Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

ABSTRACT: Pancreatic cancers are typically diagnosed at late stage where disease prognosis is poor as exemplified by a 5-year survival rate of 10%. Earlier diagnosis would be beneficial by enabling surgical resection or earlier application of therapeutic regimens. We investigated non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by interrogating changes in 5-hydroxymethylation cytosines (5hmC) of circulating cell free DNA in the plasma of a PDAC cohort (n=64) in comparison with a non-cancer cohort (n=243). 5hmC density is reduced in promoters and enhancers, whereas it is increased over 3’UTR, intron and TTS regions in PDAC compared to non-cancer cfDNA. Differential hydromethylation is rampant and found in thousands of genes. Stringent filtering by significance reveals genes related to pancreas function or development (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and/or cancer pathogenesis (YAP1, TEAD1, PROX1, ONECUT1, ONECUT2 and IGF1). Furthermore, we observe enrichment for genes that are de-regulated upon activation of KRAS and inactivation of TP53, both of which are commonly observed in PDAC tumors. Regularized regression models, built using 5hmC densities in genes with the most variable 5hmC counts, performed with AUC of 0.92 on discovery dataset and 0.92-0.94 on two independent test sets. Furthermore, investigation of 5hmC occupancy in PDAC tumor tissue revealed that tissue-derived features can be used to accurately classify PDAC cfDNA (AUC=0.88). These findings suggest that 5hmC changes, at least partially derived from tumor tissue, enable classification of PDAC patients with high fidelity and are worth further investigation on larger cohorts of patient samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152137 | GEO | 2020/08/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

An integrative analysis of genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA detects non-invasive diagnostic markers for gliomas

Project description:Background. Gliomas, especially the high-grade glioblastomas (GBM), are highly aggressive tumors in the central nervous system (CNS) with dismal clinical outcomes. Effective biomarkers, which are not currently available, may improve clinical outcomes through early detection. We sought to develop a non-invasive diagnostic approach for gliomas based on 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA). Methods. We obtained genome-wide 5hmC profiles using the 5hmC-Seal technique in cfDNA samples from 111 prospectively enrolled patients with gliomas and 111 age-, gender-matched healthy individuals, which were split into a training set and a validation set. Integrated models comprised of 5hmC levels summarized for gene bodies, long non-coding RNAs (lncRNAs), cis-regulatory elements, and repetitive elements were developed using the elastic net regularization under a case-control design. Results. The integrated 5hmC-based models differentiated healthy individuals from gliomas (AUC [area under the curve] = 84%; 95% confidence interval [CI], 74-93%), GBM patients (AUC = 84%; 95% CI, 74-94%), WHO II-III glioma patients (AUC = 86%; 95% CI, 76-96%), regardless of IDH1 (encoding isocitrate dehydrogenase) mutation status or other glioma-related pathological features such as TERT, TP53 in the validation set. Furthermore, the 5hmC biomarkers in cfDNA showed the potential as an independent indicator from IDH1 mutation status and worked in synergy with IDH1 mutation to distinguish GBM from WHO II-III gliomas. Exploration of the 5hmC biomarkers for gliomas revealed relevance to glioma biology. Conclusions. The 5hmC-Seal in cfDNA offers the promise as a non-invasive approach for effective detection of gliomas in a screening program.

2021-05-30 | GSE132118 | GEO

5-Hydroxymethylcytosine signals in serum are a predictor of chemoresistance in high-grade serous ovarian cancer

Project description:The genome-wide profiling of 5-hydroxymethylcytosine (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for a variety of diseases. The purpose of our study is to investigate if 5hmC profiles from serum cfDNA are novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5-hmC profiles associate with the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. We developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC-annotated gene that can predict response to platinum-based chemotherapy in intermediate-sensitive HGSOC. These results merit further investigation of our model as a predictive model.

2024-01-25 | GSE240535 | GEO

5-Hydroxymethylcytosines in Circulating Cell-free DNA Reveal Vascular Complications of Type 2 Diabetes

Project description:BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, non-invasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without (testing set: AUC = 0.85, 95%CI, 0.73-0.96), outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84, 95%CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, non-invasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.

