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MTORC1 promotes malignant large cell/anaplastic histology and is a therapeutically targetable vulnerability in SHH-TP53 mutant medulloblastoma

ABSTRACT: mTORC1 promotes malignant large cell/anaplastic histology and is a therapeutically targetable vulnerability in SHH-TP53 mutant medulloblastoma

PROVIDER: PRJNA762305 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15838441.fastq.gz	Fastqsanger.gz
	SRR15838442.fastq.gz	Fastqsanger.gz
	SRR15838443.fastq.gz	Fastqsanger.gz
	SRR15838444.fastq.gz	Fastqsanger.gz
	SRR15838445.fastq.gz	Fastqsanger.gz

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Project description:The outcome of patients with anaplastic gliomas varies considerably depending on histology and single molecular markers such as codeletion of 1p/19q and mutations of the isocitrate dehydrogenase (IDH) gene. Whether a molecularly-based classification of anaplastic gliomas based on large scale genomic or epigenomic analyses is superior to histopathology, may reflect distinct biological subtypes, predict outcome and guide therapy decisions had yet to be determined. Epigenome-wide DNA methylation analysis, which also allows for the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering demonstrated two main groups based on IDH mutation status: CpG island methylator phenotype (CIMP) positive (77.5%) or negative (22.5%). CIMP+ (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q, but not based on histopathology. CIMP- (IDH wild type) tumors on the other hand showed hallmark copy-number alterations of glioblastomas. These tumors clustered together with CIMP- glioblastomas without forming separate groups based on WHO grade. There was no Tumor classification based on CIMP and 1p/19q status was significantly associated with survival allowing a better prediction of outcome than the current histopathological classification alone: Patients with CIMP+ tumors with 1p/19q codeletion had the best prognosis, followed by patients with CIMP+ but intact 1p/19q status. Patients with CIMP- anaplastic gliomas had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped into three molecular subtypes with clear association to underlying biology and clinical outcome based on IDH and 1p/19q status. The data do not provide a molecular basis for the diagnosis of anaplastic oligoastrocytoma. We investigated a subset of 228 anaplastic gliomas using the Illumina 450k methylation array.

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MTORC1 promotes malignant large cell/anaplastic histology and is a therapeutically targetable vulnerability in SHH-TP53 mutant medulloblastoma

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