The incidence of colorectal cancer (CRC) is gradually increasing, making the prevention and early detection of CRC a global priority. The purpose of this study is to evaluate the effect of fecal SDC2, ADHFE1, and PPP2R5C gene methylation on the screening of early CRC in the Otog Front Banner.

This is a retrospective study that collected and analyzed data from the early colorectal cancer screening program conducted in five community health centers in the Otog Front Banner, from January 2023 to October 2023. The study collected stool samples from subjects meeting the inclusion and exclusion criteria, extracted genomic DNA from the feces, and modified it with sulfite. Methylation-specific polymerase chain reaction (MSP) was then used to detect the methylation status of the SDC2, PPP2R5C, and ADHFE1 genes, completing the early screening for colorectalcancer. Individuals with positive screening outcomes were advised to undergo a colonoscopy, and ultimately, all participants completed the questionnaire on high-risk factors for colorectal cancer . The chi-square test was utilized to analyze the positive rates of fecal SDC2, ADHFE1, and PPP2R5C gene methylation screenings, colonoscopy compliance, the positive predictive value of intestinal lesions, and to assess the risk factors associated with cancer.

A total of 9,135 effective screeners were included in this study, and 636 of them tested positive during the initial screening, yielding a positive rate of 6.9%. The positive predictive value was 50.9% for all intestinal lesions, 1.4% for colorectal cancer , and 9.7% for advanced adenoma.

Fecal SDC2, ADHFE1, and PPP2R5C gene methylation detection methods can serve as primary screening tools, supplemented by colonoscopy, to effectively detect colorectal cancer and precancerous lesions. This strategy may prove to be an effective approach for conducting large-scale colorectal cancer screening in average-risk populations.

Cholangiocarcinoma (CCA), also known as bile duct cancer, is a devastating malignancy primarily affecting the biliary tract.

To assess their performance in clinical diagnosis and monitoring of CCA, plasma methylation and circulating tumor cells were detected.

Plasma samples were collected from Hubei Cancer Hospital (n = 156). Plasma DNA was tested to detect SHOX2, HOXA9, SEPTIN9, and RASSF1A methylation using TaqMan PCR. Circulating tumor cells (CTCs) were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy. The CCA diagnostic value was estimated using the area under the curve. The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.

The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74% sensitivity and 93.88% specificity for detecting CCA. The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828 ± 0.032. RASSF1A plasma methylation was related to the prognosis of patients with CCA. We determined the prognostic hazard ratio for CCA using CTC count, tumor stage, methylation, and carbohydrate antigen 19-9 levels as key factors. Our overall survival nomogram achieved a C-index of 0.705 (0.605-0.805).

SHOX2, HOXA9, SEPTIN9, and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA. RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.

Colorectal cancer (CRC) is the third-most-common malignancy and the second-leading cause of cancer-related deaths worldwide and current screening methods such as guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and colonoscopy have their own pros and cons. This study aimed to assess the effectiveness of a fecal DNA methylation test by using methylated SDC2 (mSDC2) as the epigenetic biomarker for detecting CRC in a screening-naïve population.

Fecal mSDC2 test and FIT were simultaneously performed on eligible 40- to 74-year-old adults of a regional township in China. Subjects with positive results were recommended for colonoscopy. Data of positivity rates, positive predicted values (PPVs), and detection rates associated with clinical characteristics were analysed.

The positivity rate of mSDC2 was 7.6% for 10,578 participants with valid results from both fecal mSDC2 test and FIT. With an adherence rate of 63.8% to colonoscopy referral, 25 CRCs, 189 advanced adenomas (AAs), and 165 non-advanced adenomas (NAAs) and polyps were detected. The PPVs of mSDC2 were 4.93%, 37.28%, and 32.54% for CRC, AA, and non-advanced lesions, respectively. When the CRCs and AAs were counted as positive findings, the fecal mSDC2 test showed a higher detective rate than FIT (relative risk [RR], 1.313 [1.129-1.528], P < 0.001). When NAAs and polyps were also specified as treatable lesions, the mSDC2 test was more effective in detecting these benign growths (RR, 1.872 [1.419-2.410]; P < 0.001). A combination of mSDC2 and FIT detected 29 CRCs, 298 AAs, and 234 NAAs and polyps. Overall, the fecal mSDC2 test had a higher detection rate for both advanced and non-advanced colonic lesions. The false-positive rate of the fecal mSDC2 test was comparable to that of FIT (RR, 1.169 [0.974-1.403]; P = 0.113).

The single-target stool-based mSDC2 test can effectively and accurately detect CRC and precancerous lesions in a large-scale CRC-screening program.

NCT05374369.

Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE).

Metabolic dysfunction is a key driver of heart failure (HF) progression. Identifying metabolic hub genes in HF may reveal novel therapeutic targets.

Transcriptomic datasets from HF patients (GEO database) and metabolism-related genes (PathCards) were analyzed. Differentially expressed genes (DEGs) were intersected with metabolism-related genes, followed by the application of the LASSO, Random Forest, and XGBoost algorithms to prioritize hub genes. Candidate genes were validated via WGCNA, an HF mouse model, and plasma metabolomics. Diagnostic performance and metabolic associations were assessed using ROC analysis and ssGSEA.

