Cerebrospinal fluid cell-free DNA methylomes subtyping pediatric medulloblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE178169 | GEO | 2023/06/01
REPOSITORIES: GEO
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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.
2020-10-28 | GSE142241 | GEO
Project description:Astrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma are the main histologic subtypes of glioma. The molecular character of these subtypes has profound implications for understanding their causes and treatment. We describe the epigenetic landscape of these tumor types using novel DNA methylation profiling tools. There is a robust association of methylation profile with tumor histology and IDH1 mutation status. Furthermore, tumors with IDH1 mutation independently predict a tumor hypermethylator phenotype, histology, TP53 mutation status, patient age, and survival. Integrating tumor epigenetic and genetic alterations, this work provides a critical step toward better defining the somatic nature of glioma which will have great potential to impact clinical approaches to disease. This work provides an important step forward in classification of malignant brain tumors using DNA methylation profiling, integrating knowledge regarding IDH1 mutation in gliomas. The epigenetic homogeneity of the IDH1 mutant subclass despite histologic diversity implies that IDH1 mutation is a “driver” or functional determinant of a distinct DNA methylation phenotype, suggesting a novel role for an altered metabolic profile in the brain. This association occurs across histologic subtypes and demonstrates a clear relationship between genetic alteration and epigenetic profile. Fresh frozen tumor tissues were obtained from the University of California San Francisco (UCSF) Brain Tumor Research Center tissue bank with appropriate institutional review board approval. Tumors were diagnosed between 1990 and 2003. Tumor samples were defined as secondary GBM if the patients had prior histological diagnosis of a low-grade glioma. Tumors had previously been reviewed by UCSF neuropathologists to assign histologic subtype and grade. Normal brain tissue samples were from cancer-free patients who underwent temporal lobe resection as treatment for epilepsy at UCSF.
2010-12-20 | E-GEOD-20395 | biostudies-arrayexpress
Project description:Neuroblastoma pathogenesis has been reported to be closely associated with numerous genetic alterations. However, underlying DNA methylation patterns have not been extensively studied in this developmental malignancy. In this study, we generated microarray-based DNA methylation profiles of primary neuroblastic tumors. Stringent supervised differential methylation analyses allowed us to identify epigenetic changes characteristic for NB tumors as well as for clinical and biological subtypes of NB. We observed that gene-specific loss of DNA methylation is more prevalent than promoter hypermethylation. Overall, the differentially methylated genes showed that functional pathways affected by hypermethylation are different from those affected by hypomethylation. This study provides a comprehensive view of the global DNA methylation profile of NB tumors. Bisulphite converted DNA from the 25 neuroblastic tumor and 2 non patological tissues (fetal brain and adrenal gland) samples were hybridised to the Illumina Infinium 27k Human Methylation
2012-10-29 | E-GEOD-39626 | biostudies-arrayexpress
Project description:Astrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma are the main histologic subtypes of glioma. The molecular character of these subtypes has profound implications for understanding their causes and treatment. We describe the epigenetic landscape of these tumor types using novel DNA methylation profiling tools. There is a robust association of methylation profile with tumor histology and IDH1 mutation status. Furthermore, tumors with IDH1 mutation independently predict a tumor hypermethylator phenotype, histology, TP53 mutation status, patient age, and survival. Integrating tumor epigenetic and genetic alterations, this work provides a critical step toward better defining the somatic nature of glioma which will have great potential to impact clinical approaches to disease. This work provides an important step forward in classification of malignant brain tumors using DNA methylation profiling, integrating knowledge regarding IDH1 mutation in gliomas. The epigenetic homogeneity of the IDH1 mutant subclass despite histologic diversity implies that IDH1 mutation is a “driver” or functional determinant of a distinct DNA methylation phenotype, suggesting a novel role for an altered metabolic profile in the brain. This association occurs across histologic subtypes and demonstrates a clear relationship between genetic alteration and epigenetic profile.
2010-12-20 | GSE20395 | GEO
Project description:Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is based on only few previous molecular studies, which mainly relied on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics with the aim to identify novel therapeutic vulnerabilities in these deadly tumors. Using mass spectrometry, proteome data were acquired from FFPE tissue of 40 embryonal brain tumors (16 ETMR, 9 atypical teratoid/rhabdoid tumors (AT/RT), 15 medulloblastomas (MB)) and integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further pediatric brain tumors. Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Microdissection analyses highlighted the close relationship of ETMR histomorphology and proteome profiles, regardless of intra- or intertumoral comparisons. Integrated proteomics showcased that ETMR harbor proteasome regulatory proteins in abundancy, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Respectively, in vitro cell culture viability assays using embryonal brain tumor cell lines BT183 (ETMR), BT16 (AT/RT), and D283 (MB) highlighted that ETMR cells were highly vulnerable towards treatment with the CNS penetrant proteasome inhibitor Marizomib. In summary, histomorphology stipulates the proteome signatures of ETMR. Pervasive and histomorphology-independent abundancy of proteasome regulatory proteins in ETMR indicates a strong proteasome dependency throughout these tumors. As validated in cell culture experiments, proteasome inhibition poses a promising therapeutic option in ETMR.
