• Cancer driver genes
• Cis-regulatory elements
• DNA methylations
• Enhancers
• Expression variation
• Gene regulation
• Gene regulatory-domains
• Glioblastoma
• Silencers

• Humans
• DNA Methylation
• Regulatory Sequences, Nucleic Acid
• Gene Expression Regulation
• Mutation

• DKFZ-HIPO Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft
• 724803 HORIZON EUROPE European Research Council
• 948/16 Israel Science Foundation
• 3413/19 Israel Science Foundation
• 724803 European Research Council

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

Transcriptomes and DNA methylation of colon cancer at the single-cell level are used to identify marker genes and improve diagnoses and therapies. Seven colon cancer subtypes are recognized based on the single-cell RNA sequence, and the differentially expressed genes regulated by dysregulated methylation are identified as marker genes for different types of colon cancer. Compared with normal colon cells, marker genes of different types show very obvious specificity, especially upregulated genes in tumors. Functional enrichment analysis for marker genes indicates a possible relation between colon cancer and nervous system disease, moreover, the weak immune system is verified in colon cancer. The heightened expression of markers and the reduction of methylation in colon cancer promote tumor development in an extensive mechanism so that there is no biological process that can be enriched in different types.

• colon cancer
• comprehensive analysis
• marker genes
• methylation
• single cell
• transcriptome

• CIMP
• DNA methylation
• colorectal carcinoma
• conventional carcinoma
• epigenetics of carcinogenesis
• methylation score
• methylome
• microsatellite instability
• serrated adenocarcinoma
• serrated pathway

• DNA methylation
• colorectal cancer
• epigenetics
• gene regulation
• neoplasia

• Alternative Splicing
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Carcinogenesis/genetics
• Cell Line, Tumor
• Chromobox Protein Homolog 5
• Chromosomal Proteins, Non-Histone/metabolism
• DNA (Cytosine-5-)-Methyltransferase 1/genetics
• DNA (Cytosine-5-)-Methyltransferases/genetics
• DNA Methylation
• DNA-Binding Proteins/metabolism
• Epithelial-Mesenchymal Transition
• Exons
• Female
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Histone Code
• Humans
• Hyaluronan Receptors/genetics
• Hyaluronan Receptors/metabolism
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
• RNA Polymerase II/metabolism
• Transcription Factors/metabolism
• Transcription, Genetic
• DNA Methyltransferase 3B

• Centre National de la Recherche Scientifique
• Agence Nationale de la Recherche
• Marie Sklodowska-Curie

• autoimmune diseases
• cancer diagnosis
• circulating cell free nucleic acids
• circulating nucleic acids in plasma/serum
• epigenetic biomarkers
• precision medicine
• prenatal and genetic diagnostics

In colorectal cancer (CRC), upregulation of the C-X-C motif chemokine receptor 4 (CXCR4) is correlated with metastasis and poor prognosis, highlighting the need to further elucidate CXCR4’s regulation in CRC. For the first time, DNA methylation and 5-hydroxymethylcytosine aberrations were investigated to better understand the epigenetic regulation of CXCR4 in CRC. CXCR4 expression levels were measured using qPCR and immunoblotting in normal colon tissues, primary colon cancer tissues and CRC cell lines. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. The DNA methylation status spanning CXCR4 gene was evaluated using combined bisulfite restriction analysis (COBRA). The methylation status in the CXCR4 gene body was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. CXCR4 expression levels were significantly increased in tumor stromal cells and in tumor colonocytes, compared to matched cell types from adjacent normal-appearing mucosa. CXCR4 promoter methylation was detected in a minority of colorectal tumors in the TCGA. The CpG island of the CXCR4 promoter showed increased methylation in three of four CRC cell lines. CXCR4 protein expression differences were also notable between microsatellite stable (MSS) and microsatellite instable (MSI) tumor cell lines. While differential methylation was not detected in CXCR4, enrichment of 5-hydroxymethylcytosine (5hmC) in CXCR4 gene bodies in CRC was observed compared to adjacent mucosa.

