5-Hydroxymethylome in Circulating Cell-free DNA as A Potential Biomarker for Non-small-cell Lung Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang J
PROVIDER: S-EPMC6076378 | biostudies-other | 2018 Jun
REPOSITORIES: biostudies-other
Publications
5-Hydroxymethylome in Circulating Cell-free DNA as A Potential Biomarker for Non-small-cell Lung Cancer.
Zhang Ji J Han Xiao X Gao Chunchun C Xing Yurong Y Qi Zheng Z Liu Ruijuan R Wang Yueqin Y Zhang Xiaojian X Yang Yun-Gui YG Li Xiangnan X Sun Baofa B Tian Xin X
Genomics, proteomics & bioinformatics 20180601 3
Non-small-cell lung cancer (NSCLC), the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminating tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sens ...[more]
Similar Datasets
Project description:BackgroundNon-small cell lung cancer (NSCLC) is leading cause of cancer related death and the survival rate for patients with NSCLC remain poor so early diagnosis of NSCLC represents the best opportunity for cure. Cell-free DNA (cf-DNA) is extracellular nucleic acids found in cell-free plasma/serum of humans, given the recent approval of a liquid biopsy in lung cancer, the use of circulating tumor DNA as a novel non-invasive diagnostic and prognostic biomarker is promising.ObjectivesStudying whether the concentrations of circulating Cell Free DNA in serum can be used as a diagnostic and prognostic biomarker for NSCLC patients.MethodThis study was carried out on 140 subjects included 60 patients with non small cell lung cancer,40 patients with Chronic Obstructive Pulmonary Disease (COPD) and 40 healthy controls. Quantitative analysis of serum circulating cf-DNA was done b y AlU-based quantitative real time PCR. Serum level of CEA was measured by ELISA.ResultsNSCLC patients demonstrated significantly higher values of each of ALU 215, ALU 247, and DNA integrity than both COPD patients and controls. On ROC curve analysis, the total accuracy of ALU 247, ALU 115, DNA integrity (92.1%, 83.6%, 56.4%) at cutoff points (325, 565 & 0.48) respectively. On combining both DNA integrity and CEA, improved sensitivity to 93.3% was noted. For NSCLC patients, ALU 115 & ALU 247 increased significantly with more advanced stage and highest level was noticed in metastatic patients. Regarding survival there was better overall survival among patients with low DNA integrity.ConclusionSerum cf-DNA concentrations and integrity index may be valuable tool in early diagnosis of NSCLC and prediction of prognosis of those patients.
| S-EPMC6031238 | biostudies-literature
Project description:BackgroundRoutine clinical surveillance involves serial radiographic imaging following radical surgery in localized non-small cell lung cancer (NSCLC). However, such surveillance can detect only macroscopic disease recurrence and is frequently inconclusive. We investigated if detection of ctDNA before and after resection of NSCLC identifies the patients with risk of relapse, and furthermore, informs about response to management.MethodsWe recruited a total of 77 NSCLC patients. A high-throughput 127 target-gene capture technology and a high-sensitivity circulating single-molecule amplification and resequencing technology (cSMART) assay were used to detect the somatic mutations in the tumor tissues as well as the plasma of NSCLC patients before and after surgery to monitor for minimal residual disease (MRD). Kaplan-Meier and Cox regression analysis were performed to evaluate the relapse-free survival (RFS) and overall survival (OS) of patients with predictor variables.ResultsPatients with a higher stage (III/IV) and preoperative ctDNA-positive status demonstrated a significant 2.8-3.4-fold risk and 3.8-4.0-fold risk for recurrence and death, respectively. Preoperative ctDNA-positive patients associated with a lower RFS (HR = 3.812, p = 0.0005) and OS (HR = 5.004, p = 0.0009). Postoperative ctDNA-positive patients also associated with a lower RFS (HR = 3.076, p = 0.0015) and OS (HR = 3.195, p = 0.0053). Disease recurrence occurred among 63.3% (19/30) of postoperative ctDNA-positive patients. Most of these patients 89.5% (17/19) had detectable ctDNA within 2 weeks after surgery and was identified in advance of radiographic findings by a median of 12.6 months.ConclusionAdvanced stage and preoperative ctDNA-positive are strong predictors of RFS and OS in localized NSCLC patients undergoing complete resection. Postoperative detection of ctDNA increases chance to detect early relapse, thus can fulfill an important role in stratifying patients for immediate further treatment with adjuvant and neoadjuvant therapy.