We identified 1115 HF-associated DEGs (701 upregulated, 414 downregulated), with 119 linked to metabolism. The machine learning algorithms prioritized five genes, including SDC2, which was also validated using WGCNA and the mouse HF model. SDC2 mRNA and protein expression levels were markedly elevated in HF and demonstrated strong diagnostic accuracy. ssGSEA revealed the expression of SDC2 was correlated with dysregulated metabolic pathways, including fatty acid biosynthesis and glycerolipid metabolism, which are potentially associated with metabolic alterations in HF.

SDC2 emerges as a central regulator bridging metabolic dysfunction and HF pathogenesis, showing potential as a diagnostic biomarker and therapeutic target.

To investigate the clinical significance of fecal Syndecan-2 (SDC2) gene methylation combined with blood tumor abnormal protein (TAP) detection for the diagnosis of colorectal cancer (CRC) and its precancerous lesions.

A retrospective study was conducted to collect patients diagnosed with CRC or colorectal adenoma (Ade) from March 2020 to March 2023, and healthy people (Nor) without any gastrointestinal diseases during the same period as the control group. All participants underwent the fecal SDC2 gene methylation test, blood TAP test and fecal occult blood test (FOBT). The differences in the positivity rates of each index were compared, receiver operator characteristic curves were plotted and the area under the curve (AUC) was calculated to evaluate the diagnostic effects of different testing methods on CRC and its precancerous lesions.

A total of 146 individuals were included in the study, including 69 CRC patients, 47 patients with Ade and 30 healthy individuals. The results showed that, SDC2, TAP and the combined assay had high comprehensive diagnostic efficacy for the diagnosis of CRC, but there was no significant difference between the three methods in terms of AUC, sensitivity, and specificity. However, for Ade, the combined detection was statistically significant, with a high AUC (0.905), high sensitivity (95.7%), and high specificity (86.7%).

Fecal SDC2 gene methylation combined with blood TAP detection is an effective noninvasive screening and diagnostic method to enhance the early detection and treatment of CRC precancerous lesions, such as Ade, thereby reducing the incidence and mortality of CRC.

Noninvasive stool DNA-based methylation testing has emerged as an effective strategy for the early colorectal cancer (CRC) detection. Syndecan-2 ( SDC2 ) methylation frequently occurs in all stages of CRC; therefore, the aim of this study was to evaluate the clinical performance of a stool DNA-based SDC2 methylation test for detecting CRC in asymptomatic or high-risk CRC populations.

This multicenter prospective study was conducted to determine the clinical performance of the SDC2 methylation test on stool DNA using real-time polymerase chain reaction. Stool samples were collected from asymptomatic individuals before colonoscopy, and the test results were independently analyzed through comparison with colonoscopic findings and pathological outcomes as reference standards.

Of the 1,124 evaluable participants, 20 had CRC, 73 had advanced adenomatous polyps (≥1.0 cm), 469 had nonadvanced adenomatous polyps (<1.0 cm), 178 had non-neoplastic polyps, and 384 had negative colonoscopy results. The stool SDC2 methylation test had a sensitivity and specificity of 95.0% and 81.5%, respectively, for detecting CRC, while the sensitivity for detecting advanced adenomatous polyps and CRC was 58.1%. The rate of adenoma detection increased with polyp size ( P < 0.01), and sensitivity was not associated with CRC stage ( P = 0.864).

The stool DNA-based SDC2 methylation test attained a high sensitivity for CRC detection in an asymptomatic high-risk population. Further large-scale clinical studies are required to validate the clinical utility of this test as a population-based CRC screening tool.

Accurate identification and quantification of 5-hydroxymethylcytosine (5hmC) can help elucidate its function in gene expression and disease pathogenesis. Current 5hmC analysis methods still present challenges, especially for clinical applications, such as having a risk of false-positive results and a lack of sufficient sensitivity. Herein, a 5hmC quantification method for fragment-specific DNA sequences with extreme specificity, high sensitivity, and clinical applicability was established using a quantitative real-time PCR (qPCR)-based workflow through the combination of enzymatic digestion and biological deamination strategy (EDD-5hmC assay). The EDD-5hmC approach enriched glycosylated 5hmC via enzyme digestion and then APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like)-mediated deamination to efficiently differentiate between various cytosine(C) modification states, resulting in 5hmC quantification with extreme specificity such that nonspecific amplification is reduced over eight million-fold. Moreover, the nondestructive biological treatment process of the EDD-5hmC assay exhibits high sensitivity, yielding the limit of detection of 30 aM. For the first time, we measured 5hmC levels in colorectal cancer tissues and matched paracancerous tissues to evaluate the ability to differentiate colorectal cancer, with the area under the receiver operating characteristic curve of up to 82.8% for the single gene of Septin9 and 83.6% for the combinations of Septin9 and Syndecan-2 (SDC2), demonstrating the EDD-5hmC assay is a promising method with clinical applicability for accurately quantifying the 5hmC level.