• 5-hydroxymethylcytosine
• CXCR4 gene expression
• DNA methylation
• colorectal cancer
• epigenetic regulation

• 1R01CA240710 NCI NIH HHS
• 1RO3CA216160-01 NCI NIH HHS
• R01 CA240710 NCI NIH HHS
• U01 CA217078 NCI NIH HHS

• Cancer
• Combination therapy
• DNA methylation
• DNA methyltransferase inhibitors
• Epigenetic therapy
• Novel DNMTi

Syndecan-2 (SDC2) methylation was previously reported as a sensitive serologic biomarker for the early detection of colorectal cancer (CRC). The purpose of this study was to investigate whether SDC2 methylation is detectable in precancerous lesions and to determine the feasibility of using SDC2 methylation for the detection of CRC and precancerous lesions in bowel lavage fluid (BLF).

A total of 190 BLF samples were collected from the rectum at the beginning of colonoscopy from patients with colorectal neoplasm and healthy normal individuals. Fourteen polypectomy specimens were obtained during colonoscopy. A bisulfite pyrosequencing assay and quantitative methylation-specific polymerase chain reaction were conducted to measure SDC2 methylation in tissues and BLF DNA.

SDC2 methylation was positive in 100% of villous adenoma (VA) and high-grade dysplasia, and hyperplastic polyp samples; 88.9% of tubular adenoma samples; and 0% of normal mucosa samples. In the BLF DNA test forSDC2 methylation, the sensitivity for detecting CRC and VA was 80.0% and 64.7%, respectively, at a specificity of 88.9%. The BLF of patients with multiple tubular adenomas, single tubular adenoma and hyperplastic polyps showed 62.8%, 26.7% and 28.6% rates of methylation-positive SDC2, respectively.

Our results demonstrated that SDC2 methylation was a frequent event in precancerous lesions and showed high potential in BLF for detecting patients with colorectal neoplasm.

• Adenoma
• Colorectal neoplasms
• Feces
• Methylation
• Syndecan-2

Aberrant DNA methylation is a potential mechanism underlying the development of colorectal cancer (CRC). Thus, identification of prognostic DNA methylation markers and understanding the related molecular functions may offer a new perspective on CRC pathogenesis. To that end, we explored DNA methylation profile changes in CRC subtypes based on the microsatellite instability (MSI) status through genome-wide DNA methylation profiling analysis. Of 34 altered genes, three hypermethylated (epidermal growth factor, EGF; carbohydrate sulfotransferase 10, CHST10; ependymin related 1, EPDR1) and two hypomethylated (bone marrow stromal antigen 2, BST2; Rac family small GTPase 3, RAC3) candidates were further validated in CRC patients. Based on quantitative methylation-specific polymerase chain reaction (Q-MSP), EGF, CHST10 and EPDR1 showed higher hypermethylated levels in CRC tissues than those in adjacent normal tissues, whereas BST2 showed hypomethylation in CRC tissues relative to adjacent normal tissues. Additionally, among 75 CRC patients, hypermethylation of CHST10 and EPDR1 was significantly correlated with the MSI status and a better prognosis. Moreover, EPDR1 hypermethylation was significantly correlated with node negativity and a lower tumor stage as well as with mutations in B-Raf proto-oncogene serine/threonine kinase (BRAF) and human transforming growth factor beta receptor 2 (TGFβR2). Conversely, a negative correlation between the mRNA expression and methylation levels of EPDR1 in CRC tissues and cell lines was observed, revealing that DNA methylation has a crucial function in modulating EPDR1 expression in CRC cells. EPDR1 knockdown by a transient small interfering RNA significantly suppressed invasion by CRC cells, suggesting that decreased EPDR1 levels may attenuate CRC cell invasion. These results suggest that DNA methylation-mediated EPDR1 epigenetic silencing may play an important role in preventing CRC progression.

• CRC
• EPDR1 methylation
• MSI
• invasion
• prognosis

• Colon adenocarcinoma
• DNA methylation profiles
• Methylation markers

• Adenocarcinoma/genetics
• Biomarkers, Tumor/genetics
• Cluster Analysis
• Colonic Neoplasms/genetics
• DNA Methylation/genetics
• Gene Expression Regulation, Neoplastic
• Gene Ontology
• Genome, Human
• Humans
• Kaplan-Meier Estimate
• Prognosis

DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expression analysis of TP53 pathway genes.

