approaches to standard and investigational therapies. We highlight epigenetic profiling and integrated diagnosis as an essential component of classifying PA.
Topics: Adult; Astrocytoma; Brain Neoplasms; Child; Humans; Prognosis; Proto-Oncogene Proteins B-raf
PubMed: 33448230
DOI: 10.2217/cns-2020-0027 -
Neuro-oncology Sep 2020Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. While genome and transcriptome landscapes are well studied, data of the complete methylome, tumor...
BACKGROUND
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. While genome and transcriptome landscapes are well studied, data of the complete methylome, tumor cell composition, and immune infiltration are scarce.
METHODS
We generated whole genome bisulfite sequence (WGBS) data of 9 PAs and 16 control samples and integrated available 154 PA and 57 control methylation array data. RNA sequence data of 49 PAs and 11 control samples as well as gene expression arrays of 248 PAs and 28 controls were used to assess transcriptional activity.
RESULTS
DNA-methylation patterns of partially methylated domains suggested high stability of the methylomes during tumorigenesis. Comparing tumor and control tissues of infra- and supratentorial location using methylation arrays revealed a site specific pattern. Analysis of WGBS data revealed 9381 significantly differentially methylated regions (DMRs) in PA versus control tissue. Enhancers and transcription factor (TF) motifs of five distinct TF families were found to be enriched in DMRs. Methylation together with gene expression data-based in silico tissue deconvolution analysis indicated a striking variation in the immune cell infiltration in PA. A TF network analysis showed a regulatory relation between basic leucine zipper (bZIP) transcription factors and genes involved in immune-related processes.
CONCLUSION
We provide evidence for a link of focal methylation differences and differential gene expression to immune infiltration.
Topics: Astrocytoma; Basic-Leucine Zipper Transcription Factors; Child; DNA Methylation; Demethylation; Humans; Immunity
PubMed: 32052037
DOI: 10.1093/neuonc/noaa035 -
Acta Neuropathologica Jun 2015Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year... (Review)
Review
Pilocytic astrocytomas (PAs) were recognized as a discrete clinical entity over 70 years ago. They are relatively benign (WHO grade I) and have, as a group, a 10-year survival of over 90%. Many require merely surgical removal and only very infrequently do they progress to more malignant gliomas. While most show classical morphology, they may present a spectrum of morphological patterns, and there are difficult cases that show similarities to other gliomas, some of which are malignant and require aggressive treatment. Until recently, almost nothing was known about the molecular mechanisms involved in their development. The use of high-throughput sequencing techniques interrogating the whole genome has shown that single abnormalities of the mitogen-activating protein kinase (MAPK) pathway are exclusively found in almost all cases, indicating that PA represents a one-pathway disease. The most common mechanism is a tandem duplication of a ≈2 Mb-fragment of #7q, giving rise to a fusion between two genes, resulting in a transforming fusion protein, consisting of the N-terminus of KIAA1549 and the kinase domain of BRAF. Additional infrequent fusion partners have been identified, along with other abnormalities of the MAP-K pathway, affecting tyrosine kinase growth factor receptors at the cell surface (e.g., FGFR1) as well as BRAF V600E, KRAS, and NF1 mutations among others. However, while the KIAA1549-BRAF fusion occurs in all areas, the incidence of the various other mutations identified differs in PAs that develop in different regions of the brain. Unfortunately, from a diagnostic standpoint, almost all mutations found have been reported in other brain tumor types, although some retain considerable utility. These molecular abnormalities will be reviewed, and the difficulties in their potential use in supporting a diagnosis of PA, when the histopathological findings are equivocal or in the choice of individualized therapy, will be discussed.
Topics: Astrocytoma; Central Nervous System Neoplasms; Genetic Predisposition to Disease; Humans; Models, Molecular; Molecular Biology; Neuroimaging
PubMed: 25792358
DOI: 10.1007/s00401-015-1410-7 -
Medicine Nov 2022This study aimed to evaluate the diagnostic performance of dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging and apparent diffusion coefficient...
This study aimed to evaluate the diagnostic performance of dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging and apparent diffusion coefficient (ADC) for differentiating common posterior fossa tumors, pilocytic astrocytoma (PA), medulloblastoma (MB), and hemangioblastoma (HB). Between January 2016 and April 2022, we enrolled 23 (median age, 7 years [range, 2-26]; 12 female), 13 (10 years [1-24]; 3 female), and 12 (43 years [23-73]; 7 female) patients with PA, MB, and HB, respectively. Normalized relative cerebral blood volume and flow (nrCBV and nrCBF) and normalized mean ADC (nADCmean) were calculated from volume-of-interest and statistically compared. nADCmean was significantly higher in PA than in MB (PA: median, 2.2 [range, 1.59-2.65] vs MB: 0.93 [0.70-1.37], P < .001). nrCBF was significantly higher in HB than in PA and MB (PA: 1.10 [0.54-2.26] vs MB: 1.62 [0.93-3.16] vs HB: 7.83 [2.75-20.1], all P < .001). nrCBV was significantly different between all 3 tumor types (PA: 0.89 [0.34-2.28] vs MB: 1.69 [0.93-4.23] vs HB: 8.48 [4.59-16.3], P = .008 for PA vs MB; P < .001 for PA vs HB and MB vs HB). All tumors were successfully differentiated using an algorithmic approach with a threshold value of 4.58 for nrCBV and subsequent threshold value of 1.38 for nADCmean. DSC parameters and nADCmean were significantly different between PA, MB, and HB. An algorithmic approach combining nrCBV and nADCmean may be useful for differentiating these tumor types.
Topics: Humans; Female; Child; Medulloblastoma; Hemangioblastoma; Retrospective Studies; Diagnosis, Differential; Astrocytoma; Magnetic Resonance Imaging; Diffusion Magnetic Resonance Imaging; Perfusion; Cerebellar Neoplasms; Brain Neoplasms
PubMed: 36343086
DOI: 10.1097/MD.0000000000031708 -
Neuro-oncology Oct 2021Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult... (Review)
Review
Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pLGGs and an incomplete understanding of their molecular and cellular pathogenesis. While large-scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA), in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.
Topics: Astrocytoma; Brain Neoplasms; Child; Glioma; Humans; MAP Kinase Signaling System; Signal Transduction
PubMed: 34131743
DOI: 10.1093/neuonc/noab138 -
JCO Precision Oncology Apr 2022
Topics: Astrocytoma; Humans; Morpholines; Mutation; Pyrimidines; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1
PubMed: 35507888
DOI: 10.1200/PO.21.00371 -
Brain Pathology (Zurich, Switzerland) Sep 2023Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and...
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
Topics: Child; Female; Humans; Adaptor Proteins, Vesicular Transport; Astrocytoma; Brain Neoplasms; Ganglioglioma; Glioma; Oncogene Fusion
PubMed: 37399073
DOI: 10.1111/bpa.13185