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Genome-wide methylation analysis of cerebrospinal fluid circulating tumor DNA: a new biomarker for recurrent glioblastoma [mRNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205512 | GEO | 2023/05/01

REPOSITORIES: GEO

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Genome-wide methylation analysis of cerebrospinal fluid circulating tumor DNA: a new biomarker for recurrent glioblastoma [MeDIP-Seq]

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

Genome-wide analysis of circulating tumor DNA methylation profiles in cerebrospinal fluid: a clinical trial of oncolytic virus for glioblastoma [mRNA-Seq]

Project description:Background: Glioblastoma (GBM) is a common malignant tumor of the central nervous system (CNS) with a poor prognosis and short survival period. A novel tumor lysing virus, Ad-TD-nsIL-12, has demonstrated good anti-tumor properties in preclinical studies. However, there is still a gap in the treatment of GBM with Ad-TD-nsIL-12. Methods: We collected cerebrospinal fluid (CSF) and tumor tissues from patients injected with Ad-TD-nsIL-12 at different times and analyzed CSF circulating tumor DNA (ctDNA) methylation profiles and expression profiles. The differential genes were screened by Lasso Cox regression analyses, and Cox regression analyses. The CIBERSORT algorithm was used to assess the abundance of glioma immune cell infiltration in the TCGA dataset. The role of hub genes in diagnosis, prognosis, and immune cell correlation was analyzed using R software, SPSS software, and Graphpad Prism. Results: By observing the trend of methylation levels in different samples, 3631 differential methylation regions (DMRs) were up-regulated and 497 DMRs were down-regulated after Ad-TD-nsIL-12 injection, and these DMRs recovered their methylation levels within 70-82 days. Combined with the TCGA dataset, eight hub genes were screened to construct diagnostic and prognostic models. There was a significant correlation between hub genes and immune cells. Conclusions: This study analyzed the approximate therapeutic concentrations, doses, and cycles of Ad-TD-nsIL-12 for GBM. Revealed that the hub genes in CSF can be used as a biomarker for the diagnosis and prognosis of GBM, as well as boldly speculated the effect of the hub gene on the immune mechanism of Ad-TD-nsIL-12.

2023-12-01 | GSE205590 | GEO

Genome-wide analysis of circulating tumor DNA methylation profiles in cerebrospinal fluid: a clinical trial of oncolytic virus for glioblastoma [MeDIP-Seq]

2023-12-01 | GSE205519 | GEO

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.

2022-10-20 | GSE205178 | GEO

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.

2020-10-28 | GSE142241 | GEO

Comprehensive Proteomic Profiling and Identification of Potential Hub Genes in Primary and Recurrent Glioblastoma Multiforme

Project description:Glioblastoma multiforme (GBM) is the most lethal brain malignant neoplasm, associated with poor prognosis and high recurrence. The mechanisms involved in GBM development and recurrent remains largely unknown. Hence, it’s considerably imperative to explore the potential targets and unravel the mechanism implicated in GBM tumorigenesis and recurrence. In our study, mass spectrometry-based label-free quantitative proteomics was employed to explore the proteomic profiling in non-paired samples of primary and recurrent GBM. Bioinformatic analysis of differentially expression proteins (DEPs) were applied to screen the hub genes. Subsequently, hub genes expression was verified by western blot and immunohistochemistry (IHC) in GBM tissues, followed by its biological effect on GBM at a cellular level determined. We contoured the divergent landscape of proteome between primary and recurrent GBM, with only ten overlapped DEPs included. The several hub genes screened (e.g., CKAP4 and CANX) and enriched pathways correlated with primary GBM such as post-translation, metabolism, energy pathways and cell growth were profiled. Furthermore, CKAP4 was implicated in proliferation, migration and invasion of A172 and T98G cell lines. However, UQCRC1, together with relative enriched pathways such as oxidative phosphorylation, were screened in recurrent GBM. Establishment of the proteomics and several candidate proteins identified could pose considerable access to understand complex biochemical processes and obtain a better picture of GBM biology.