2024-01-08 | PXD045268 | Pride
Project description:This study aims to compared ctDNA methylation status induced by ionizing to different ograns. SD rats were irradiated with local radaition to brain, lung or skin. Serum was collected and subjiected to ctDNA extraction. ctDNA were then treated by methylation-sensive bisulfite and sequencing.
2021-12-23 | GSE163763 | GEO
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However, at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood references were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1. This study was designed to investigate the relationship between copy number and DNA methylation alterations in head and neck squamous cell carcinoma. Data in this submission relates to the copy number portion only. Each patient tumor has been de-identified and assigned a number (1-19) and the blood samples with the same number correspond to the respectively-numbered tumor. The supplementary file 'GSE20939_tumor_copy_number.txt' contains the (blood normalized) copy number calls for each tumor sample.
2010-11-11 | E-GEOD-20939 | biostudies-arrayexpress
Project description:Background: Glioblastoma (GBM) is a common malignancy of the central nervous system (CNS) that is prone to recurrent and has a short survival period. Clinical biomarkers for the diagnosis and prognosis of recurrent GBM are lacking.Methods: We collected 4 cerebrospinal fluid (CSF) samples and 1 normal CSF sample from recurrent GBM, as well as paired tissue samples. Genome-wide methylation profiles of CSF circulating tumor DNA (ctDNA) and tissue mRNA transcription profiles were analyzed, and genes were screened by univariate Cox analysis, Lasso regression analysis, and multivariate Cox analysis by the Chinese Glioma Genome Atlas (CGGA) database. Data analysis and visualization were performed using R software, SPSS software, and Graphpad Prism.Results: By taking the intersection of differentially methylated regions (DMRs) and differentially expressed genes (DEGs), 892 genes were selected for Lasso regression analysis and multivariate Cox analysis, and 12 hub genes were finally screened to construct diagnostic and prognostic models. The diagnostic (AUC=0.982) and prognostic (5-years AUC=0.931) models based on the 12 hub genes had high accuracy.Conclusions: This study reveals that 12 hub genes in CSF ctDNA can diagnose and prognosticate recurrent GBM and provide new biomarkers for clinical research into the mechanisms of GBM recurrent.
2023-05-01 | GSE205513 | GEO
Project description:Background: Glioblastoma (GBM) is a common malignancy of the central nervous system (CNS) that is prone to recurrent and has a short survival period. Clinical biomarkers for the diagnosis and prognosis of recurrent GBM are lacking.Methods: We collected 4 cerebrospinal fluid (CSF) samples and 1 normal CSF sample from recurrent GBM, as well as paired tissue samples. Genome-wide methylation profiles of CSF circulating tumor DNA (ctDNA) and tissue mRNA transcription profiles were analyzed, and genes were screened by univariate Cox analysis, Lasso regression analysis, and multivariate Cox analysis by the Chinese Glioma Genome Atlas (CGGA) database. Data analysis and visualization were performed using R software, SPSS software, and Graphpad Prism.Results: By taking the intersection of differentially methylated regions (DMRs) and differentially expressed genes (DEGs), 892 genes were selected for Lasso regression analysis and multivariate Cox analysis, and 12 hub genes were finally screened to construct diagnostic and prognostic models. The diagnostic (AUC=0.982) and prognostic (5-years AUC=0.931) models based on the 12 hub genes had high accuracy.Conclusions: This study reveals that 12 hub genes in CSF ctDNA can diagnose and prognosticate recurrent GBM and provide new biomarkers for clinical research into the mechanisms of GBM recurrent.
2023-05-01 | GSE205512 | GEO
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood referents were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1. This study was designed to investigate the relationship between copy number and DNA methylation alterations in head and neck squamous cell carcinoma. Data in this submission relates to the methylation portion only. Each patient tumor has been de-identified and assigned a number (1-19). We included 11 normal head and neck samples, procured through the National Research Disease Interchange, that were used for reference when comparing tumor to normal. One ug of tissue DNA extracted using the Qiagen Blood and Tissue Kit was bisulfite-modified using a Zymo Research EZ DNA Methylation Kit. Samples were processed and arrayed on the Illumina GoldenGate Methylation Cancer Panel 1 at the University of California-San Francisco Institute for Genetics, Genomic Core Facility.
2010-06-23 | E-GEOD-20742 | biostudies-arrayexpress