Aggressive human MenG C meningiomas have a molecular counterpart in canines
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ABSTRACT:
PROVIDER: PRJNA1053343 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27226000_1.fastq.gz | Fastqsanger.gz | |||
| SRR27226000_2.fastq.gz | Fastqsanger.gz | |||
| SRR27226001_1.fastq.gz | Fastqsanger.gz | |||
| SRR27226001_2.fastq.gz | Fastqsanger.gz | |||
| SRR27226002_1.fastq.gz | Fastqsanger.gz |
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Project description:We found that canine meningiomas can be classified molecularly, and the aggressive group of tumors in canines is similar to human MenG C tumors. This aggressive class exhibits chromosomal instability, cell cycle activation, and increased MKI67 expression. Further studies of canine meningiomas in larger cohorts might help advance treatment options for both canines and humans.
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Project description:Meningiomas are typically considered a benign tumor that can be cured by complete surgical resection; however, a percentage of patients have recurrent disease, even after apparently complete resections. These patients require additional surgeries, radiation therapy, chemotherapy, or a combination of all three. The ability to recognize these patients prior to recurrence would promote earlier use of adjuvant therapy, thus improving overall patient outcome. Unfortunately, identification of meningiomas with this more aggressive phenotype is difficult, and standard histopathological techniques rarely suffice. The identification of genetic and molecular parameters that can help to define these more aggressive tumors would improve prognostication and treatment planning for patients with meningiomas. 1. Establish gene profiles for benign (grade 1) and aggressive (grades 2 and 3) meningiomas. 2. Determine if there are particular expression profiles that can help differentiate between benign and aggressive meningiomas. 3. Determine if there is/are specific gene(s) whose expression is/are altered in benign vs aggressive tumors. 4. Determine if there is a correlation between specific genetic abnormalities in these tumors (as analyzed by fluorescent in situ hybridization; FISH) and gene expression profiles. Our overall hypothesis is that there are molecular and biochemical changes that can be used to identify meningiomas that will have a more aggressive clinical course. Specific Aims 1 and 2: RNA from flash frozen or RNA-later preserved tissue (from all three grades of meningiomas) has been used for RNA isolation using standard protocols. RNA quantity has been determined using a RiboGreen RNA quantitation Kit (Molecular Probes), and RNA quality has been demonstrated using standard formaldehyde gels. These samples will be sent to the NINDS/NIMH microarray consortium for Affymetrix microarray analyses. Data analysis will be done using GeneSpring software (Silicon Genetics, Inc.) with assistance from consortium personnel. Specific Aim 3: Differentially expressed genes identified through microarray analyses will be analyzed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Real time qRT-PCR is a standard technique used in our laboratory for gene expression analysis. Specific Aim 4: FISH analyses of paraffin-embedded tissue has been completed for 77 tumors. We have frozen tissue from a number of these patients. RNA from these samples will be used for microarray analyses (Specific Aims 1-3). The results of Speicifc Aims 1 and 2 will affect how we perform our correlation analyses. This will be done with the assistance of contracted statistical personnel.
2008-06-12 | E-GEOD-4039 | biostudies-arrayexpress
Project description:Meningiomas represent one of the most common and clinically heterogeneous brain tumor types that only modestly correlate with histopathologic features. While emerging molecular profiling efforts have linked specific genomic drivers to distinct clinical patterns, the proteomic landscape of meningiomas remains largely unexplored. We utilize mass spectrometry to profile a clinically well-annotated cohort (n=69) of meningiomas stratified to span all three World Health Organization (WHO) grades and various degrees of clinical aggressiveness. In total, we quantify 3042 unique proteins and compare the patterns across different clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic (n=106 proteins, Welch’s t-test, P<0.01) and pathway-level (e.g. Notch and PI3K/AKT/mTOR) differences between convexity and skull base meningiomas. Supervised comparative analyses of different pathological grades revealed distinct patterns between benign (WHO Grade I) and atypical/malignant (WHO Grade II and III) meningiomas with classic oncogenes often enriched in higher grade lesions. Independent of WHO grade, clinically aggressive meningiomas, that rapidly recurred, also had distinctive protein patterns that converged on mRNA processing and impaired activation of the extracellular matrix naba matrisome complex. Larger sized meningiomas, and those with previous radiation exposure, also had distinct protein profiles. Collectively, we highlight distinct clinically-dependent proteomic patterns of meningiomas that may help better predict outcome and guide the development of more personalized and directed therapies.
