Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes.
Ontology highlight
ABSTRACT:
SUBMITTER: Nuzzo PV
PROVIDER: S-EPMC8288043 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundOvarian cancer (OC) is a highly lethal gynecologic cancer, and it is hard to diagnose at an early stage. Clinically, there are no ovarian cancer-specific markers for early detection. Here, we demonstrate the use of cell-free DNA (cfDNA) methylomes to detect ovarian cancer, especially the early-stage OC.Experimental designPlasma from 74 epithelial ovarian cancer patients, 86 healthy volunteers, and 20 patients with benign pelvic masses was collected. The cfDNA methylomes of these samples were generated by cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). The differentially methylated regions (DMRs) were identified by the contrasts between tumor and non-tumor groups, and the discrimination performance was evaluated with the iterative training and testing method.ResultsThe DMRs identified for cfDNA methylomes can well discriminate tumor groups and non-tumor groups (ROC values from 0.86 to 0.98). The late-stage top 300 DMRs are more late-stage-specific and failed to detect early-stage OC. However, the early-stage markers have the potential to discriminate all-stage OCs from non-tumor samples.ConclusionsThis study demonstrates that cfDNA methylomes generated with cfMeDIP-seq could be used to identify OC-specific biomarkers for OC, especially early OC detection. To detect early-stage OC, the biomarkers should be directly identified from early OC plasma samples rather than mix-stage ones. Further exploration of DMRs from a k larger early-stage OC cohort is warranted.
| S-EPMC9185905 | biostudies-literature
Project description:Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging.
| S-EPMC8500275 | biostudies-literature
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:BackgroundCell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established.MethodsHere, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine.ResultsOur data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings.ConclusionsThese data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
| S-EPMC7048087 | biostudies-literature
Project description:BackgroundEpigenetic variants carried by circulating tumor DNA can be used as biomarkers for early detection of hepatocellular carcinoma (HCC) by noninvasive liquid biopsy. However, traditional methylation analysis method, bisulfite sequencing, with disadvantages of severe DNA damage, is limited in application of low-amount cfDNA analysis.ResultsThrough mild enzyme-mediated conversion, enzymatic methyl sequencing (EM-seq) is ideal for precise determination of cell-free DNA methylation and provides an opportunity for HCC early detection. EM-seq of methylation control DNA showed that enzymatic conversion of unmethylated C to U was more efficient than bisulfite conversion. Moreover, a relatively large proportion of incomplete converted EM-seq reads contains more than 3 unconverted CH site (CH = CC, CT or CA), which can be removed by filtering to improve accuracy of methylation detection by EM-seq. A cohort of 241 HCC, 76 liver disease, and 279 normal plasma samples were analyzed for methylation value on 1595 CpGs using EM-seq and targeted capture. Model training identified 283 CpGs with significant differences in methylation levels between HCC and non-HCC samples. A HCC screening model based on these markers can efficiently distinguish HCC sample from non-HCC samples, with area under the curve of 0.957 (sensitivity = 90%, specificity = 97%) in the test set, performing well in different stages as well as in serum α-fetoprotein/protein induced by vitamin K absence-II negative samples.ConclusionFiltering of reads with ≥ 3 CHs derived from incomplete conversion can significantly reduce the noise of EM-seq detection. Based on targeted EM-seq analysis of plasma cell-free DNA, our HCC screening model can efficiently distinguish HCC patients from non-HCC individuals with high sensitivity and specificity.