Long interspersed nuclear element-1 (LINE-1) BS-PCR followed by pyrosequencing was performed for the estimation of global DNA metlyation levels along the colorectal normal-adenoma-carcinoma sequence. Methyl capture sequencing was done on 6 normal adjacent (NAT), 15 adenomatous (AD) and 9 CRC tissues. Overall quantitative methylation analysis, selection of top hyper/hypomethylated genes, methylation analysis on mutation regions and TP53 pathway gene promoters were performed. Mutations of 12 CRC-related genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53) were evaluated. mRNA expression of TP53 pathway genes was also analyzed.

According to the LINE-1 methylation results, overall hypomethylation was observed along the normal-adenoma-carcinoma sequence. Within top50 differential methylated regions (DMRs), in AD-N comparison TP73, NGFR, PDGFRA genes were hypermethylated, FMN1, SLC16A7 genes were hypomethylated. In CRC-N comparison DKK2, SDC2, SOX1 genes showed hypermethylation, while ERBB4, CREB5, CNTN1 genes were hypomethylated. In certain mutation hot spot regions significant DNA methylation alterations were detected. The TP53 gene body was addressed by hypermethylation in adenomas. APC, TP53 and KRAS mutations were found in 30, 15, 21% of adenomas, and in 29, 53, 29% of CRCs, respectively. mRNA expression changes were observed in several TP53 pathway genes showing promoter methylation alterations.

DNA methylation with consecutive phenotypic effect can be observed in a high number of promoter and gene body regions through CRC development.

The online version of this article (10.1186/s12885-018-4609-x) contains supplementary material, which is available to authorized users.

• Adenoma
• Colorectal cancer
• DNA methylation
• Methyl capture sequencing
• Mutation
• TP53 signaling pathway

• DNA hypermethylation
• LINC00472
• colorectal cancer
• function
• regulatory network

Accumulating evidence highlights the role of long non-coding RNAs (lncRNAs) in tumors. However, the genome-wide expression and roles of lncRNAs in colorectal cancer (CRC) remain unknown. Here, we systematically examined the global gene expressions in primary and synchronous liver metastases CRC tissue, in which thousands of aberrantly expressed lncRNAs were characterized. Co-expression analysis revealed that some lncRNAs correlated to their neighboring mRNAs in expression levels, whereas others formed networks with protein-coding genes in trans. We observed H3K4me3 was enriched at expressed lncRNA transcription start sites (TSSs) and correlated to dysregulated lncRNAs. Furthermore, we identified primary and metastasis tumor linked lncRNA signatures positively correlated with poor-prognosis gene set. Finally, functional experiments demonstrated two candidate lncRNAs were required for proliferation and migration of CRC cells. In summary, we provided a new framework for lncRNA associated clinical prognosis evaluation and target selection of gene therapy in CRC.

• colorectal cancer
• epigenetic regulation
• expression profiling
• lncRNA
• poor prognosis

• Colorectal cancer
• DNA methylation
• Epigenetics
• Epitranscriptomics
• Histone modifications
• RNA editing

Epigenetic changes, like DNA methylation, affect gene expression and in colorectal cancer (CRC), a distinct phenotype called the CpG island methylator phenotype (“CIMP”) has significantly higher levels of DNA methylation at so-called “Type C loci” within the genome. We postulate that enhancer-gene pairs are coordinately controlled through DNA methylation in order to regulate the expression of key genes/biomarkers for a particular phenotype.

Firstly, we found 24 experimentally-validated enhancers (VISTA enhancer browser) that contained statistically significant (FDR-adjusted q-value of <0.01) differentially methylated regions (DMRs) (1000bp) in a study of CIMP versus non-CIMP CRCs. Of these, the methylation of 2 enhancers, 1702 and 1944, were found to be very well correlated with the methylation of the genes Wnt3A and IGDCC3, respectively, in two separate and independent datasets.

We show for the first time that there are indeed distinct and dynamic changes in the methylation pattern of specific enhancer-gene pairs in CRCs. Such a coordinated epigenetic event could be indicative of an interaction between (1) enhancer 1702 and Wnt3A and (2) enhancer 1944 and IGDCC3. Moreover, our study shows that the methylation patterns of these 2 enhancer-gene pairs can potentially be used as biomarkers to delineate CIMP from non-CIMP CRCs.

