• biomarkers
• colorectal cancer
• diagnosis
• imaging
• screening

• Colorectal cancer
• DNA methylation analysis
• Logistic regression
• Targeted sequencing

• Humans
• DNA Methylation
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/diagnosis
• Septins/genetics
• Feces/chemistry
• Syndecan-2/genetics
• Male
• Female
• Biomarkers, Tumor/genetics
• Middle Aged
• Aged
• Adult
• High-Throughput Nucleotide Sequencing/methods

• Biomarkers
• Colorectal neoplasms
• Diagnosis
• Epigenetic
• Prognosis

• Innate immunity
• Secretome
• Transcriptome
• WNT signalling
• p53

• Dactinomycin/pharmacology
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Cell Line, Tumor
• Proteomics
• Camptothecin/pharmacology
• Gene Expression Profiling
• Apoptosis/genetics
• Neoplasms
• Imidazoles
• Piperazines

• biomarkers
• colorectal cancer
• epigenetics
• methylation
• ncRNA

• Humans
• Epigenesis, Genetic
• Prognosis
• DNA Methylation/genetics
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/genetics
• Biomarkers
• Tumor Microenvironment/genetics

• 22JHQ084 Shaanxi Fundamental Science Research Project for Chemistry & Biology

• Epithelial membrane protein 3
• Epithelial-mesenchymal transition
• Glioblastoma
• Prognostic biomarker

• Humans
• Glioblastoma/pathology
• Prognosis
• Brain Neoplasms/pathology
• Glioma/pathology
• Epithelial-Mesenchymal Transition/genetics
• Membrane Glycoproteins/genetics
• Membrane Glycoproteins/metabolism

• SDC2/NDRG4 methylation
• advanced adenoma
• colorectal cancer
• diagnosis
• multicenter clinical study

• Humans
• DNA Methylation
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Biomarkers, Tumor/genetics
• Syndecan-2/genetics
• Sensitivity and Specificity
• Early Detection of Cancer
• Adenoma/diagnosis
• Adenoma/genetics
• Muscle Proteins/genetics
• Nerve Tissue Proteins/genetics

• 2021JJ40512 This work was supported by Project of the Natural Science Foundation of Hunan Province

• cancer
• colorectal cancer
• diagnostic biomarkers
• epigenetic biomarkers
• genetic biomarkers

• Humans
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/diagnosis
• Biomarkers, Tumor/genetics
• Epigenesis, Genetic
• Early Detection of Cancer/methods
• Septins/genetics
• DNA Methylation/genetics
• Syndecan-2/genetics
• Vimentin/genetics

• colorectal cancer
• diagnosis
• epigenetics
• metabolomics
• metagenomics
• methylome
• proteomics
• transcriptomics

• VRID PDO C22 Universidad San Sebastián

• C-type lectin receptor
• CRC
• DCs
• interleukins
• metabolic syndrome
• microbiota

• colorectal cancer
• ctDNA
• liquid biopsy
• metastasis
• methylation

• DNA methylation
• lymph node metastasis
• microarray analysis
• papillary thyroid carcinoma
• pathway enrichment analysis

• JYLJ202016 Clinical Research Program of 9th People's Hospital, Shanghai Jiao Tong University School of Medicine

• Age
• Alcohol
• Colon cancer
• Gender
• Race
• Stage
• Transcriptome
• circRNA
• lncRNA
• miRNA
• siRNA

• cancer
• colon
• colon cancer
• colon cancer prevention
• colon cancer surveillance
• colon polyps
• colonoscopy
• colorectal cancer
• fit test
• fobt

• Colon cancer
• NDRG4
• miR-23a-3p

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Cell Movement
• Colonic Neoplasms/genetics
• Muscle Proteins
• Nerve Tissue Proteins

Noninvasive diagnostic markers that are capable of distinguishing patients with colorectal cancer (CRC) from healthy individuals or patients with other cancer types are lacking. We report the discovery and validation of a panel of methylation-based markers that specifically detect CRC.