| S-EPMC7523087 | biostudies-literature
Project description:BackgroundNon-small cell lung cancer (NSCLC) is one of the most prevalent causes of cancer-related death worldwide. Recently, there are many important medical advancements on NSCLC, such as therapies based on tyrosine kinase inhibitors and immune checkpoint inhibitors. Most of these therapies require tumor molecular testing for selecting patients who would benefit most from them. As invasive biopsy is highly risky, NSCLC molecular testing based on liquid biopsy has received more and more attention recently.ObjectiveWe aimed to introduce liquid biopsy and its potential clinical applications in NSCLC patients, including cancer diagnosis, treatment plan prioritization, minimal residual disease detection, and dynamic monitoring on the response to cancer treatment.MethodWe reviewed recent studies on circulating tumor DNA (ctDNA) testing, which is a minimally invasive approach to identify the presence of tumor-related mutations. In addition, we evaluated potential clinical applications of ctDNA as blood biomarkers for advanced NSCLC patients.ResultsMost studies have indicated that ctDNA testing is critical in diagnosing NSCLC, predicting clinical outcomes, monitoring response to targeted therapies and immunotherapies, and detecting cancer recurrence. Moreover, the changes of ctDNA levels are associated with tumor mutation burden and cancer progression.ConclusionThe ctDNA testing is promising in guiding the therapies on NSCLC patients.
| S-EPMC8375502 | biostudies-literature
Project description:BackgroundEarly diagnosis of non-small cell lung cancer (NSCLC) is crucial for treatment. Circulating cell-free DNA (cfDNA) is an extracellular nucleic acid found in serum, and tumor cfDNA circulating in the blood may be used as a biomarker for early diagnosis. The purpose of this study was to evaluate the application value of cfDNA as a biomarker for the diagnosis of NSCLC through meta-analysis.MethodsWe searched the China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science databases using the following search terms: lung cancer, NSCLC, biomarkers, circulating cfDNA, cfDNA, circulating tumor DNA (ctDNA), circulating cell-free tumor DNA, and diagnosis. The retrieval period was set until September 2021. According to PICOS (patients, intervention, comparison, outcomes, and study design) principles the inclusion criteria were: aged ≥18 years; at least 10 NSCLC cases; NSCLC patients diagnosed by histopathology or cytology; circulating cfDNA was detected; outcome data could be completely extracted. Bias risk assessment was conducted according to the QUADAS (Quality Assessment of Diagnostic Accuracy Studies). RevMan 5.3 was used for meta-analysis.ResultsEight studies met the inclusion criteria, including a total of 618 NSCLC patients and 635 healthy subjects. The overall sensitivity and specificity were 0.79 [95% confidence interval (CI): 0.75-0.82] and 0.81 (95% CI: 0.78-0.84), respectively. The area under the curve (AUC) of the summary receiving operating characteristic (SROC) curve was 0.8941. The pooled positive likelihood ratio, pooled negative likelihood ratio, and pooled diagnostic odds ratio were 5.37 (95% CI: 2.67-10.81), 0.24 (95% CI: 0.15-0.38), and 24.68 (95% CI: 8.85-68.84), respectively. The patient selection bias was high in two articles was high, unclear in one article, and low in the remaining five ones. The risk of bias in the research index test was unclear in one article, and low in the remaining seven articles. The reference standard bias, and flow and time bias of all articles was low.ConclusionsCirculating cfDNA is an efficacy biomarker in diagnosis of NSCLC. Its clinical application technology is worthy of further research.