2021-06-06 | PXD026503 | iProX

Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

Project description:Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.

2016-05-20 | GSE80399 | GEO

ctDNA methylation markers in diagnosis and prognosis of hepatocellular carcinoma

Project description:To develop diagnostic and prognostic biomarkers, we compared methylation profiles of HCC tissues and normal blood by analyzing 485,000 CpG markers and identified a HCC enriched methylation marker panel compared to that of normal blood. We found there was a highly correlation of methylation profiles between DNA from HCC cancer tissue and matched plasma ctDNA within the same patient. We then selected 10 markers from this panel and created a combined diagnosis score (cd-score) which showed high diagnostic specificity and sensitivity in both a training cohort and an independent validation cohort. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. Additional, we generated 8 markers from unicox and LASSO-cox analysis and created a combined prognosis score (cp-score) which could predict prognosis and survival. Together, these findings demonstrated the utility of ctDNA methylation markers in the diagnosis, treatment evaluation and prognosis of HCC.

2019-01-01 | GSE93203 | GEO

Diagnostic accuracy of liquid biopsy in endometrial cancer

Project description:INTRODUCTION. Liquid biopsies are a minimally invasive collection of a patient body fluid sample. In oncology, they offer several advantages compared to traditional tissue biopsies. However, potential of this method in endometrial cancer (EC) remains poorly explored. We studied the utility of tumor educated platelets (TEPs) and circulating tumor DNA (ctDNA) for preoperative EC diagnosis, including histology determination. MATERIALS AND METHODS. TEPs from 297 subjects (53 EC patients, 40 patients with benign gynecologic conditions and 204 healthy women) were RNA-sequenced. DNA sequencing was performed in 519 primary tumor tissue samples and in16 plasma samples. Artificial intelligence was applied to sample classification. RESULTS. Platelet-dedicated classifier yielded AUC of 93.1% in test set when discriminating between healthy subjects and cancer patients. However, the discrimination between endometrial cancer and benign gynecologic conditions was relatively low, with AUC of 60.7%. ctDNA-dedicated classifier discriminated primary tumor tissue samples with AUC of 91.4% and ctDNA blood samples with AUC of 87.5%. CONCLUSIONS Liquid biopsies show potential in EC diagnosis. Both TEPs and ctDNA profiles coupled with artificial intelligence constitute a source of useful information. Further work, involving more cases, is warranted.

2021-12-01 | GSE184904 | GEO

Gene expression profiling of benign and matched tumour prostate tissue from patients diagnosed with prostate cacner (PCa)

Project description:An integrated transcriptome-wide gene expression analysis, including differential gene expression analysis and weighted gene co-expression network analysis (WGCNA), was carried out based on transcriptomics data from a series of nine matched, histologically confirmed PCa and benign samples using the Affymetrix Clariom D Human array. The analysis identified a set of potential gene markers highly associated with tumor status (malignant vs. benign). We then used these genes to establish a minimal progression-free survival (PFS)-associated gene signature (GS) (PCBP1, PABPN1, PTPRF, DANCR, and MYC) using the least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox regression analyses from The Cancer Genome Atlas prostate adenocarcinoma (TCGA-PRAD) dataset. Our signature was able to predict PFS over 1, 3, and 5 years in the TCGA-PRAD dataset, with an area under the curve (AUC) of 0.64–0.78, and our signature remained as a prognostic factor independent of age, Gleason score, and pathological T and N stages. A nomogram combining the signature and Gleason score demonstrated improved predictive capability for PFS (AUC: 0.71–0.85) and was superior to the Cambridge Prognostic Group (CPG) model alone and some conventionally used clinicopathological factors in predicting PFS. In conclusion, we have identified and validated a novel five-gene signature and established a nomogram that effectively predicted PFS in patients with PCa. These findings may improve current prognostic tools for PFS and contribute to clinical decision-making in PCa treatment.

2023-10-31 | GSE246282 | GEO

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