IntroductionEarly diagnosis of colorectal cancer (CRC) poses a significant clinical challenge. This study aims to develop machine learning (ML) models for CRC risk prediction using clinical laboratory data.MethodsThis retrospective, single-center study analyzed laboratory examination data from healthy controls (HC), polyp patients (Polyp), and CRC patients between 2013 and 2023. Five ML algorithms, including adaptive boosting (AdaBoost), extreme gradient boosting (XGBoost), decision tree (DT), logistic regression (LR), and random forest (RF), were employed to classify subjects into HC vs Polyp vs CRC, HC vs CRC, and Polyp vs CRC, respectively.ResultsThis study included 31 539 subjects: 11 793 HCs, 10 125 polyp patients, and 9621 CRC patients. The XGBoost model achieved the highest AUCs of 0.966 for differentiating HC from CRC and 0.881 for Polyp from CRC, outperforming carcino-embryonic antigen (CEA) and fecal occult blood testing (FOBT) tests. This model could also identify CEA-negative or FOBT-negative CRC patients. Incorporating stool miR-92a detection into the model further improved diagnostic performance. Shapley additive explanations (SHAP) plots indicated that FOBT, CEA, lymphocyte percentage (LYMPH%), and hematocrit (HCT) were the most significant features contributing to CRC diagnosis. Additionally, a computational tool for predicting CRC risk based on the optimal model was developed, designed for researchers with programming experience.ConclusionFive ML models for CRC diagnosis, based on ten routine laboratory test items, were developed, achieving higher diagnostic accuracies than traditional CRC biomarkers. The diagnostic capabilities of these ML models can be further enhanced by including stool miR-92a levels.

Colorectal cancer (CRC) is a major public health concern and the second leading cause of cancer-related deaths worldwide. However, challenges remain in deploying effective screening strategies for early-stage CRC. This study aimed to evaluate the effectiveness of a fecal-based syndecan-2 (SDC2) methylation test for the detection of colorectal lesions and CRC.

We retrospectively collected data on participants who underwent fecal SDC2 methylation testing from January 1, 2019, to May 30, 2023. Patients with positive results were recommended to undergo colonoscopy. Performance indicators associated with certain clinical characteristics, including positive rate (PR), positive predictive value (PPV), and colonoscopy compliance rate (CCR), were subjected to statistical analysis.

We analyzed data from 113,209 participants, of whom 11,841 (10.4% PR) had positive fecal SDC2 methylation test results. A total of 4315 participants with positive results adhered to the colonoscopy recommendations, and the CCR was 36.4%. Finally, 3169 colorectal lesions were detected, including 1134 polyps, 875 non-advanced adenomas (NAAs), 770 advanced adenomas (AAs), and 390 CRCs, with PPV values of 26.3% (1134/4315), 20.3% (875/4315), 17.8% (770/4315), and 9.0% (390/4315), respectively. Notably, the PPV for CRC increased significantly with age (χ 2 = 164.40, P < 0.0001). In addition, as the cycle threshold (CT) values increased, the PPVs of AAs and CRCs generally decreased, whereas those of NAAs and polyps significantly increased. Moreover, the clinical patient group had the highest incidence of late-stage CRC (stage II and higher), whereas asymptomatic populations from the staff physical examination group and rural town-based screening programs had the highest number of stage 0 and I CRCs detected (P = 0.0107).

This study indicates that fecal SDC2 methylation testing combined with colonoscopy may be an effective screening method for colorectal lesions and CRC.

Atmospheric particulate matter (PM) is one of the most dangerous air pollutants of anthropogenic origin; it consists of a heterogeneous mixture of inorganic and organic components, including transition metals and polycyclic aromatic hydrocarbons. Although previous studies have focused on the effects of exposure to highly concentrated PM on the respiratory and cardiovascular systems, emerging evidence supports a significant impact of air pollution on the gastrointestinal (GI) tract by linking exposure to external stressors with conditions such as appendicitis, colorectal cancer, and inflammatory bowel disease. In general, it has been hypothesized that the main mechanism involved in PM toxicity consists of an inflammatory response and this has also been suggested for the GI tract. In the present study, we analyzed the effect of specific redox-active PM components, such as copper (Cu) and iron (Fe), in human intestinal cells focusing on ultrastructural integrity, redox homeostasis, and modulation of some mitochondrial-related markers. According to our results, exposure to Cu- and Fe-PM components and their combination induced ultrastructural alterations in the endoplasmic reticulum and in the mitochondria with an additive effect when combined. The increase in ROS and the loss of the mitochondrial mass in the cells exposed to PM indicates that mitochondria are a target of acute metal exposure. Furthermore, the gene expression and the protein levels of mitochondria dynamics markers were affected by the PM exposure. In particular, OPA1 increases at both gene and protein levels in all conditions while Mitofusin1 decreases significantly only in the presence of Fe. The increase in PINK expression is modulated by Fe, while Cu seems to affect mainly Parkin. Finally, a significant decrease in trans-epithelial resistance was also observed. In general, our study can confirm the correlation observed between pollution exposure areas and increased incidence of GI tract conditions.

The feasibility of population screening for colorectal cancer has been demonstrated in several studies. Most of these studies have considered individual characteristics, diagnostic approaches, epidemiological data, and socioeconomic factors. In this article, we comment on an editorial by Metaxas et al published in the recent issue of the journal. The authors emphasized the need to raise public awareness through health education programs and the possibility of using easily accessible non-invasive screening methods. Here, we focus on non-invasive molecular genetic approaches that can aid in colorectal cancer screening. On the one hand, we highlighted the use of tumor DNA/RNA markers directly for screening and, on the other hand, underline the use of polygenic risk assessment and hereditary predisposition to select individuals for more thorough cancer screening.

Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications.

We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis.

Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing.