| S-EPMC9264058 | biostudies-literature
Project description:We used computed tomography (CT) to explore the prognostic value of cell-free (cf) DNA quantification and its predictive efficacy over time after chemotherapy in non-small-cell lung cancer (NSCLC) patients. In total, 177 NSCLC patients were enrolled in a prospective biomarker trial. Consecutive paired blood collection was performed to determine cfDNA concentrations at baseline CT and throughout serial follow-ups. The best cfDNA cut-off value to predict progression-free and overall survival was determined using X-tile analysis. Among 112 chemo-naive patients with stage IV adenocarcinoma, 43 were available for follow-up analysis. Cox regression multivariate analysis indicated that a high cfDNA concentration was an independent negative prognostic factor for progression-free survival (hazard ratio: 2.60; 95% confidence interval: 1.65-4.10; p = 0.008) and overall survival (hazard ratio: 2.63; 95% confidence interval: 1.66-4.17; p < 0.001). However, cfDNA concentration changes during treatment did not correlate with radiological CT responses at first follow-up or best response. No pattern was noted in the percent change in the cfDNA concentration from baseline or subsequently measured level to progression. The serum cfDNA concentration is thus associated with NSCLC patient prognosis, but does not appear to be a clinically valid marker for tumor responses.
| S-EPMC5706884 | biostudies-other
Project description:Immune checkpoint inhibitors, such as pembrolizumab, are revolutionizing therapeutic strategies for different cancer types, including non-small-cell lung cancer (NSCLC). However, only a subset of patients benefits from this therapy, and new biomarkers are needed to select better candidates. In this study, we explored the value of liquid biopsy analyses, including circulating free DNA (cfDNA) and circulating tumour cells (CTCs), as a prognostic or predictive tool to guide pembrolizumab therapy. For this purpose, a total of 109 blood samples were collected from 50 patients with advanced NSCLC prior to treatment onset and at 6 and 12 weeks after the initiation of pembrolizumab. Plasma cfDNA was measured using hTERT quantitative PCR assay. The CTC levels at baseline were also analysed using two enrichment technologies (CellSearch® and Parsortix systems) to evaluate the efficacy of both approaches at detecting the presence of programmed cell death ligand 1 on CTCs. Notably, patients with high baseline hTERT cfDNA levels had significantly shorter progression-free survival (PFS) and overall survival (OS) than those with low baseline levels. Moreover, patients with unfavourable changes in the hTERT cfDNA levels from baseline to 12 weeks showed a higher risk of disease progression. Additionally, patients in whom CTCs were detected using the CellSearch® system had significantly shorter PFS and OS than patients who had no CTCs. Finally, multivariate regression analyses confirmed the value of the combination of CTCs and cfDNA levels as an early independent predictor of disease progression, identifying a subgroup of patients who were negative for CTCs, who presented low levels of cfDNA and who particularly benefited from the treatment.
| S-EPMC8564635 | biostudies-literature
Project description:Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer.
| S-EPMC4627334 | biostudies-literature
Project description:BACKGROUND:The overall aim was to investigate the change over time in circulating cell free DNA (cfDNA) in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemo-radiotherapy. Furthermore, to assess the possibility of detecting circulating cell free tumor DNA (ctDNA) using shallow whole genome sequencing (sWGS) and size selection. METHODS:Ten patients were included in a two-phase study. The first four patients had blood samples taken prior to a radiation therapy (RT) dose fraction and at 30 minutes, 1 hour and 2 hours after RT to estimate the short-term dynamics of cfDNA concentration after irradiation. The remaining six patients had one blood sample taken on six treatment days 30 minutes post treatment to measure cfDNA levels. Presence of ctDNA as indicated by chromosomal aberrations was investigated using sWGS. The sensitivity of this method was further enhanced using in silico size selection. RESULTS:cfDNA concentration from baseline to 120 min after therapy was stable within 95% tolerance limits of +/- 2 ng/ml cfDNA. Changes in cfDNA were observed during therapy with an apparent qualitative difference between adenocarcinoma (average increase of 0.69 ng/ml) and squamous cell carcinoma (average increase of 4.0 ng/ml). Tumor shrinkage on daily cone beam computer tomography scans during radiotherapy did not correlate with changes in concentration of cfDNA. CONCLUSION:Concentrations of cfDNA remain stable during the first 2 hours after an RT fraction. However, based on the sWGS profiles, ctDNA represented only a minor fraction of cfDNA in this group of patients. The detection sensitivity of genomic alterations in ctDNA strongly increases by applying size selection.