• DNA methylation
• bioinformatics
• colon cancer
• enhancers
• epigenetics

The aim of this study was to evaluate the potential effects of methyl donor supplementation of pregnant animals in the presence or absence of a concomitant lactation on the methylome of the offspring. Twenty Holstein cows, 10 nulliparous (non-lactating while pregnant) and 10 multiparous (lactating while pregnant) were blocked by parity and randomly assigned to an i.m. weekly injections of a placebo (CTRL) or a solution containing methyl donors (MET). After calving, 5 calves randomly selected from each treatment (two born to non-lactating and three to lactating dams) were blood-sampled to determine their full methylome. There were more than 2,000 CpG differentially methylated between calves born to CTRL and those born to MET, and also between calves born to lactating and non-lactating dams. Most of the differences affected genes involved in immune function, cell growth regulation and differentiation, kinase activity, and ion channeling. We conclude that the coexistence of pregnancy and lactation affects the methylome of the offspring, and that supplementation of methyl donors early in gestation has also consequences on the methylome.

• Animals
• Cattle
• DNA Methylation
• Dairying
• Female
• Lactation
• Pregnancy

• Spanish Ministry of Economics, Industry, and Competitiveness
• CERCA Program (Generalitat de Catalunya)
• European Social Fund

In normal colon, claudin-2 expression is restricted to the crypt bottom containing the undifferentiated and proliferative colonocytes. Claudin-2 expression is also upregulated in colorectal cancer (CRC) and promotes carcinogenesis. However, cellular mechanism/s regulated by increased claudin-2 expression during the CRC and mechanism/s regulating this increase remain poorly understood. Epigenetic mechanisms help regulate expression of cancer-associated genes and inhibition of Histone Deacetylases (HDACs) induces cell cycle arrest and differentiation. Accordingly, based on a comprehensive in vitro and in vivo analysis we here report that Histone Deacetylases regulate claudin-2 expression in causal association with colonocyte dedifferentiation to promote CRC. Detailed differentiation analyses using colon cancer cells demonstrated inverse association between claudin-2 expression and epithelial differentiation. Genetic manipulation studies revealed the causal role of HDAC-4 in regulating claudin-2 expression during this process. Further analysis identified transcriptional regulation as the underlying mechanism, which was dependent on HDAC-4 dependent modulation of the EGFR-ERK1/2 signaling. Accordingly, colon tumors demonstrated marked upregulation of the HDAC-4/ERK1/2/Claudin-2 signaling. Taken together, we demonstrate a novel role for HDAC-4/EGFR/ERK1/2 signaling in regulating claudin-2 expression to modulate colonocyte differentiation. These findings are of clinical significance and highlight epigenetic regulation as potential mechanism to regulate claudin-2 expression during mucosal pathologies including CRC.

• cell cycle
• claudin
• colon cancer
• differentiation
• epigenetic regulation

This study sought to evaluate the diagnostic value of the methylation of multiple gene promoters in serum in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). A total of 343 participants were enrolled, including 98 patients with HCC, 75 patients with liver cirrhosis (LC), 90 patients with chronic hepatitis B (CHB), and 80 healthy individuals. RASSF1A, APC, BVES, TIMP3, GSTP1, and HOXA9 were selected as the candidate genes. The MethyLight method was used to assay promoter methylation statuses. The diagnostic performances of markers were assessed by constructing receiver operating characteristic (ROC) curves. The prevalences of methylation for RASSF1A, APC, BVES, HOXA9, GSTP1, and TIMP3 were 52.04%, 36.73%, 29.59%, 20.41%, 17.35%, and 11.22%, respectively. APC methylation completely overlapped with RASSF1A methylation. The area under the curve (AUC) for RASSF1A methylation (0.718) was better than the corresponding AUC for AFP (0.609) in distinguishing HCC from CHB. When RASSF1A, BVES, HOXA9, and AFP were combined, the AUC was 0.852 (95% CI = 0.796–0.908, P = 0.028), and the sensitivity and specificity were 83.7% and 78.9%, respectively. In conclusion, an assay that combines methylation of the RASSF1A, BVES, and HOXA9 gene promoters in serum and AFP could significantly improve HBV-related HCC diagnoses.

