A novel modeling of high-grade transformation in IDH mutant glioma
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ABSTRACT:
PROVIDER: PRJNA1110217 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28991982_1.fastq.gz | Fastqsanger.gz | |||
| SRR28991982_2.fastq.gz | Fastqsanger.gz | |||
| SRR28991983_1.fastq.gz | Fastqsanger.gz | |||
| SRR28991983_2.fastq.gz | Fastqsanger.gz | |||
| SRR28991984_1.fastq.gz | Fastqsanger.gz |
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Project description:Background. High-grade transformation (HT) is a key feature of IDH-mutant glioma, which is inevitable and unpredictable. Both genomic and metabolomic landscapes are going through dynamic processes during the transformation. Although HT phenomena have been observed clinically, the research of mechanisms underlying HT have been limited by the lack of in vitro models that can recapitulate the evolution of malignant transformation. Methods. Here we established a unique pair of cell lines that was generated using tumor samples from the same patient at different stages of the disease. 403L cell line was obtained when patient’s tumor was astrocytoma, WHO grade 2 and 403H cell line was obtained when the tumor was transformed to astrocytoma, WHO grade 4. Using genomic, transcriptomic, and metabolomic analyses, the two cell models have been characterized extensively. The cell lines have been used to establish orthotopic xenograft models of the disease.
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Project description:Background. High-grade transformation (HT) is common in IDH-mutant glioma, which is inevitable and unpredictable. Both genomic and metabolomic landscapes are going through dynamic processes during the transformation. Although HT phenomena have been observed clinically, the research of mechanisms underlying HT have been limited by the lack of preclinical models that can recapitulate the evolution of malignant transformation. Methods. Here we established a unique pair of matched cell lines, 403L and 403H, by utilizing tumor samples of an IDH-mutant astrocytoma from the same patient when the tumor was diagnosed as WHO grade 2 and 4, respectively. Using genetic, epigenetic, and metabolomic analyses, the two cell models have been characterized extensively. The cell lines have been used to establish orthotopic xenograft models of the disease.
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Project description:A novel model for high-grade transformation in IDH mutant glioma (Methylation Analysis)
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Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage. 80 tumor samples, one normal tissue sample (brain)
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Project description:Gliomas are the most common primary brain tumor in humans. Low-grade gliomas (WHO grade II) invariably progress to high-grade gliomas (WHO grade III or IV). Although malignant progression may take many years, the survival rate after transformation to a high-grade glioma is poor, often only 12-15 months. In this data set, we have identified low-grade gliomas that have progressed to high-grade gliomas or high-grade gliomas that have progressed from low-grade gliomas. Some cases are matched pairs (meaning we have both the original low-grade tumor and the subsequent high-grade tumor). The samples deposited have been analyzed with bulk-RNA sequencing. They are also de-identified but are clinically annotated. When available, genetic information including IDH mutation status, 1p/19q deletion and histological subtype are also included.
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Project description:RNA-sequencing for myeloid inflammation-related genes was conducted on primary tumor samples from patients with IDH-wildtype glioblastoma (GBM) and grade 4 IDH-mutant astrocytoma (G4IMA). In addition, the IDH-wildtype murine glioma cell line GL261 and a strain of IDH-mutant GL261 were also sequenced using the murine counterpart of the RNA-sequencing myeloid innate immunity panel.
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Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage.
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Project description:Human ESC-based modeling of H3.3G34R-mutant high grade glioma
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Project description:Mutant-IDH (mIDH) inhibition significantly improves progression free survival in patients with mIDH WHO grade 2 glioma, however almost all patients will progress, and there is a lack of understanding on the mechanisms of adaptation to mIDH inhibition. In the first pre- and post-treatment perioperative trial in patients with mIDH1 low-grade glioma, we tested safusidenib (AB-218 / DS-1001b), an oral, blood brain barrier penetrant IDH1 R132X inhibitor, in a single arm, open label study. The primary endpoint demonstrated the feasibility and acceptability of conducting a two-stage perioperative trial and treatment was well tolerated, with ongoing follow-up for safety and efficacy. Tumor 2-hydroxyglutarate quantification revealed on-target activity, resulting in significant alterations in differentiation programs and neural excitability, functionally validated by patch clamp electrophysiology. Taken together, these results provide a detailed understanding on mechanisms of mIDH inhibition in glioma and the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, advancing drug development in glioma. Funded by AnHeart Therapeutics (a Nuvation Company) and the Victorian Government; ClinicalTrials.gov number NCT05577416.
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