Fecal DNA-based Syndecan 2 (SDC2) methylation detection is a promising non-invasive strategy for early colorectal cancer (CRC) screening. In China, commercial assays for SDC2 methylation detection vary in sensitivity and specificity, yet there is no standardized external quality assessment (EQA) to ensure accuracy. This study utilized CRISPR-Cas9 and homology-directed repair (HDR) technologies to edit the SDC2 promoter in 293T cells, creating hypermethylated and heterogeneous cell lines. These cell lines were used to develop an EQA panel for SDC2 methylation. We established a 10-sample panel, encompassing a range of methylation levels, and conducted an EQA across 140 laboratories. Among 1,400 results, 0.57% were incorrect. The optimized EQA materials effectively monitor the accuracy of SDC2 methylation detection in CRC, supporting reliable and consistent clinical testing and contributing to early CRC screening and diagnosis in China.

Background: Early screening for colorectal cancer (CRC) has the potential to improve patient prognosis, but current screening methods are limited. In this prospective study, we aimed to evaluate the multigene (Septin9, SDC2, KCNQ5, and IKZF1) detection in patient plasma for CRC diagnosis. Methods: Overall, 67 participants were enrolled, including 31 patients with CRC, 17 patients with colorectal polyp, and 19 normal controls who underwent colonoscopy. Carcinoembryonic antigen (CEA) and Septin9, SDC2, KCNQ5, and IKZF1 methylation tests were performed. Sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve were used to evaluate the diagnostic value of each biomarker. The association between positive rates of methylated Septin9, SDC2, KCNQ5, and IKZF1 and the clinicopathological characteristics of CRC was also analyzed. Results: The positive rate of multigene methylation detection was 87.1% (27/31) in patients with CRC, which was higher than single indicators: CEA (51.61%, 16/31), Septin9 (41.94%, 13/31), SDC2 (41.94%, 13/31), KCNQ5 (58.06%, 18/31), and IKZF1 (32.26%, 10/31). In the colorectal polyp group, the rate of multigene methylation detection is 88.24% (15/17), which was also higher than single indicator: CEA (17.65%, 3/17), Septin9 (11.76%, 2/17), SDC2 (64.71%, 11/17), KCNQ5 (58.82%, 10/17), and IKZF1 (35.29%, 6/17). The ROC curves further showed better diagnostic value of the multigene test for CRC than any single gene. Correlation analysis found that the positive rate of the test was not affected by patients' clinicopathologic characteristics. Conclusion: The combination of methylated Septin9, SDC2, KCNQ5, and IKZF1 tests is preferable to individual gene tests for patients with CRC and polyp.

Early detection, diagnosis, and treatment of colorectal cancer and its precancerous lesions can significantly improve patients' survival rates. The purpose of this research is to identify methylation markers specific to colorectal cancer tissues and validate their diagnostic capability in colorectal cancer and precancerous changes by measuring the level of DNA methylation in stool samples.

We analyzed samples from six cancer tissues and adjacent normal tissues and fecal samples from 758 participants, including 62 patients with interfering diseases. Bioinformatics databases were used to screen for candidate biomarkers for CRC, and quantitative methylation-specific PCR methods were applied for identification. The methylation levels of the candidate biomarkers in fecal and tissue samples were measured. Logistic regression and random forest models were built and validated using fecal sample data from one of the centers, and the independent or combined diagnostic value of the candidate biomarkers in fecal samples for CRC and precancerous lesions was analyzed. Finally, the diagnostic capability and stability of the model were validated at another medical center.

This study identified two colorectal cancer CpG sites with tissue specificity. These two biomarkers have certain diagnostic power when used individually, but their diagnostic value for colorectal cancer and colorectal adenoma is more significant when they are used in combination.

The results indicate that a DNA methylation biomarker combined diagnostic model based on two CpG sites, cg13096260 and cg12587766, has the potential for screening and diagnosing precancerous lesions and colorectal cancer. Additionally, compared to traditional diagnostic models, machine learning algorithms perform better but may yield more false-positive results, necessitating further investigation.

This study was conducted with the primary objective of assessing the performance of cfDNA methylation in the detection of colorectal cancer (CRC). Five tumor tissue, 20 peripheral blood leucocyte, and 169 cfDNA samples were collected for whole-genome bisulfite sequencing (WGBS) analysis. Bioinformatic analysis was conducted to identify differentially methylated regions (DMRs) and their functional characteristics. Quantitative methylation-specific PCR (qMSP) was used to validate the methylation levels of DMRs in the tissues and leucocytes. cfDNA samples from CRC patients and healthy controls were used to evaluate the performance of the DMR analysis. WGBS analysis revealed a decrease in DNA methylation levels in the CpG context in CRC tumor tissues compared with adjacent normal tissues. A total of 132 DMRs in cfDNA were identified as potential markers for diagnosing CRC. In a cohort of 95 CRC patients and 74 healthy controls, a combination of the three DMRs (DAB1, PPP2R5C, and FAM19A5) yielded an AUC of 0.763, achieving 64.21% sensitivity and 78.38% specificity in discriminating CRC patients from healthy controls. This study provides insights into DNA methylation patterns in CRC and identifies a set of DMRs in cfDNA with potential diagnostic value for CRC. These DMRs hold promise as biomarkers for CRC detection, offering promise for non-invasive CRC diagnosis. Further research is warranted to validate these findings in larger cohorts.