• DNA methylation
• LIFR
• cancer
• diagnosis
• sequencing
• targeted NGS

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date.

An epigenetic component is hypothesised in PAH: an overview of the current literature and future perspectiveshttp://ow.ly/7miS3002BYw

• Bloom syndrome gene
• CpG island promoter hypomethylation
• DNA damage response
• DNA repair
• Phosphorylated ataxia telangiectasia mutated
• γH2AX

• Ataxia Telangiectasia/genetics
• Bloom Syndrome/complications
• Bloom Syndrome/genetics
• Bloom Syndrome/metabolism
• Cell Line, Tumor
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• CpG Islands/genetics
• Cytoplasm/metabolism
• DNA Damage
• DNA Methylation
• DNA Repair
• DNA, Neoplasm/genetics
• Female
• Gene Expression Profiling/methods
• Gene Silencing
• Humans
• Male
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasm Staging
• RNA, Messenger/genetics
• RecQ Helicases/genetics
• RecQ Helicases/metabolism
• Signal Transduction/genetics
• Up-Regulation

A myriad of diseases is caused or characterized by alteration of epigenetic patterns, including changes in DNA methylation, post-translational histone modifications, or chromatin structure. These changes of the epigenome represent a highly interesting layer of information for disease stratification and for personalized medicine. Traditionally, epigenomic profiling required large amounts of cells, which are rarely available with clinical samples. Also, the cellular heterogeneity complicates analysis when profiling clinical samples for unbiased genome-wide biomarker discovery. Recent years saw great progress in miniaturization of genome-wide epigenomic profiling, enabling large-scale epigenetic biomarker screens for disease diagnosis, prognosis, and stratification on patient-derived samples. All main genome-wide profiling technologies have now been scaled down and/or are compatible with single-cell readout, including: (i) Bisulfite sequencing to determine DNA methylation at base-pair resolution, (ii) ChIP-Seq to identify protein binding sites on the genome, (iii) DNaseI-Seq/ATAC-Seq to profile open chromatin, and (iv) 4C-Seq and HiC-Seq to determine the spatial organization of chromosomes. In this review we provide an overview of current genome-wide epigenomic profiling technologies and main technological advances that allowed miniaturization of these assays down to single-cell level. For each of these technologies we evaluate their application for future biomarker discovery. We will focus on (i) compatibility of these technologies with methods used for clinical sample preservation, including methods used by biobanks that store large numbers of patient samples, and (ii) automation of these technologies for robust sample preparation and increased throughput.

• ATAC-Seq
• Automation
• Biomarker discovery
• DNA methylation
• Genome-wide epigenetic profiling
• Miniaturization
• Precision medicine
• Single cell
• Stratification
• WGBS

• Biomarkers
• Colorectal cancer
• DNA methylation
• Diagnosis
• Population screening
• Prognosis

• Bipolar disorder
• DNA methylation
• DNA methyltransferase
• Depression
• Epigenetics
• Mood disorders
• Mood stabilizers

Ten Eleven Translocation (TET) protein-catalyzed 5mC oxidation not only creates novel DNA modifications, such as 5hmC, but also initiates active or passive DNA demethylation. TETs’ role in the crosstalk with specific histone modifications, however, is largely elusive. Here, we show that TET2-mediated DNA demethylation plays a primary role in the de novo establishment and maintenance of H3K4me3/H3K27me3 bivalent domains underlying methylated DNA CpG islands (CGIs). Overexpression of wild type (WT), but not catalytic inactive mutant (Mut), TET2 in low-TET-expressing cells results in an increase in the level of 5hmC with accompanying DNA demethylation at a subset of CGIs. Most importantly, this alteration is sufficient in making de novo bivalent domains at these loci. Genome-wide analysis reveals that these de novo synthesized bivalent domains are largely associated with a subset of essential developmental gene promoters, which are located within CGIs and are previously silenced due to DNA methylation. On the other hand, deletion of Tet1 and Tet2 in mouse embryonic stem (ES) cells results in an apparent loss of H3K27me3 at bivalent domains, which are associated with a particular set of key developmental gene promoters. Collectively, this study demonstrates the critical role of TET proteins in regulating the crosstalk between two key epigenetic mechanisms, DNA methylation and histone methylation (H3K4me3 and H3K27me3), particularly at CGIs associated with developmental genes.

