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Reliable tumor detection using cerebrospinal fluid cell-free DNA methylomes in pediatric medulloblastoma

ABSTRACT: Reliable tumor detection using cerebrospinal fluid cell-free DNA methylomes in pediatric medulloblastoma

PROVIDER: PRJNA596280 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10725733.fastq.gz	Fastqsanger.gz
	SRR10725734.fastq.gz	Fastqsanger.gz
	SRR10725735.fastq.gz	Fastqsanger.gz
	SRR10725736.fastq.gz	Fastqsanger.gz
	SRR10725737.fastq.gz	Fastqsanger.gz

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Cerebrospinal fluid cell-free DNA methylomes subtyping pediatric medulloblastoma

Project description:Cerebrospinal fluid cell-free DNA methylomes subtyping pediatric medulloblastoma

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Reliable tumor detection using cerebrospinal fluid cell-free DNA methylomes in pediatric medulloblastoma

Project description:Medulloblastoma (MB) is an embryonal tumor of the cerebellum and a highly malignant childhood brain tumor. Cell-free circulating tumor DNA (ctDNA) from the cerebrospinal fluid (CSF) of patients with brain tumors faithfully represent genomic alterations of brain tumors. Distinct epigenetic signatures among subgroups of MB allow us to detect epigenetic alterations in CSF to aid classify and guide therapy of MB tumors. Here, we evaluate DNA methylation and hydroxymethylation of ctDNA derived from small amount of CSF (200 µL) and matched tumor DNA from 3 MB patients. We find highly concordance of DNA methylation and hydroxymethylation between CSF ctDNA and tumor DNA, especially in CpG islands. Importantly, CSF ctDNA can mostly recapitulate the dynamic changes of DNA methylation and hydroxymehtylation in tumor species compared to healthy cerebellums. Those MB tumor signature CpGs’ DNA methylation status are recovered in CSF ctDNA can clearly distinguish MB subgroups by utilizing public large cohort data. We further identified potential diagnostic and prognostic DNA methylation markers in CSF ctDNA. Our results show that CSF ctNDA methylation and hydroxymethylation can be a minimal invasive method to assess epigenetic alterations of MB, which is complementary to current diagnoses of MB tumors.

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Cerebrospinal fluid cell-free DNA methylomes subtyping pediatric medulloblastoma

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Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children. There remains an unmet need for diagnostics to sensitively detect the disease, particularly recurrences. Cerebrospinal fluid (CSF) provides a window into the central nervous system, and liquid biopsy of CSF could provide a relatively non-invasive means for disease diagnosis. CSF samples from patients with or without medulloblastoma (MB) were subjected to RNA-sequencing to identify differentially expressed transcripts. Although the transcriptomic signatures in CSF to differentiate MB subgroup separation was challenging, we were able to identify a group of gene signatures that could separate cancer from normal CSF. Our approach provides several candidate signatures that deserve further validation, including the novel circular RNA circ_463, and insights into the impact of MB on the CSF microenvironment.

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Whole-genome sequencing of Extrachromosomal circular DNA (eccDNA) of cerebrospinal fluid of Medulloblastoma

Project description:Background: Medulloblastoma (MB) is one of the malignant tumors of the central nervous system (CNS) with a poor prognosis and lack of effective detection. Extrachromosomal circular DNA (eccDNA) has been reported to be closely related to CNS tumors. However, there is still a gap in eccDNA of MB.Methods: Genomic features of eccDNAs were identified in MB tissues and matched cerebrospinal fluid (CSF) using a circle-map, compared with normal. The nucleotides on both sides of the eccDNAs breakpoint were analyzed to investigate the mechanisms of eccDNAs formation. Bioinformatics analysis combined with the GEO database identified reliable features of eccDNA-related genes in MB. Lasso Cox regression model, univariate and multivariate Cox regression analysis, time-dependent ROC, and Kaplan–Meier curve were used to assess the potential diagnostic and prognostic value of the Hub genes.Results: 35179 eccDNAs were identified, with the majority less than 1000 base pairs (bp). The distribution of eccDNAs on the genome was closely related to gene density. EccDNAs in CSF exhibited phase parallelism with matched MB tissues and were shown differently in tumors and normal. Ten core genes were identified in combination with GEO and showed reliable diagnostic and prognostic value in independent datasets through univariate and multivariate Cox regression. Nomogram included Hub-gene signatures was established and showed clinical benefit.Conclusions: This study described the characteristics and formation mechanism of eccDNAs in MB and CSF. The role of eccDNA in MB was revealed, and eccDNA-associated hub genes in CSF could be used as diagnostic and prognostic biomarkers for MB.

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miRNA expression profiles of pediatric medulloblastoma

Project description:The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. Although the molecular basis of medulloblastoma has received considerable attention over the past decade, the role of microRNAs (miRNAs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify miRNA involved in leptomeningeal dissemination and to elucidate its target mechanisms. We analyzed miRNA expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. The differential expressed miRNAs (DEmiRNAs) were validated on 29 medulloblastoma tissues and three medulloblastoma cells. The biological function of the selected miRNA was evaluated using in vitro studies. A total of 12 DEmiRNAs were identified including miRNA-192 in medulloblastoma with seeding. The reduced expression of miRNA-192 was confirmed in tumor seeding group and the medulloblastoma cells. Overexpression of miRNA-192 inhibited cellular proliferation targeting dihydrofolate reductase (DHFR). MiRNA-192 decreased cellular anchoring via repression of integrin subunits (Î±V, Î²1, and Î²3) and CD47. Medulloblastoma with seeding showed specific DEmiRNAs compared with those without seeding. MicroRNA-192 suppresses leptomeningeal dissemination of medulloblastoma through modulating cell proliferation and anchoring ability. leptomeningeal dissemination in 29 pediatric medulloblastoma patients

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