This was a large-scale discovery study based on publicly available datasets coupled with a validation study where multiple types of specimens from six cohorts with CRC, other cancer types, and healthy individuals were used to identify and validate the tissue-specific methylation patterns of CRC and assess their diagnostic performance.

In the discovery and validation cohort (N = 9307), ten hypermethylated CpG sites located in three genes, C20orf194, LIFR, and ZNF304, were identified as CRC-specific markers. Different analyses have suggested that these CpG sites are CRC-specific hypermethylated and play a role in transcriptional silencing of corresponding genes. A random forest model based on ten markers achieved high accuracy rates between 85.7 and 94.3% and AUCs between 0.941 and 0.970 in predicting CRC in three independent datasets and a low misclassification rate in ten other cancer types. In the in-house validation cohort (N = 354), these markers achieved consistent discriminative capabilities. In the cfDNA pilot cohort (N = 14), hypermethylation of these markers was observed in cfDNA samples from CRC patients. In the cfDNA validation cohort (N = 155), the two-gene panel yielded a sensitivity of 69.5%, specificity of 91.7%, and AUC of 0.806.

Hypermethylation of the ten CpG sites is a CRC-specific alteration in tissue and has the potential use as a noninvasive cfDNA marker to diagnose CRC.

The online version contains supplementary material available at 10.1186/s13148-022-01312-9.

• Colorectal cancer
• Integrative analysis
• Noninvasive test
• Tissue-specific methylation

• Biomarkers, Tumor/genetics
• Colonoscopy
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• DNA Methylation
• Humans
• Occult Blood

DNA methylation biomarkers for early detection, risk stratification and treatment response in cancer have been of great interest over the past decades. Nevertheless, clinical implementation of these biomarkers is limited, as only < 1% of the identified biomarkers is translated into a clinical or commercial setting. Technical factors such as a suboptimal genomic location of the assay and inefficient primer or probe design have been emphasized as important pitfalls in biomarker research. Here, we use eleven diagnostic DNA methylation biomarkers for colorectal cancer (ALX4, APC, CDKN2A, MGMT, MLH1, NDRG4, SDC2, SFRP1, SFRP2, TFPI1 and VIM), previously described in a systematic literature search, to evaluate these pitfalls.

To assess the genomic assay location, the optimal genomic locations according to TCGA data were extracted and compared to the genomic locations used in the published assays for all eleven biomarkers. In addition, all primers and probes were technically evaluated according to several criteria, based on literature and expert opinion. Both assay location and assay design quality varied widely among studies.

Large variation in both assay location and design hinders the development of future DNA methylation biomarkers as well as inter-study comparability.

• Assay design
• Biomarkers
• Cancer biomarkers
• DNA methylation
• Diagnosis
• Epigenetics
• Genomic location

• Colorectal cancer
• DNA methylation
• DNA mutation
• circulating tumor cells
• colon capsule endoscopy
• cost effectiveness
• microRNA
• microbial markers
• screening
• virtual colonoscopy

• Biomarker discovery
• Diagnosis
• Epigenetics
• HumanMethylation450K
• HumanMethylationEPIC
• Methlyome
• Plasma
• Stool

The present study investigated the expression, mutation, and methylation profile of PNN and its prognostic value in digestive tract cancers. The disparities in signaling pathways and the immune landscape in colon adenocarcinoma (COAD) based on PNN expression were specifically explored.

The expression, mutation, methylation levels of PNN, and survival data in esophageal cancer, gastric adenocarcinoma, COAD, and rectal adenocarcinoma were evaluated using several bioinformatic databases. Gene Ontology (GO) enrichment analysis and gene set enrichment analysis (GSEA) were performed to investigate the enriched biological functions and pathways in COAD. Several acknowledged bioinformatic algorithms were employed to assess the correlation between PNN expression and the tumor immune landscape in COAD.