Technological advancements in cell-free DNA (cfDNA) liquid biopsy have triggered exponential growth in numerous clinical applications. While cfDNA-based liquid biopsy has made significant strides in personalizing cancer treatment, the exploration and translation of epigenetics in liquid biopsy to clinical practice is still nascent. This comprehensive review seeks to provide a broad yet in-depth narrative of the present status of epigenetics in cfDNA liquid biopsy and its associated challenges. It highlights the potential of epigenetics in cfDNA liquid biopsy technologies with the hopes of enhancing its clinical translation. The momentum of cfDNA liquid biopsy technologies in recent years has propelled epigenetics to the forefront of molecular biology. We have only begun to reveal the true potential of epigenetics in both our understanding of disease and leveraging epigenetics in the diagnostic and therapeutic domains. Recent clinical applications of epigenetics-based cfDNA liquid biopsy revolve around DNA methylation in screening and early cancer detection, leading to the development of multi-cancer early detection tests and the capability to pinpoint tissues of origin. The clinical application of epigenetics in cfDNA liquid biopsy in minimal residual disease, monitoring, and surveillance are at their initial stages. A notable advancement in fragmentation patterns analysis has created a new avenue for epigenetic biomarkers. However, the widespread application of cfDNA liquid biopsy has many challenges, including biomarker sensitivity, specificity, logistics including infrastructure and personnel, data processing, handling, results interpretation, accessibility, and cost effectiveness. Exploring and translating epigenetics in cfDNA liquid biopsy technology can transform our understanding and perception of cancer prevention and management. cfDNA liquid biopsy has great potential in precision oncology to revolutionize conventional ways of early cancer detection, monitoring residual disease, treatment response, surveillance, and drug development. Adapting the implementation of liquid biopsy workflow to the local policy worldwide and developing point-of-care testing holds great potential to overcome global cancer disparity and improve cancer outcomes.

Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes.

By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions.

The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Bronchoscopic-assisted discrimination of lung tumors presents challenges, especially in cases with contraindications or inaccessible lesions. Through meta-analysis and validation using the HumanMethylation450 database, this study identified methylation markers for molecular discrimination in lung tumors and designed a sequencing panel. DNA samples from 118 bronchial washing fluid (BWF) specimens underwent enrichment via multiplex PCR before targeted methylation sequencing. The Recursive Feature Elimination Cross-Validation and deep neural network algorithm established the CanDo classification model, which incorporated 11 methylation features (including 8 specific to the TBR1 gene), demonstrating a sensitivity of 98.6% and specificity of 97.8%. In contrast, bronchoscopic rapid on-site evaluation (bronchoscopic-ROSE) had lower sensitivity (87.7%) and specificity (80%). Further validation in 33 individuals confirmed CanDo's discriminatory potential, particularly in challenging cases for bronchoscopic-ROSE due to pathological complexity. CanDo serves as a valuable complement to bronchoscopy for the discriminatory diagnosis and stratified management of lung tumors utilizing BWF specimens.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a persistent infectious disease threatening human health. The existing diagnostic methods still have significant shortcomings, including a low positivity rate in pathogen-based diagnoses and the inability of immunological diagnostics to detect active TB. Hence, it is urgent to develop new techniques to detect TB more accurate and earlier. This research aims to scrutinize and authenticate DNA methylation markers suitable for tuberculosis diagnosis. Concurrently, Providing a new approach for tuberculosis diagnosis.

Blood samples from patients with newly diagnosed tuberculosis and healthy controls (HC) were utilized in this study. Examining methylation microarray data from 40 whole blood samples (22TB + 18HC), we employed two procedures: signature gene methylated position analysis and signature region methylated position analysis to pinpoint distinctive methylated positions. Based on the screening results, diagnostic classifiers are constructed through machine learning, and validation was conducted through pyrosequencing in a separate queue (22TB + 18HC). Culminating in the development of a new tuberculosis diagnostic method via quantitative real-time methylation specific PCR (qMSP).

The combination of the two procedures revealed a total of 10 methylated positions, all of which were located in the promoter region. These 10 signature methylated positions facilitated the construction of a diagnostic classifier, exhibiting robust diagnostic accuracy in both cross-validation and external test sets. The LDA model demonstrated the best classification performance, achieving an AUC of 0.83, specificity of 0.8, and sensitivity of 0.86 on the external test set. Furthermore, the validation of signature methylated positions through pyrosequencing demonstrated high agreement with screening outcomes. Additionally, qMSP detection of 2 potential hypomethylated positions (cg04552852 and cg12464638) exhibited promising results, yielding an AUC of 0.794, specificity of 0.720, and sensitivity of 0.816.

Our study demonstrates that the validated signature methylated positions through pyrosequencing emerge as plausible biomarkers for tuberculosis diagnosis. The specific methylation markers in the TSPAN4 gene, identified in whole blood samples, hold promise for improving tuberculosis diagnosis. This approach could significantly enhance diagnostic accuracy and speed, offering a new avenue for early detection and treatment.

Gastric cancer (GC) is one of the most common and deadly cancers worldwide. Early detection offers the best chance for curative treatment and reducing its mortality. However, the optimal population-based early screening for GC remains unmet. Aberrant DNA methylation occurs in the early stage of GC, exhibiting cancer-specific genetic and epigenetic changes, and can be detected in the media such as blood, gastric juice, and feces, constituting a valuable biomarker for cancer early detection. Furthermore, DNA methylation is a stable epigenetic alteration, and many innovative methods have been developed to quantify it rapidly and accurately. Nonetheless, large-scale clinical validation of DNA methylation serving as tumor biomarkers is still lacking, precluding their implementation in clinical practice. In conclusion, after a critical analysis of the recent existing literature, we summarized the evolving roles of DNA methylation during GC occurrence, expounded the newly discovered noninvasive DNA methylation biomarkers for early detection of GC, and discussed its challenges and prospects in clinical applications.