| S-EPMC7188247 | biostudies-literature
Project description:MLL3 histone methyltransferase, encoded by the KMT2C gene, is a tumor suppressor that has an essential role in cell-type-specific gene expression. We evaluated the prognostic significance of KMT2C promoter methylation as a circulating epigenetic biomarker in plasma cell-free DNA (cfDNA) in non-small cell lung cancer (NSCLC). We examined the methylation status of KMT2C promoter using a novel highly specific and sensitive real-time methylation-specific PCR (MSP) assay in (a) operable NSCLC: 48 fresh-frozen NSCLC tissues, their corresponding adjacent non-neoplastic tissues, and 48 matched plasma samples; (b) metastatic NSCLC: 91 plasma samples; and (c) 60 plasma samples from healthy donors (HD). KMT2C promoter methylation in plasma cfDNA was detected in 7/48 (14.6%) patients with operable and in 18/91 (19.8%) patients with advanced NSCLC but in none (0/60, 0%) of the plasma samples from HD. In operable NSCLC, in corresponding adjacent non-neoplastic tissue samples, KMT2C promoter methylation was detected in 3/48 (6.3%) cases. Moreover, in operable NSCLC, KMT2C promoter methylation in plasma cfDNA was related to reduced disease-free survival (ΗR = 0.239; P = 0.001) and worse overall survival (OS; HR = 0.342, P = 0.023). In metastatic NSCLC, KMT2C promoter methylation in plasma cfDNA was related to worse progression-free survival (PFS; HR = 0.431; P = 0.005) and worse OS (HR = 0.306; P < 0.001). Our data strongly suggest that the detection of KMT2C promoter methylation in plasma cfDNA predicts poor prognosis in patients with both operable and metastatic NSCLCs. KMT2C promoter methylation in plasma cfDNA therefore merits further evaluation and validation as a noninvasive circulating epigenetic biomarker.
| S-EPMC8410531 | biostudies-literature
Project description:: The treatment of advanced non-small cell lung cancer (NSCLC) has been revolutionized by immune checkpoint inhibitors (ICIs). The identification of prognostic and predictive factors in ICIs-treated patients is presently challenging. Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) were evaluated in 89 previously treated NSCLC patients receiving nivolumab. Blood samples were collected before therapy and at the first and second radiological response assessments. CTCs were isolated by a filtration-based method. cfDNA was extracted from plasma and estimated by quantitative PCR. Patients with baseline CTC number and cfDNA below their median values (2 and 836.5 ng from 3 mL of blood and plasma, respectively) survived significantly longer than those with higher values (p = 0.05 and p = 0.04, respectively). The two biomarkers were then used separately and jointly as time-dependent covariates in a regression model confirming their prognostic role. Additionally, a four-fold risk of death for the subgroup presenting both circulating biomarkers above the median values was observed (p < 0.001). No significant differences were found between circulating biomarkers and best response. However, progressing patients with concomitant lower CTCs and cfDNA performed clinically well (p = 0.007), suggesting that jointed CTCs and cfDNA might help discriminate a low-risk population which might benefit from continuing ICIs beyond progression.
| S-EPMC6679117 | biostudies-literature