PNN was upregulated and remarkably related to tumor stage in digestive tract cancers. High expression of PNN was positively associated with poor progression‐free survival and overall survival time, specifically in COAD. PNN expression was identified as an independent prognostic factor in COAD. GO and GSEA analyses revealed that PNN participates in multiple biological processes underlying carcinogenicity in COAD. Further investigation showed that PNN expression was significantly associated with tumor‐infiltrating immune cells, immune cell functions, and several immune checkpoints in COAD. The PNN low expression group had a lower tumor immune dysfunction and exclusion (TIDE) score and a higher immunophenoscore (IPS), indicating a better response to immunotherapy.

PNN was highly expressed in digestive tract cancers and could act as an independent prognostic factor and a response predictor for immunotherapy in COAD.

• PNN
• The Cancer Genome Atlas
• colon adenocarcinoma
• immune landscape
• prognosis

The N-Myc downstream-regulated gene (NDRG) family is comprised of four members (NDRG1-4) involved in various important biological processes. However, there is no systematic evaluation of the prognostic of the NDRG family in hepatocellular carcinoma (HCC).

To analyze comprehensively the biological role of the NDRG family in HCC.

The NDRG family expression was explored using The Cancer Genome Atlas. DNA methylation interactive visualization database was used for methylation analysis of the NDRG family. The NDRG family genomic alteration was assessed using the cBioPortal. Single-sample Gene Set Enrichment Analysis was used to determine the degree of immune cell infiltration in tumors.

NDRG1 and NDRG3 were up-regulated in HCC, while NDRG2 was down-regulated. Consistent with expression patterns, high expression of NDRG1 and NDRG3 was associated with poor survival outcomes (P < 0.05). High expression of NDRG2 was associated with favorable survival (P < 0.005). An NDRG-based signature that statistically stratified the prognosis of the patients was constructed. The percentage of genetic alterations in the NDRG family varied from 0.3% to 11.0%, and the NDRG1 mutation rate was the highest. NDRG 1-3 expression was associated with various types of infiltrated immune cells. Gene ontology analysis revealed that organic acid catabolism was the most important biological process related to the NDRG family. Gene Set Enrichment Analysis showed that metabolic, proliferation, and immune-related gene sets were enriched during NDRG1 and NDRG3 high expression and NDRG2 low expression.

Overexpression of NDRG1 and NDRG3 and down-expression of NDRG2 are correlated with poor overall HCC prognosis. Our results may provide new insights into the indispensable role of NDRG1, 2, and 3 in the development of HCC and guide a promising new strategy for treating HCC.

• N-Myc downstream-regulated gene family
• Bioinformatics
• Hepatocellular carcinoma
• Prognosis
• Tumor-infiltrating immune cells

Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.

• colorectal cancer
• diagnostic biomarkers
• early detection

Background:SDC2 methylation is a feasible biomarker for colorectal cancer detection. Its specificity for colorectal cancer is higher than 90%, but the sensitivity is normally lower than 90%. This study aims to improve the sensitivity of SDC2 detection through finding a high positive target from the false-negative samples of SDC2 detection based on analysis of the bowel subsite difference in methylation.

Methods: Hypermethylated TFPI2 was identified in SDC2 hypomethylated colorectal cancer samples retrieved from TCGA database with the methylation level lower than 0.2. The methylation-specific PCR assay was developed and then evaluated using tissue samples (184 cancer and 54 healthy control samples) and stool samples (289 cancer, 190 adenoma, and 217 healthy control samples).

Results:TFPI2 was hypermethylated in most SDC2 hypomethylated colorectal cancer samples. When the SDC2/TFPI2-combined PCR assay was performed in stool specimens, the AUC value of cancer vs. control was 0.98, with the specificity of 96.40% and sensitivity of 96.60%, and the AUC value of adenoma vs. control was 0.87, with the specificity of 95.70% and the sensitivity of 80.00%. The improvement in sensitivity was the most momentous in the left colon. As the detection index, the Ct value was better in improving the sensitivity of detection than the methylation level based on the 2^−ΔΔCt value.