Recent studies have identified methylated SDC2 and NDRG4 in colorectal cancer (CRC), however, the diagnostic value of the combined two genes remains undefined. This study aims to investigate the methylation of SDC2 and NDRG4 in stool samples and their application in diagnosis of CRC.

Five groups were enrolled in our study which consisted of CRC (n = 138), advanced adenomas (n = 27), polyp (n = 35), intestinal disease control (n = 150), and healthy individuals (n = 28). Methylation status of SDC2 and NDRG4 in fecal samples were tested with appropriate commercial kits. Primary data were collected and statistical analyses were performed.

The positive rates of both SDC2 and NDRG4 methylation in stool samples of CRC group were significantly higher (P < 0.001) than those of either group of advanced adenomas, or polyp, or intestinal disease or the healthy control. It was suggested that both methylated SDC2,NDRG4, SDC2/NDRG4 and age were independent risk factors for CRC. The sensitivity of SDC2 and NDRG4 for CRC diagnosis were 73.9 % and 63.0 %, respectively, while SDC2 combined with NDRG4 had a higher sensitivity of 85.5 %. The specificity of SDC2, NDRG4 and SDC2 combined with NDRG4 achieved 91.6 %, 88.3 % and 84.6 %, respectively. The AUC for methylated SDC2 and NDRG4 were 0.828 (95 % CI: 0.780-0.876) and 0.757 (95 % CI: 0.703-0.811), respectively. In contrast, SDC2 combined with NDRG4 improved the AUC to 0.850 (95 % CI: 0.807-0.893).

This research confirmed the significance of detection of SDC2 and NDRG4 methylation by using noninvasive samples of stool. More importantly, attributing to their high level and frequency of methylation in stool, SDC2 and NDRG4 could be promising biomarkers for stool-based method for screening and early diagnosis of CRC, especially when combined.

The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice.

Colorectal cancer (CRC) is a multifaceted disease influenced by the interplay of genetic and environmental factors. The clinical heterogeneity of CRC cannot be attributed exclusively to genetic diversity and environmental exposures, and epigenetic markers, especially DNA methylation, play a critical role as key molecular markers of cancer. This review compiles a comprehensive body of evidence underscoring the significant involvement of DNA methylation modifications in the pathogenesis of CRC. Moreover, this review explores the potential utility of DNA methylation in cancer diagnosis, prognostics, assessment of disease activity, and prediction of drug responses. Recognizing the impact of DNA methylation will enhance the ability to identify distinct CRC subtypes, paving the way for personalized treatment strategies and advancing precision medicine in the management of CRC.

Purpose: The performance and clinical accuracy of combined SDC2/NDRG4 methylation were evaluated in diagnosing colorectal cancer (CRC) and advanced adenoma. Methods: A total of 2333 participants were enrolled to assess the sensitivity and specificity of biomarkers in diagnosing CRC in a multicenter clinical trial through feces DNA methylation tests. Results: SDC2/NDRG4 methylation showed excellent performance for CRC detection in biomarker research and the real world. Its sensitivity for detecting CRC, early CRC and advanced adenoma were 92.06%, 91.45% and 62.61%, respectively. Its specificity was 94.29%, with a total coincidence rate of 88.28%. When interference samples were included, the specificity was still good (82.61%). Therefore, the SDC2/NDRG4 methylation test showed excellent performance in detecting CRC and advanced adenoma under clinical application.

Colorectal cancer (CRC) is one of the most frequent types of cancer, with high incidence rates and mortality globally. The extended timeframe for developing CRC allows for the potential screening and early identification of the disease. Furthermore, studies have shown that survival rates for patients with cancer are increased when diagnoses are made at earlier stages. Recent research suggests that the development of CRC, including its precancerous lesion, is influenced not only by genetic factors but also by epigenetic variables. Studies suggest epigenetics plays a significant role in cancer development, particularly CRC. While this approach is still in its early stages and faces challenges due to the variability of CRC, it shows promise as a potential method for understanding and addressing the disease. This review examined the current evidence supporting genetic and epigenetic biomarkers for screening and diagnosis. In addition, we also discussed the feasibility of translating these methodologies into clinical settings. Several markers show promising potential, including the methylation of vimentin (VIM), syndecan-2 (SDC2), and septin 9 (SEPT9). However, their application as screening and diagnostic tools, particularly for early-stage CRC, has not been fully optimized, and their effectiveness needs validation in large, multi-center patient populations. Extensive trials and further investigation are required to translate genetic and epigenetic biomarkers into practical clinical use. biomarkers, diagnostic biomarkers.

Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis.

AOM/DSS was used to induce tumor in BALB/c mice. Using an in vivo-jetPEI transfection reagent, transient transfection of AEG-1 and EXT-1 siRNAs were achieved. Histological scoring, immunohistochemical staining, and gene expression studies were performed from excised tissues. Data from the Cancer Genomic Atlas and GEO databases were obtained to identify the expression status of AEG-1 and itsassociation with the survival.

In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients.

This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion.