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Project description:Meningiomas are frequent central nervous system tumors. Although most meningiomas are benign (WHO grade I) and curable by surgery, WHO grade II and III tumors remain therapeutically challenging due to frequent recurrence. Interestingly, relapse also occurs in some WHO grade I meningiomas. Hence, we investigated the transcriptional features defining aggressive (recurrent, malignantly progressing or WHO grade III) meningiomas in 144 cases. Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M) in addition to their WHO grade. Unsupervised transcriptomic analysis in 62 meningiomas revealed transcriptional profiles lining up according to WHO grade and clinical subgroup. Notably aggressive subgroups (R+M tumors and WHO grade III) shared a large set of differentially expressed genes (n=332; p<0.01, FC>1.25). In an independent multicenter validation set (n=82), differential expression of 10 genes between WHO grades was confirmed. Additionally, among WHO grade I tumors differential expression between NR and aggressive R+M tumors was af rmed for PTTG1, AURKB, ECT2, UBE2C and PRC1, while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors. Univariate survival analysis revealed a significant association with progression-free survival for PTTG1, LEPR, MN1, ECT2, PRC1, COX10, UBE2C expression, while multivariate analysis identified a prediction for PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. Finally, stainings of PTTG1 and LEPR confirmed malignancy-associated protein expression changes. In conclusion, based on the so far largest study sample of WHO grade III and recurrent meningiomas we report a comprehensive transcriptional landscape and two prognostic markers. Comparative transcriptomic analysis of 62 low- and high-grade meningiomas
2016-02-15 | E-GEOD-74385 | biostudies-arrayexpress
Project description:Meningiomas are frequent central nervous system tumors. Although most meningiomas are benign (WHO grade I) and curable by surgery, WHO grade II and III tumors remain therapeutically challenging due to frequent recurrence. Interestingly, relapse also occurs in some WHO grade I meningiomas. Hence, we investigated the transcriptional features defining aggressive (recurrent, malignantly progressing or WHO grade III) meningiomas in 144 cases. Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M) in addition to their WHO grade. Unsupervised transcriptomic analysis in 62 meningiomas revealed transcriptional profiles lining up according to WHO grade and clinical subgroup. Notably aggressive subgroups (R+M tumors and WHO grade III) shared a large set of differentially expressed genes (n=332; p<0.01, FC>1.25). In an independent multicenter validation set (n=82), differential expression of 10 genes between WHO grades was confirmed. Additionally, among WHO grade I tumors differential expression between NR and aggressive R+M tumors was af rmed for PTTG1, AURKB, ECT2, UBE2C and PRC1, while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors. Univariate survival analysis revealed a significant association with progression-free survival for PTTG1, LEPR, MN1, ECT2, PRC1, COX10, UBE2C expression, while multivariate analysis identified a prediction for PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. Finally, stainings of PTTG1 and LEPR confirmed malignancy-associated protein expression changes. In conclusion, based on the so far largest study sample of WHO grade III and recurrent meningiomas we report a comprehensive transcriptional landscape and two prognostic markers.
2016-02-15 | GSE74385 | GEO
Project description:Meningiomas account for roughly one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular groups that reliably predicted clinical severity. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular group as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, resulting in cell cycle activation, and only tumors in this group tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.
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Project description:Aims: Whereas recent molecular analysis has revealed that sporadic meningioma has various genetic, epigenetic, and transcriptomic profiles, those of meningioma in NF2 patients are not fully elucidated. This study probed meningiomas' clinical, histological, and molecular characteristics in NF2 patients. Methods: A long-term retrospective follow-up (13.5 ± 5.5 years) study involving 159 meningiomas in NF2 patients was performed. We assessed their characteristics by performing immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in NF2 patients were compared with those of 189 sporadic NF2-altered meningiomas. Results: Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/yr. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade 1 meningiomas in NF2 patients` were more frequent than in sporadic NF2-altered meningiomas (92.9% vs 80.9%). Transcriptomic analysis for NF2 patients`/sporadic NF2-altered WHO grade 1 meningiomas (n = 14 versus 15, respectively) showed that tumours in NF2 patients had still higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this higher immune response by identifying myeloid cell infiltration, especially macrophages. Conclusions: Clinical, histological, and transcriptomic analyses for meningiomas in NF2 patients demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited marked immune response by identifying myeloid cell infiltration, especially macrophages.
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Project description:Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, histopathologic analysis has poor predictive value for malignant behavior and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increased histopathologic grade suggesting progressive epigenetic dysregulation is associated with increasing tumor aggressiveness. These findings are a starting point for future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in early stages of meningioma formation as well as studies of the utility of polycomb inhibitors for treatment of aggressive meningiomas.
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Project description:Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, histopathologic analysis has poor predictive value for malignant behavior and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increased histopathologic grade suggesting progressive epigenetic dysregulation is associated with increasing tumor aggressiveness. These findings are a starting point for future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in early stages of meningioma formation as well as studies of the utility of polycomb inhibitors for treatment of aggressive meningiomas.
2023-06-22 | GSE176457 | GEO