Conclusion:TFPI2 can improve the sensitivity of SDC2 methylation–specific detection of colorectal tumorous lesions while maintaining high specificity, in particular reducing the missed detection of left colon cancer and adenoma.

• SDC2
• TFPI2
• adenomas
• colorectal cancer
• methylation

WHO grade I meningiomas occasionally show regrowth after radiosurgical treatment, which cannot be predicted by clinical features. There is increasing evidence that certain biomarkers are associated with regrowth of meningiomas. The aim of this retrospective study was to asses if these biomarkers could be of value to predict regrowth of WHO grade I meningiomas after additive radiosurgery. Forty-four patients with WHO grade I meningiomas who underwent additive radiosurgical treatment between 2002 and 2015 after Simpson IV resection were included in this study, of which 8 showed regrowth. Median follow-up time was 64 months (range 24–137 months). Tumors were analyzed for the proliferation marker Ki-67 by immunohistochemistry and for deletion of 1p36 by fluorescence in situ hybridization (FISH). Furthermore, genomic DNA was analyzed for promoter hypermethylation of the genes NDRG1–4, SFRP1, HOXA9 and MGMT. Comparison of meningiomas with and without regrowth after radiosurgery revealed that loss of 1p36 (p = 0.001) and hypermethylation of NDRG1 (p = 0.046) were correlated with regrowth free survival. Loss of 1p36 was the only parameter that was significantly associated with meningioma regrowth after multivariate analysis (p = 0.01). Assessment of 1p36 loss in tumor tissue prior to radiosurgery might be considered an indicator of prognosis/regrowth. However, this finding has to be validated in an independent larger set of tumors.

• Fibulin-2
• Ndrg4
• Nidogen-1
• colorectal cancer
• enteric nervous system

• Calcium-Binding Proteins
• Colorectal Neoplasms/genetics
• Enteric Nervous System
• Extracellular Matrix Proteins
• Humans
• Membrane Glycoproteins
• Muscle Proteins
• Nerve Tissue Proteins/genetics
• Neurons
• Tumor Microenvironment

• UM 2013-6075 KWF Kankerbestrijding (DCS)
• 016.186.124 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
• 016.196.367 Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
• KWF Kankerbestrijding (DCS)
• Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)

• COVID-19
• DNA
• colorectal cancer
• genetic test
• pandemic
• screening
• stool

Colon cancer remains one of the leading causes of cancer-related deaths worldwide. Transformation of colon epithelial cells into invasive adenocarcinomas has been well known to be due to the accumulation of multiple genetic and epigenetic changes. In the past decade, the etiology of inflammatory bowel disease (IBD) which is characterized by chronic inflammation of the intestinal mucosa, was only partially explained by genetic studies providing susceptibility loci, but recently epigenetic studies have provided critical evidences affecting IBD pathogenesis. Over the past decade, A deep understanding of epigenetics along with technological advances have led to identifying numerous genes that are regulated by promoter DNA hypermethylation in colorectal diseases. Recent advances in our understanding of the role of DNA methylation in colorectal diseases could improve a multitude of powerful DNA methylation-based biomarkers, particularly for use as diagnosis, prognosis, and prediction for therapeutic approaches. This review focuses on the emerging potential for translational research of epigenetic alterations into clinical utility as molecular biomarkers. Moreover, this review discusses recent progress regarding the identification of unknown hypermethylated genes in colon cancers and IBD, as well as their possible role in clinical practice, which will have important clinical significance, particularly in the era of the personalized medicine.