Epigenetic modifications have long been recognized as an essential level in transcriptional regulation linking behavior and environmental conditions or stimuli with biological processes and disease development. Among them, methylation is the most abundant of these reversible epigenetic marks, predominantly occurring on DNA, RNA, and histones. Methylation modification is intimately involved in regulating gene transcription and cell differentiation, while aberrant methylation status has been linked with cancer development in several malignancies. Early detection and precise restoration of dysregulated methylation form the basis for several epigenetics-based therapeutic strategies. In this review, we summarize the current basic understanding of the regulation and mechanisms responsible for methylation modification and cover several cutting-edge research techniques for detecting methylation across the genome and transcriptome. We then explore recent advances in clinical diagnostic applications of methylation markers of various cancers and address the current state and future prospects of methylation modifications in therapies for different diseases, especially comparing pharmacological methylase/demethylase inhibitors with the CRISPRoff/on methylation editing systems. This review thus provides a resource for understanding the emerging role of epigenetic methylation in cancer, the use of methylation-based biomarkers in cancer detection, and novel methylation-targeted drugs.

Microrchidia 2 (MORC2) is a universally expressed molecule that has recently been identified as a chromatin modulator and elevated in many malignancies. However, its prognostic value and immunological role of MORC2 in colon adenocarcinoma (COAD) have never been illustrated.

The clinical parameters and MORC2 expression datasets of COAD patients were obtained from The Cancer Genome Atlas (TCGA). Cancer and adjacent tissue specimens from surgically resected COAD patients were collected, and quantitative real-time PCR was used to detect MORC2 expression. Differentially expressed genes related to MORC2 were discovered and used for functional enrichment analysis. The diagnostic and prognostic values of MORC2 in COAD were conducted using receiver operating characteristics (ROC), Kaplan-Meier survival curve analysis, PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA) public databases and nomograms. Eventually, the association of MORC2 with tumor microenvironment was analyzed by using TIMER and GSVA package of R (v3.6.3).

MORC2 expression was upregulated in COAD tissues, and the RT-qPCR results further verified the reliability of our differential analysis at the transcriptional level. Additionally, higher expression of MORC2 was correlated to a poor prognosis for COAD patients. MORC2 was an independent prognostic factor for COAD and could be a diagnostic factor for early COAD. Furthermore, MORC2 expression was positively correlated with immune cells such as NK cells, TFH cells and so on.

The findings demonstrated that overexpression of MORC2 was correlated with worse prognosis and immune infiltrates of COAD. MORC2 can serve as a reliable diagnostic and prognostic biomarker and a target of immunotherapy for COAD patients.

The impact of coronavirus disease 2019 (COVID-19) on the management of colorectal cancer (CRC) may worse in elderly population, as almost all COVID-19 deaths occurred in the elderly patients. This study aimed to evaluate the impact of COVID-19 on CRC management in the elderly population.

The numbers of patients who underwent colonoscopy, who visited hospitals or operated for CRC in 2020 and 2021 (COVID-19 era) were compared with those in 2019, according to 3 age groups (≥70 years, 50-69 years, and ≤49 years), based on the nationwide, population-based database (2019-2021) in South Korea.

The annual volumes of colonoscopy and hospital visits for CRC in 2020 were more significantly declined in the old age group than in the young age group (both P<0.001). In addition, the annual volume of patients operated for CRC numerically more declined in old age group than in young age group. During the first surge of COVID-19 (March and April 2020), old age patients showed statistically significant declines for the monthly number of colonoscopies (-46.5% vs. -39.3%, P<0.001), hospital visits (-15.4% vs. -7.9%, P<0.001), CRC operations (-33.8% vs. -0.7%, P<0.05), and colonoscopic polypectomies (-41.8% vs. -38.0%, P<0.001) than young age patients, compared with those of same months in 2019.

Elderly population are more vulnerable for the management of CRC during the COVID-19 pandemic. Therefore, the elderly population are more carefully cared for in the management of CRC during the next pandemic.

Colorectal cancer (CRC) is a disease of global concern, and its increasing incidence suggests the need for early and accurate diagnosis. The aim of this study was to investigate the value of combined detection of SDC2, ADHFE1 and PPP2R5C gene methylation in stool samples for early CRC screening.

Stool samples from patients with CRC (n = 105), advanced adenoma (AA) (n = 54), non-advanced adenoma (NA) (n = 57), hyperplastic or other polyps (HOP) (n = 47) or no evidence of disease (NED) (n = 100) were collected from September 2021 to September 2022. The methylation levels of SDC2, ADHFE1 and PPP2R5C were quantified by quantitative methylation-specific polymerase chain reaction (qMSP), and faecal immunochemical testing (FIT) was performed. The diagnostic value was assessed using reporter operating characteristic (ROC) curve analysis.

The sensitivity of combined detection of SDC2/ADHFE1/PPP2R5C methylation in predicting CRC (0-IV) was 84.8%, the specificity was 98.0%, and the AUC was 0.930 (95% CI 0.889-0.970). Compared to FIT and serum tumour biomarkers, it showed better diagnostic performance for different stages of CRC.

The results of this study verified that the methylation levels of SDC2, ADHFE1 and PPP2R5C in stool DNA were significantly increased in CRC patients. Combined detection of SDC2/ADHFE1/PPP2R5C methylation is a potential non-invasive diagnostic method for CRC and precancerous lesion screening.

Chinese Clinical Trials Registry, ChiCTR2100046662, registered on 26 May 2021, prospective registration.

To explore the value of testing methylated SDC2 (SDC2) in stool DNA combined with fecal immunochemical test (FIT) and serum tumor markers (TM) for the early detection of colorectal neoplasms.

