The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma
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PROVIDER: PRJNA819454 | ENA |
REPOSITORIES: ENA
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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 | GSE199361 | 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 | GSE199358 | GEO
Project description:The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma [850k array]
| PRJNA819453 | ENA
Project description:The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma [RNA-Seq]
| PRJNA819451 | ENA
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 astrocytoma is the most common type of brain tumor in pediatric population, generally connected with favorable prognosis, although recurrences or dissemination sometimes are also observed. For tumors originating in supra- or infratentorial location different molecular background was suggested but plausible correlations between transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features and clinical pattern of the disease. According to the radiological features presented on MRI, all cases were divided into four subtypes: solid or mainly solid, cystic with an enhancing cyst wall, cystic with a non-enhancing cyst wall and solid with central necrosis. Bioinformatic analyses showed that gene expression profile of pilocytic astrocytoma highly depends on the tumor location. Most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression which could distinguish pilocytic astrocytomas of different location even within supratentorial region. Analysis of the genes potentially associated between radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression. Here we showed that pilocytic astrocytomas of three different locations could be precisely differentiated on the basis of gene expression level but their transcriptional profiles did not strongly reflect the radiological appearance of the tumor or the course of the disease. Gene expression profiling was performed in 47 pilocytic astrocytoma tumours characterized by different localization, radiology and progression.
2015-10-30 | E-GEOD-73066 | biostudies-arrayexpress
Project description:BackgroundUnresectable 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.MethodsWe 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).ResultsThe 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.ConclusionsWe 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.
| S-EPMC10076943 | biostudies-literature
Project description:Pilocytic astrocytoma is the most common type of brain tumor in pediatric population, generally connected with favorable prognosis, although recurrences or dissemination sometimes are also observed. For tumors originating in supra- or infratentorial location different molecular background was suggested but plausible correlations between transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features and clinical pattern of the disease. According to the radiological features presented on MRI, all cases were divided into four subtypes: solid or mainly solid, cystic with an enhancing cyst wall, cystic with a non-enhancing cyst wall and solid with central necrosis. Bioinformatic analyses showed that gene expression profile of pilocytic astrocytoma highly depends on the tumor location. Most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression which could distinguish pilocytic astrocytomas of different location even within supratentorial region. Analysis of the genes potentially associated between radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression. Here we showed that pilocytic astrocytomas of three different locations could be precisely differentiated on the basis of gene expression level but their transcriptional profiles did not strongly reflect the radiological appearance of the tumor or the course of the disease.
2015-10-30 | GSE73066 | GEO
Project description:Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.
2023-10-24 | PXD035773 | Pride
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