• DNA methylation
• biomarkers
• colorectal cancer
• epigenetic regulation
• inflammatory bowel diseases (IBDs)

Colonoscopy and the fecal immunochemical test (FIT) are currently the most widely used screening modalities for colorectal cancer (CRC), however, both with their own limitations. Here we aim to identify and validate stool-based DNA methylation markers for the early detection of CRC and investigate the biological pathways prone to DNA methylation.

DNA methylation marker discovery was performed using The Cancer Genome Atlas (TCGA) colon adenocarcinoma data set consisting of normal and primary colon adenocarcinoma tissue. The performance of the five best candidate markers and a previously identified marker, NDRG4, was evaluated on tissues and whole stool samples of healthy subjects and CRC patients using quantitative MSP assays. The results were compared and combined with FIT data. Finally, pathway and gene ontology enrichment analyses were performed using ToppFun, GOrilla and clusterProfiler.

GDNF, HAND2, SLC35F3, SNAP91 and SORCS1 were ranked as the best performing markers. Gene combinations of all five markers, NDRG4 and FIT were evaluated to establish the biomarker panel with the highest diagnostic potential, resulting in the identification of GDNF/SNAP91/NDRG4/FIT as the best performing marker panel. Pathway and gene ontology enrichment analyses revealed that genes associated with the nervous system were enriched in the set of best performing CRC-specific biomarkers.

In silico discovery analysis using TCGA-derived data yielded a novel DNA-methylation-based assay for the early detection of CRC, potentially improving current screening modalities. Additionally, nervous system-related pathways were enriched in the identified genes, indicating an epigenetic regulation of neuronal genes in CRC.

The online version contains supplementary material available at 10.1186/s13148-021-01067-9.

• Colorectal cancer
• DNA methylation
• Diagnostic markers
• In silico discovery
• Nervous system

• Counterfactual framework
• Mediation
• Methylated region

• Biomarker
• Colorectal cancer
• DNA methylation
• Liquid biopsy
• cfDNA

• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• DNA Methylation
• Early Detection of Cancer
• Humans
• Prospective Studies

• NTNU Norwegian University of Science and Technology (incl St. Olavs Hospital - Trondheim University Hospital)

Background: Noninvasive stool-based DNA methylation testing emerges as a new approach for detecting colorectal cancer (CRC). However, its feasibility for early detection of CRC and precancerous lesions in the Chinese population remains inconclusive.

Methods: In this study, we establish a possibilities screening method (sDNA-FOBT) for detecting CRC and precancerous lesions (hyperplastic polyps [HP] and adenomas [AD]) and evaluate its detection performance in the Chinese population. This method combined a molecular assay of DNA methylation markers (BMP3, NDRG4, and SDC2) with the human hemoglobin test (FOBT) in stool samples.

Results: The sensitivity of sDNA-FOBT was 85.42% for CRC, 85.71% for AD, and 28.21% for HP, respectively, at the specificity of 92%. The diagnostic efficacy of sDNA-FOBT for detecting CRC and precancerous lesions was significantly higher than FOBT alone (sensitivity: 61.70% vs. 51.06%, P<0.01; AUC: 0.78 vs. 0.72, P<0.001), especially for CRC (AUC: 0.91 vs. 0.86, P<0.001) and AD (AUC: 0.91 vs. 0.75, P<0.05). No significant difference was observed between the detection sensitivity of sDNA-FOBT and the clinical variables. Notably, compared with FOBT, sDNA-FOBT was more effective in the detection of CRC and precancerous lesions in the patients aged >50 y (62.34% vs 54.55%, P<0.05).

Conclusion: Our results demonstrate that sDNA-FOBT is a promising method for screening CRC and precancerous lesions in the Chinese population. Further studies are required to validate the results in a larger sample capacity.