2020-01-31 | GSE125929 | GEO

Genome-wide Mapping of 5-Hydroxymethylcytosines in Circulating Cell-free DNA as a Non-invasive Approach for Early Detection of Hepatocellular Carcinoma

Project description:Background: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. Methods: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2,554 Chinese subjects: 1,204 HCC patients, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC), and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularization for feature selection. Results: The 5hmC-Seal data from HCC patients showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer (BCLC) staging system from non-HCC (validation set: AUC = 88.4%; 95% CI, 85.8-91.1%), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumors (e.g., ≤ 2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC = 84.6%; 95% CI, 80.6-88.7%), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (e.g., smoking/alcohol intake history). Conclusions: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.

2019-08-07 | GSE112679 | GEO

DNA 5-hydroxymethylcytosines from cell-free circulating DNA as diagnostic biomarkers for human cancers

Project description:DNA modifications such as 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression, and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here genome-wide 5hmC profiling in circulating cell-free DNA (cfDNA) and paired tumor/adjacent tissues collected from a cohort of 90 healthy individuals and 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver, or thyroid cancer. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-specific epigenetic signatures in cfDNA were identified in different cancers. 5hmC-based biomarkers demonstrated highly accurate predictive value for patients with colorectal and gastric cancers versus healthy controls, superior to conventional biomarkers, and comparable to epigenetic biomarkers from tissue biopsies. This new strategy could lead to the development of an effective blood-based, minimally-invasive cancer diagnosis and prognosis approach.

2017-09-05 | GSE89570 | GEO

Cell-free DNA 5-hydroxymethylcytosine as a marker for common cancer detection

Project description:We used a highly sensitive nano-5hmC-Seal method and profiled the genome-wide distribution of 5-hydroxymethylcytosine (5hmC) in plasma cell-free DNA (cfDNA) from 384 patients with bladder, breast, colorectal, kidney, lung, or prostate cancer and 221 controls. We used machine learning and developed plasma cfDNA 5hmC signatures that are highly sensitive for cancer detection and cancer origin determination. We also identified genes and signaling pathways with aberrant DNA hydroxymethylation in six cancers.

2022-09-23 | GSE202988 | GEO

Prognostic implications of 5-hydroxymethylcytosines from circulating cell-free DNA in diffuse large B-cell lymphoma

Project description:Elevated level of circulating cell-free DNA (cfDNA) has been associated with poor prognosis and relapse in patients with diffuse large B-cell lymphoma (DLBCL), but the tumor-specific molecular alterations in cfDNA with prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosines (5hmC), a mark of active demethylation and gene activation, in cfDNA from blood plasma and prognosis in DLBCL. We used the 5hmC-Seal, a highly sensitive chemical labeling technique, to profile genome-wide 5hmC in plasma cfDNA samples from 48 newly diagnosed patients with DLBCL at the University of Chicago between 2010 and 2012. Patients were followed through December 31, 2017. We found a distinct genomic distribution of 5hmC in cfDNA marking tissue-specific enhancers, consistent with their potential roles in gene regulation. The 5hmC profiles in cfDNA differed by cell-of-origin, and were associated with clinical prognostic features including Ann Arbor stage, serum lactate dehydrogenase (LDH) level, and the International Prognostic Index (IPI). We developed a 29 gene-based weighted prognostic score (wp-score) for predicting event-free survival (EFS) and overall survival (OS), by applying the elastic net regularization on the Cox proportional hazard model. The wp-scores showed significantly improved prognostic accuracy and/or sensitivity/specificity than the established prognostic factors. In multivariate Cox models, patients with high wp-scores were associated with worse event-free survival (Hazard Ratio [HR] = 9.17, 95% confidence interval [CI] = 2.01- 41.89, p = 0.004), compared with those in the low risk group. Our findings suggest that the 5hmC signatures in cfDNA at the time of diagnosis are associated with clinical outcomes in DLBCL and may provide a novel non-invasive prognostic approach for DLBCL.

