Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA638395 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2020-08-26 | GSE152137 | GEO
Project description:Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92-0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.
| S-EPMC7572413 | biostudies-literature
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
Project description:Bisulfite-free direct detection of 5-methylcytosine and 5-hydroxymethylcytosine at base resolution
| PRJNA448064 | ENA
Project description:High-resolution detection of genome-wide 5-hydroxymethylcytosine (5hmC) sites of small-scale samples represents a continuous challenge. Here, we present CATCH-seq, a bisulfite-free, base-resolution method for the genome-wide detection of 5hmC. CATCH-seq is based on selective 5hmC oxidation, labeling and subsequent C-to-T transition during PCR. Applications of CATCH-seq to nano-scale DNA samples reveal previously underappreciated non-CG 5hmCs in the hESC genome and base-resolution hydroxymethylome in human cell-free DNA.
2018-10-09 | GSE112048 | GEO
Project description:DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (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 the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.
| S-EPMC5630683 | biostudies-literature
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
Project description:After curative surgical resection, detection of metastatic lymph node remains the main prognostic validated criteria on which is based the decision of adjuvant therapy. To date, none of the molecular alterations, identified as potentially predictive factor, are used in routine for therapeutic decision. The circulating markers, either in the form of free circulating DNA or in the form of circulating tumoral cells seems important potential candidates. To investigators knowledge, only one study estimated with several interesting results the prognostic interest of a coupled detection of the free circulating mutant DNA (gene KRAS) and by the hypermethylation of the p16 gene. Definitive conclusions remain however difficult to achieve because of the small number of patient included (n=58) and the fact that this study included different stages. For colorectal cancer a Chinese team presented a series of results suggesting that the presence of CTC during the postoperative course is a factor significantly related to the risk of recurrence. In multivariate analysis integrating the lymph node status and the vascular invasion, the presence of CTC appeared as an independent factor for recurrence with a hazard ratio of 29.5.
The aim of the present study is to compare the prognostic value of two circulating tumoral markers KRAS point mutations and RASSF2A methylation (free tumoral DNA) and Circulating tumoral cells (CTC). The primary objective is to compare sensibility and specificity of two circulating markers (free tumoral DNA and tumoral cells) on 2 years disease free survival rate. Secondary objective is to confirm the prognostic value of circulating free tumoral DNA and circulating tumoral cells in localised colorectal cancer.
| 2198606 | ecrin-mdr-crc
Project description:Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML). However, MRD cannot be detected in many patients using current methods. We developed a highly sensitive 5-hydroxymethylcytosine (5hmC) signature in cell-free DNA by analyzing 115 AML patients and 86 controls. The 5hmC method detected MRD in 20 of 29 patients with negative MRD by multiparameter flow cytometry and 11 of 14 patients with negative MRD by molecular methods. MRD detection by the 5hmC method was significantly associated with relapse-free survival. This novel method can be used in most AML patients and may significantly impact AML patient management.
2023-12-31 | GSE237057 | GEO
Project description:ObjectivesPancreatic ductal adenocarcinoma (PDAC) presents the lowest survival rate of all cancers because only 6% of patients reach five-year survival. Alterations in the expression of several microRNAs (miRNAs) occur in the tumor of PDAC and in preneoplastic lesions as the called intraductal papillary mucinous neoplasm (IPMN). Here, we aimed at identifying which miRNAs are significantly altered in liquid biopsies from patients with PDAC and IPMN to find new noninvasive biomarkers for early detection of PDAC.MethodsWe analyzed by real-time quantitative reverse transcription-PCR (qRT-PCR) the expression of 17 circulating miRNAs, previously found to be significantly overexpressed in tissue pancreatic neoplasms, in a set of 182 plasma samples (94 PDAC, 19 IPMN, 18 chronic pancreatitis, and 51 disease-free controls). Then, we analyzed CA19.9 levels in the same plasma set, and we assessed the diagnostic values of differentially expressed miRNAs, CA19.9, and all possible combinations.ResultsOf note, 16, 14, and 9 miRNAs were significantly increased in PDAC, IPMN, and chronic pancreatitis, respectively, compared with control plasmas. miR-21-5p, miR-33a-3p, miR-320a, and miR-93-5p showed the highest discriminating capacity for pancreatic neoplasia (PDAC or IPMN) with an area under the receiver operating characteristic curve (AUC) of 0.86, 0.85, 0.85, and 0.80, respectively. 2-miRNA combinations improved these performances reaching AUC = 0.90 for "miR-33a-3p+miR-320a." Addition of CA19.9 increased the diagnostic potential of miRNA signatures even further achieving an AUC of 0.95 (93% sensitivity and 85% specificity) for the combination of "miR-33a-3p+miR-320a+CA19.9."ConclusionsNovel signatures combining miRNAs and CA19.9 could be used as noninvasive biomarkers for early detection of PDAC.
| S-EPMC6602779 | biostudies-literature