• CRC screening
• DNA methylation marker
• fecal occult blood testing
• stool DNA testing

The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors. Functionally, NDRGs play an important role in the malignant progression of cancer cells. However, little is known about the potential implications of NDRG4 in pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to elucidate the expression pattern of NDRG4 in PDAC and evaluate its potential cellular biological effects. Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function. Data mining demonstrated that NDRG4 was significantly down-regulated in PDAC tissues and cells. PDAC patients with low NDRG4 expression showed poor prognosis. Epigenetic regulation by DNA methylation was closely associated with NDRG4 down-regulation. NDRG4 overexpression dramatically suppressed PDAC cell growth and metastasis. Further functional analysis demonstrated that up-regulated NDRG4 in SW1990 and Canpan1 cells resulted in attenuated mitochondrial function, including reduced ATP production, decreased mitochondrial membrane potential, and increased fragmented mitochondria. However, opposite results were obtained for HPNE cells with NDRG4 knockdown. These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients.

Colorectal cancer (CRC) is a common clinical malignancy globally ranked as the fourth leading cause of cancer mortality. Some microbes are known to contribute to adenoma-carcinoma transition and possess diagnostic potential. Advances in high-throughput sequencing technology and functional studies have provided significant insights into the landscape of the gut microbiome and the fundamental roles of its components in carcinogenesis. Integration of scattered knowledge is highly beneficial for future progress. In this study, literature review and information extraction were performed, with the aim of integrating the available data resources and facilitating comparative research. A knowledgebase of the human CRC microbiome was compiled to facilitate understanding of diagnosis, and the global signatures of CRC microbes, sample types, algorithms, differential microorganisms and various panels of markers plus their diagnostic performance were evaluated based on statistical and phylogenetic analyses. Additionally, prospects about current changelings and solution strategies were outlined for identifying future research directions. This type of data integration strategy presents an effective platform for inquiry and comparison of relevant information, providing a tool for further study about CRC-related microbes and exploration of factors promoting clinical transformation (available at: http://gsbios.com/index/experimental/dts_ mben?id=1).

• biomarkers
• colorectal cancer
• database
• diagnosis
• microbiome

Esophageal adenocarcinoma has become a major clinical challenge in the western world due to its rapid increasing incidence and poor overall prognosis. Understanding the molecular events of its tumorigenesis is the key to better diagnosis and development of better therapeutic strategies. In the current study we aimed to identify epigenetic alteration targets in esophageal adenocarcinoma. We focused on a candidate gene, NDRG4 (N-myc downregulated gene 4). We found that NDRG4 was frequent downregulated in esophageal adenocarcinoma through DNA hypermethylation of its promoter region. Re-expression of NRDG4 in cancer cells significantly suppressed tumor growth via inhibition of cell proliferation. These results will improve our understanding on how dysfunction of NDRG4 contributes to esophageal adenocarcinoma. DNA hypermethylation of NDRG4 may be a useful biomarker in clinical monitoring of esophageal adenocarcinoma patients.

The incidence of esophageal adenocarcinoma (EAC) has been rising dramatically in the past few decades in the United States and Western world. The N-myc downregulated gene 4 (NDRG4) belongs to the human NDRG family. In this study, we aimed to identify the expression levels, regulation, and functions of NDRG4 in EAC. Using an integrative epigenetic approach, we identified genes showing significant downregulation in EAC and displaying upregulation after 5-Aza-deoxycitidine. Among these genes, likely to be regulated by DNA methylation, NDRG4 was among the top 10 candidate genes. Analyses of TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) data sets and EAC tissue samples demonstrated that NDRG4 was significantly downregulated in EAC (p < 0.05). Using Pyrosequencing technology for quantification of DNA methylation, we detected that NDRG4 promoter methylation level was significantly higher in EAC tissue samples, as compared to normal esophagus samples (p < 0.01). A strong inverse correlation between NDRG4 methylation and its gene expression levels (r = −0.4, p < 0.01) was observed. Treatment with 5-Aza restored the NDRG4 expression, confirming that hypermethylation is a driving force for NDRG4 silencing in EAC. Pathway and gene set enrichment analyses of TCGA data suggested that NDRG4 is strongly associated with genes related to cell cycle regulation. Western blotting analysis showed significant downregulation of Cyclin D1, CDK4 and CDK6 in EAC cells after overexpression of NDRG4. Functionally, we found that the reconstitution of NDRG4 resulted in a significant reduction in tumor cell growth in two-dimensional (2D) and three-dimensional (3D) organotypic culture models and inhibited tumor cell proliferation as indicated by the EdU (5-ethynyl-2′-deoxyuridine) proliferation assay.