2019-11-15 | GSE126676 | GEO

DNA methylation biomarkers for non-invasive detection of triple negative breast cancer using liquid biopsy

Project description:Non-invasive detection of aberrant DNA methylation could provide invaluable biomarkers for earlier detection of triple negative breast cancer (TNBC) which could help clinicians for easier and more efficient treatment options. We evaluated genome-wide DNA methylation data derived from TNBC and normal breast tissues, peripheral blood of TNBC cases and controls, and reference samples of sorted blood and mammary cells. Differentially methylated regions (DMRs) between TNBC and normal breast tissues were stringently selected, verified, and externally validated. A machine learning algorithm was applied to select the top DMRs, which then were evaluated on plasma-derived circulating cell-free DNA (cfDNA) samples of TNBC patients and healthy controls. We identified 23 DMRs accounting for the methylation profile of blood cells and reference mammary cells and then selected six top DMRs for cfDNA analysis. We quantified un-/methylated copies of these DMRs by droplet digital PCR analysis in a plasma test set from TNBC patients and healthy controls and confirmed our findings obtained on tissues. Differential cfDNA methylation was confirmed in an independent validation set of plasma samples. A methylation score combining signatures of the top three DMRs overlapping with the SPAG6, LINC10606, and TBCD/ZNF750 genes had the best capability to discriminate TNBC patients from controls (AUC=0.74 in test set and AUC=0.77 in validation set). Our findings demonstrate the usefulness of cfDNA-based methylation signatures as non-invasive liquid biopsy markers for diagnosis of TNBC.

2022-11-23 | GSE207998 | GEO

Shotgun sequencing of 5-hydroxymethylcysotine circulating cell-free DNA from the blood distinguishes solid tumor tissues of origin

Project description:5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in cell-free DNA (cfDNA), the circulating DNA found in human plasma which represents a noninvasive window into the health status of the body. We showed that the genome-wide 5hmC distribution in cfDNA can be reliably sequenced by chemical labeling-based 5hmC enrichment. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that can be used for monitoring disease status and progression. Specifically, we discovered that lung cancer leads to a stage-dependent hypohydroxymethlation in cfDNA, whereas hepatocellular carcinoma (HCC) and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our results demonstrate that cell-free 5hmC can be used not only to track the stage of cancer but also to identify tissue of origin in some solid tumors.

2017-07-13 | GSE81314 | GEO

Cell free DNA 5-hydroxymethylcytosine as an emerging marker of acute myeloid leukemia

Project description:Aberrant changes in 5-hydroxymethylcytosine (5hmC) are a unique epigenetic feature in many cancers including acute myeloid leukemia (AML). However, genome-wide analysis of 5hmC in plasma cell-free DNA (cfDNA) remains unexploited in AML patients. We used a highly sensitive and robust nano-5hmC-Seal technology and profiled genome-wide 5hmC distribution in 239 plasma cfDNA samples from 103 AML patients and 81 non-cancer controls. We developed a 5hmC diagnostic model that precisely differentiates AML patients from controls with high sensitivity and specificity. We also developed a 5hmC prognostic model that accurately predicts prognosis in AML patients. High weighted prognostic scores (wp-scores) in AML patients were significantly associated with adverse overall survival (OS) in both training (P = 3.31e-05) and validation (P = .000464) sets. The wp-score was also significantly associated with genetic risk stratification and displayed dynamic changes with varied disease burden. Moreover, we found that high wp-scores in a single gene, BMS1 and GEMIN5 predicted OS in AML patients in both the training set (P =.023 and .031, respectively) and validation set (P = 9.66e-05 and 0.011, respectively). Lastly, our study demonstrated the genome-wide landscape of DNA hydroxymethylation in AML and revealed critical genes and pathways related to AML diagnosis and prognosis. Our data reveal plasma cfDNA 5hmC signatures as sensitive and accurate markers for AML diagnosis and prognosis. Plasma cfDNA 5hmC analysis will be an effective and minimally invasive tool for AML management.

2022-06-15 | GSE163846 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data