| S-EPMC9814445 | biostudies-literature
Project description:PurposeNo liquid biomarkers are approved in metastatic renal cell carcinoma (mRCC) despite the need to predict and monitor response noninvasively to tailor treatment choices. Urine and plasma free glycosaminoglycan profiles (GAGomes) are promising metabolic biomarkers in mRCC. The objective of this study was to explore if GAGomes could predict and monitor response in mRCC.Patients and methodsWe enrolled a single-center prospective cohort of patients with mRCC elected for first-line therapy (ClinicalTrials.gov identifier: NCT02732665) plus three retrospective cohorts (ClinicalTrials.gov identifiers: NCT00715442 and NCT00126594) for external validation. Response was dichotomized as progressive disease (PD) versus non-PD every 8-12 weeks. GAGomes were measured at treatment start, after 6-8 weeks, and every third month in a blinded laboratory. We correlated GAGomes with response and developed scores to classify PD versus non-PD, which were used to predict response at treatment start or after 6-8 weeks.ResultsFifty patients with mRCC were prospectively included, and all received tyrosine kinase inhibitors (TKIs). PD correlated with alterations in 40% of GAGome features. We developed plasma, urine, and combined glycosaminoglycan progression scores that monitored PD at each response evaluation visit with the area under the receiving operating characteristic curve (AUC) of 0.93, 0.97, and 0.98, respectively. For internal validation, the scores predicted PD at treatment start with the AUC of 0.66, 0.68, and 0.74 and after 6-8 weeks with the AUC of 0.76, 0.66, and 0.75. For external validation, 70 patients with mRCC were retrospectively included and all received TKI-containing regimens. The plasma score predicted PD at treatment start with the AUC of 0.90 and at 6-8 weeks with the AUC of 0.89. The pooled sensitivity and specificity were 58% and 79% at treatment start. Limitations include the exploratory study design.ConclusionGAGomes changed in association with mRCC response to TKIs and may provide biologic insights into mRCC mechanisms of response.
| S-EPMC10309541 | biostudies-literature
Project description:Circulating tumor DNA (ctDNA) carries genetic information consistent with tumor cells and has potential value for molecular diagnosis of tumors. The present study analysed the gene mutations of plasma circulating cell-free DNA (cfDNA) and tumor tissue DNA in hepatocellular carcinoma (HCC) patients and explored the clinical application value of plasma cfDNA as a tumor marker in HCC molecular diagnosis. Samples from 29 patients with primary HCC were collected. Hotspot mutations in 50 tumor-associated genes were analysed using amplicon sequencing technology and gene loci with a mutant allele frequency (MAF) >1% were analysed. 35 mutant genes in total were detected by deep sequencing method of which the genes with maximum mutation frequencies were TP53, ATM, and ALK. In addition, a total of 21 patients were found to have a consistent gene mutation in plasma cfDNA and tumor tissue DNA and 17 cases had consistent gene mutations in the paracancerous tissue and tumor tissue DNA. Further analysis showed that the MAFs in the TP53, CTNNB1, PIK3CA, and CDKN2A genes were higher in patients with tumor diameters >5 cm than those with tumor diameters <5 cm. And the MAFs in the TP53, RET, FGFR3 and APC genes were significantly higher in patients with multiple tumors or with metastasis than in single tumor patients. In conclusion, amplicon sequencing technology is highly sensitive for the detection of mutant genes in the plasma cfDNA of HCC patients. Plasma cfDNA might be an effective molecular marker for HCC molecular diagnosis.
| S-EPMC6456549 | biostudies-literature
Project description:The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.
| S-EPMC8353948 | biostudies-literature
Project description: Not available
| S-EPMC7049928 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, we explored the feasibility of detecting tumor-derived CTNNB1 mutations in cell-free DNA (cfDNA) extracted from the urine of HCC patients. Using a short amplicon qPCR assay targeting HCC mutational hotspot CTNNB1 codons 32-37 (exon 3), we detected CTNNB1 mutations in 25% (18/73) of HCC tissues and 24% (15/62) of pre-operative HCC urine samples in two independent cohorts. Among the CTNNB1-mutation-positive patients with available matched pre- and post-operative urine (n = 13), nine showed apparent elimination (n = 7) or severalfold reduction (n = 2) of the mutation in urine following tumor resection. Four of the seven patients with no detectable mutations in postoperative urine remained recurrence-free within five years after surgery. In contrast, all six patients with mutation-positive in post-operative urine recurred, including the two with reduced mutation levels. This is the first report of association between the presence of CTNNB1 mutations in pre- and post-operative urine cfDNA and HCC recurrence with implications for minimum residual disease detection.
| S-EPMC8393790 | biostudies-literature