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Project description:Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable, non-NF1-associated, hypothalamic/optic pathway PA. Tumors were classified as low- (6.9%), intermediate- (43.1%), and high-risk (50%) based on their response to treatment. High-risk tumors were defined as those that progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue, and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in pilocytic astrocytoma, such as MAPK and PI3K/AKT/mTOR, were also enriched, as well as pathways related to mitochondrial biogenesis and oxidative phosphorylation. 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 in hypothalamic/optic pathway PA, highlighting potential new targets for combination therapy and refining disease prognosis.
2022-12-21 | GSE199358 | GEO
Project description:Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable, non-NF1-associated, hypothalamic/optic pathway PA. Tumors were classified as low- (6.9%), intermediate- (43.1%), and high-risk (50%) based on their response to treatment. High-risk tumors were defined as those that progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue, and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in pilocytic astrocytoma, such as MAPK and PI3K/AKT/mTOR, were also enriched, as well as pathways related to mitochondrial biogenesis and oxidative phosphorylation. 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 in hypothalamic/optic pathway PA, highlighting potential new targets for combination therapy and refining disease prognosis.
2022-12-21 | GSE199361 | GEO
Project description:INTRODUCTION:Pilocytic astrocytoma (PA) is the most common primary brain neoplasm in children and treated in curative intent with gross total resection (GTR). However, PA is rare in adults, resulting in limited knowledge on the natural clinical course. This study aimed to describe the clinical course and identify prognostic factors of adult patients with PA. METHODS:46 patients???18 years at diagnosis of PA and neurosurgical resection or biopsy between 2000 and 2018 were identified from the Neuro-Biobank of the Medical University of Vienna. In two cases with differing histopathological diagnosis at recurrence, DNA methylation analysis was performed using Illumina Infinium HumanMethylation850 BeadChip (850 k) arrays and the Molecular Neuropathology classifier. Clinico-pathological features were correlated with patient outcomes. RESULTS:Median age at diagnosis was 32.5 years (range: 19-75) and median Ki67 proliferation index was 2.8% (0.5-13.4%). Tumor location significantly correlated with resectability (p?<?0.001). Tumor progression or recurrence was observed in 9/46 (19.6%) patients after a median follow up time of 53.0 months (range 0.5-300). 5-year overall and progression-free survival rates were 85.3% and 70.0%, respectively. 2/9 (22.2%) patients presented with histological changes in the recurrent tumor specimen. In detail, methylation classification redefined the histological diagnosis to anaplastic astrocytoma with piloid features and glioma in one patient, each. Age?>?40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p?<?0.05). CONCLUSIONS:Tumor recurrence or progression in adult PA patients was higher than the one reported in pediatric patients. Higher age and BMI were associated with impaired prognosis.
| S-EPMC7280326 | biostudies-literature
Project description:Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions.
| S-EPMC3350769 | biostudies-literature
Project description:Genome wide DNA methylation profiling of 79 histologically diagnosed pilocytic astrocytoma (PA) in adults, of which we were able to upload 71 samples. The methylation profiling indicates that many of the histologically diagnosed PA do not show a concordant methylation classification.
2024-01-01 | GSE244566 | GEO
Project description:Pilocytic astrocytomas (PAs) are the most common glioma in children. While many PAs are slow growing or clinically indolent, others exhibit more aggressive features with tumor recurrence and death. In order to identify genetic signatures that might predict PA clinical behavior, we performed gene expression profiling on 41 primary PAs arising sporadically and in patients with neurofibromatosis type 1 (NF1). While no expression signature was found that could discriminate clinically-aggressive or recurrent tumors from more indolent cases, PAs arising in patients with NF1 did exhibit a unique gene expression pattern. In addition, we identified a gene expression signature that stratified PAs by location (supratentorial versus infratentorial). Keywords: Human, WHO grade I, Brain tumor, Pilocytic astrocytoma, NF1
2007-03-14 | GSE5675 | GEO
Project description:Pilocytic astrocytomas (PAs) are the most common glioma in children. While many PAs; are slow growing or clinically indolent, others exhibit more aggressive features with tumor; recurrence and death. In order to identify genetic signatures that might predict PA clinical; behavior, we performed gene expression profiling on 41 primary PAs arising sporadically and in; patients with neurofibromatosis type 1 (NF1). While no expression signature was found that; could discriminate clinically-aggressive or recurrent tumors from more indolent cases, PAs; arising in patients with NF1 did exhibit a unique gene expression pattern. In addition, we; identified a gene expression signature that stratified PAs by location (supratentorial versus; infratentorial). Experiment Overall Design: 41 pilocytic astrocytoma samples were analyzed.
| S-ECPF-GEOD-5675 | biostudies-other
Project description:Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5' gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAFWT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.
| S-EPMC5407815 | biostudies-literature
Project description:Optic nerve astrocytomas (ONAs) are frequent types of optic nerve gliomas (ONGs), which can affect the visual pathway. An 18-year-old male patient was admitted to our department with right-sided intraorbital/retrobulbar swelling, which progressively grew over several months. Clinical examination showed right-sided diplopia, mydriasis, low visual acuity (0.4), exophthalmus (3?cm), epiphora, and severe retrobulbar pain. There was a family history of high-grade (IV) astrocytomas in which two of the family members died due to the disease. Preoperative MRI scan revealed a soft tissue mass around the retrobulbar area of the right eye with intact orbital bony walls. Surgery was performed whereby it was dissected freely from the muscles and was separated from the optic nerve and the globe. Histopathologic analysis confirmed a benign astrocytoma. The follow-up examination revealed no recurrent or residual tumor. A systemic review of the literature indicates that early diagnosis and experienced multidisciplinary management are required in case of unilateral, resectable forms of ONAs with no distant metastasis, in order to provide a long-time survival of patients. Surgical intervention of unilateral ONAs is a relatively safe procedure, allowing complete or partial tumor removal with minimal morbidity and low recurrence rate.
| S-EPMC5733200 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.pone.0175638.].
| S-EPMC5589245 | biostudies-literature