A total of 533 patients, including 150 with CRC (67 with early-stage CRC), 23 with APL, 85 with non-advanced adenomas and general polyps, and 275 with benign lesions and healthy controls. SDC2 was detected by methylation-specific PCR, FIT (hemoglobin, Hb and transferrin, TF) was detected by immunoassay, and the relationships between SDC2, FIT, and clinicopathological features were analyzed. Pathological biopsy or colonoscopy were used as gold standards for diagnosis, and the diagnostic efficacy of SDC2 combined with FIT and TM in CRC and APL evaluated using receiver operating characteristic (ROC) curves.

SDC2 positive rates in early-stage CRC and APL were 77.6% (38/49) and 41.2% (7/17), respectively, and combination of SDC2 with FIT increased the positive rates to 98.0% (48/49) and 82.4% (14/17). The positive rates of SDC2 combined with FIT assay in the APL and CRC groups at stages 0-IV were 82.4% (14/17), 85.7% (6/7), 100% (16/16), 100% (26/26), 97.4% (38/39), and 100% (22/22), respectively. Compared to the controls, both the CRC and APL groups showed significantly higher positive detection rates of fecal SDC2 and FIT (χ2 = 114.116, P < 0.0001 and χ2 = 85.409, P < 0.0001, respectively). Our results demonstrate a significant difference in the qualitative methods of SDC2 and FIT for the detection of colorectal neoplasms (McNemar test, P < 0.0001). ROC curve analysis revealed that the sensitivities of SDC2 and FIT, alone or in combination, for the detection of early CRC and APL were 69.9%, 86.3%, and 93.9%, respectively (all P<0.0001). When combined with CEA, the sensitivity increased to 97.3% (P<0.0001).

SDC2 facilitates colorectal neoplasms screening, and when combined with FIT, it enhances detection. Furthermore, the combination of SDC2 with FIT and CEA maximizes overall colorectal neoplasm detection.

The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden. The journey from the discovery of DNA methylation (DNAm) as a biological process to its emergence as a diagnostic tool is one of the finest examples of such metamorphosis and has taken nearly a century. Particularly in the last decade, the application of DNA methylation studies in the clinic has been standardized more than ever before, with great potential to diagnose a multitude of diseases that are associated with a burgeoning number of genes with this epigenetic alteration. Fetal DNAm detection is becoming useful for noninvasive prenatal testing, whereas, in very preterm infants, DNAm is also shown to be a potential biological indicator of prenatal risk factors. In the context of cancer, liquid biopsy-based DNA-methylation profiling is offering valuable epigenetic biomarkers for noninvasive early-stage diagnosis. In this review, we focus on the applications of DNA methylation in prenatal diagnosis for delivering timely therapy before or after birth and in detecting early-stage cancers for better clinical outcomes. Furthermore, we also provide an up-to-date commercial landscape of DNAm biomarkers for cancer detection and screening of cancers of unknown origin.

Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC.

Colorectal cancer (CRC) is the second most common cause of cancer-related death (9.4% of the 9.9 million cancer deaths). However, CRC develops slowly, and early detection and intervention can effectively improve the survival rate and quality of life. Although colonoscopy can detect and diagnose CRC, it is unsuitable for CRC screening in average-risk populations. Some commercial kits based on DNA mutation or methylation are approved for screening, but the low sensitivity for advanced adenoma or early-stage CRC would limit the applications.

Recently, researchers have focused on developing noninvasive or minimally invasive, easily accessible biomarkers with higher sensitivity and accuracy for CRC screening. Numerous reports describe advances in biomarkers, including DNA mutations and methylation, mRNA and miRNA, gut microbes, and metabolites, as well as low-throughput multiomics panels. In small cohorts, the specificity and sensitivity improved when fecal immunochemical testing combined with other biomarkers; further verification in large cohorts is expected. In addition, the continuous improvement of laboratory technology has also improved the sensitivity of detection technology, such as PCR, and the application of CRISPR/Cas technology. Besides, artificial intelligence has extensively promoted the mining of biomarkers. Machine learning was performed to construct a diagnosis model for CRC screening based on the cfDNA fragment features from whole-genome sequencing data. In another study, multiomics markers, including cfDNA, epigenetic, and protein signals, were also discovered by machine learning. Finally, advancements in sensor technology promote the applicability of volatile organic compounds in CRC early detection.

Here, the authors review advances in early detection and screening of CRC based on different biomarker types. Most studies reported optimistic findings based on preliminary research, and prospective clinical studies are ongoing. These promising biomarkers are expected to more accurately identify early-stage patients with CRC and be applied in the future.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Aberrant regulation of DNA methylation in promoters of tumor suppressor genes or proto-oncogenes is one of the fundamental processes driving the initiation and progression of CRC. Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and function in many important biological processes related to tumorigenesis. Herein, we detected abnormal hypermethylation of the ZNF334 gene in CRC tissues compared with normal tissues, and this modification downregulated the expression of ZNF334. Furthermore, ten-eleven translocation 1 (TET1) was identified to be involved in regulating the methylation level of ZNF334. Next, a dCas9-multiGCN4/scFv-TET1CD-sgZNF334-targeted demethylation system was constructed to reverse the expression of ZNF334 through sgRNA targeting the ZNF334 promoter. Both in vitro and in vivo experiments demonstrated the targeted demethylation system upregulated ZNF334 expression and inhibited CRC growth. Collectively, targeted DNA demethylation of the ZNF334 promoter sheds light on the precise treatment of CRC.