• DNA methylation
• NDRG4
• esophageal adenocarcinoma
• tumor suppressor

• P30 CA240139 NCI NIH HHS

• Age Factors
• Colorectal Neoplasms/epidemiology
• Early Detection of Cancer
• Female
• Humans
• Male
• Middle Aged

• R37 CA214679 NCI NIH HHS

Patient screening is important for early diagnosis of colorectal cancer (CRC). The present study aimed to compare the multitarget stool DNA (mt-sDNA) test with the fecal occult blood test (FOBT) for CRC screening. A total of 151 individuals were screened using colonoscopy, mt-sDNA and FOBT for the detection of CRC and adenoma. The results of the mt-sDNA test and FOBT were compared with colonoscopy to examine their sensitivity and specificity. Subsequently, the sensitivity and specificity of the mt-sDNA test were compared with those of FOBT in CRC and large adenoma. Stool samples were collected from patients with CRC (n=50) or large adenoma (n=51), as well as from normal controls (n=50). The mt-sDNA test outperformed FOBT in detecting CRC with a sensitivity of 90.0% (45/50) vs. 42.0% (21/50), advanced adenoma with a sensitivity of 70.6% (36/51) vs. 19.6% (10/51), stage I–III CRC with a sensitivity of 91.9% (34/37) vs. 29.7% (11/37), and stage IV CRC with a sensitivity of 84.6% (11/13) vs. 76.9% (10/13). In addition, the mt-sDNA test exhibited a specificity of 94.0% (47/50) in detecting CRC, which was superior to FOBT with a specificity of 90.0% (45/50). Therefore, the mt-sDNA test may have higher sensitivity and specificity compared with FOBT in diagnosing both CRC and advanced adenoma.

• adenoma
• colorectal cancer
• multitarget stool DNA
• sensitivity
• specificity

• Colorectal cancer screening
• Diagnostic biomarkers
• Gut microbiota
• Tumour biomarkers
• microRNA

• NDRG4
• PBMC
• TFPI2
• colorectal cancer
• quantitative methylation analysis

NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/β-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/β-catenin signaling and enhanced CSC-like properties were responsible for NDRG3- mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of β-catenin, as well as provides a potential therapeutic target for future therapeutic interventions.

Recent technology has made it possible to measure DNA methylation profiles in a cost-effective and comprehensive genome-wide manner using array-based technology for epigenome-wide association studies. However, identifying differentially methylated regions (DMRs) remains a challenging task because of the complexities in DNA methylation data. Supervised methods typically focus on the regions that contain consecutive highly significantly differentially methylated CpGs in the genome, but may lack power for detecting small but consistent changes when few CpGs pass stringent significance threshold after multiple comparison. Unsupervised methods group CpGs based on genomic annotations first and then test them against phenotype, but may lack specificity because the regional boundaries of methylation are often not well defined. We present coMethDMR, a flexible, powerful, and accurate tool for identifying DMRs. Instead of testing all CpGs within a genomic region, coMethDMR carries out an additional step that selects co-methylated sub-regions first. Next, coMethDMR tests association between methylation levels within the sub-region and phenotype via a random coefficient mixed effects model that models both variations between CpG sites within the region and differential methylation simultaneously. coMethDMR offers well-controlled Type I error rate, improved specificity, focused testing of targeted genomic regions, and is available as an open-source R package.