• Immunohistochemistry
• Lynch syndrome
• MSI
• Promoter methylation
• Surrogate markers

• DNA methylation
• deconvolution
• epigenome-wide sequencing
• region-specific colonic variation

Histone-modifying enzymes are required for cell identity and lineage commitment, however little is known about the regulatory origins of the epigenome during embryonic development. Here we generate a comprehensive set of epigenome reference maps, which we use to determine the extent to which maternal factors shape chromatin state in Xenopus embryos. Using α-amanitin to inhibit zygotic transcription, we find that the majority of H3K4me3- and H3K27me3-enriched regions form a maternally defined epigenetic regulatory space with an underlying logic of hypomethylated islands. This maternal regulatory space extends to a substantial proportion of neurula stage-activated promoters. In contrast, p300 recruitment to distal regulatory regions requires embryonic transcription at most loci. The results show that H3K4me3 and H3K27me3 are part of a regulatory space that exerts an extended maternal control well into post-gastrulation development, and highlight the combinatorial action of maternal and zygotic factors through proximal and distal regulatory sequences.

Histone modifying enzymes are required for cell differentiation and lineage commitment during embryonic development. By a comprehensive set of epigenome reference maps of Xenopus embryos, the authors show that H3K4me3 and H3K27me3 exert an extended maternal control well into post-gastrulation development.

• dna methylation
• early detection of cancer
• sensitivity and specificity
• pancreatic neoplasms
• pancreatic juice

• Aged
• Area Under Curve
• Biomarkers, Tumor
• Case-Control Studies
• CpG Islands
• DNA Methylation
• Epigenesis, Genetic
• Epigenomics/methods
• Female
• Gene Dosage
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Pancreatic Juice
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/genetics
• Real-Time Polymerase Chain Reaction
• Reproducibility of Results
• Sequence Analysis, DNA

• K12 CA090628 NCI NIH HHS
• P50 CA102701 NCI NIH HHS
• P30DK084567 NIDDK NIH HHS
• P30 CA015083 NCI NIH HHS
• CA90628 NCI NIH HHS
• P30 DK084567 NIDDK NIH HHS

While genome-wide differential DNA methylation regions (DMRs) have been extensively identified, the comprehensive prioritization of their functional importance is still poorly explored. Here, we aggregated multiple data resources rooted in the genome, epigenome and transcriptome to systematically prioritize functional DMRs (fDMRs) in colorectal cancer (CRC). As demonstrated, the top-ranked fDMRs from all of the data resources showed a strong enrichment for known methylated genes. Additionally, we analyzed those top 5% DMR-coupled coding genes using functional enrichment, which resulted in significant disease-related biological functions in contrast to the tail 5% genes. To further confirm the functional importance of the top-ranked fDMRs, we applied chromatin modification alterations of CRC cell lines to characterize their functional regulation. Specifically, we extended the utility of the top-ranked DMR-coupled genes to serve as classification and survival biomarkers, which showed a robust performance across diverse independent data sets. Collectively, our results established an integrative framework to prioritize fDMRs, which could help characterize aberrant DNA methylation-induced potential mechanisms underlying tumorigenesis and uncover epigenome-based biomarkers for clinical diagnosis and prognosis.

• Co-methylation network
• Colorectal cancer
• DNA methylation
• Functional annotation
• Long noncoding RNAs

• Werner syndrome protein
• meningioma
• methylation

Colorectal cancer is a serious health problem, a challenge for research, and a model for studying the molecular mechanisms involved in its development. According to its incidence, this pathology manifests itself in three forms: family, hereditary, and most commonly sporadic, apparently not associated with any hereditary or familial factor. For the types having inheritance patterns and a family predisposition, the tumours develop through defined stages ranging from adenomatous lesions to the manifestation of a malignant tumour. It has been established that environmental and hereditary factors contribute to the development of colorectal cancer, as indicated by the accumulation of mutations in oncogenes, genes which suppress and repair DNA, signaling the existence of various pathways through which the appearance of tumours may occur. In the case of the suppressive and mutating tracks, these are characterised by genetic disorders related to the phenotypical changes of the morphological progression sequence in the adenoma/carcinoma. Moreover, alternate pathways through mutation in BRAF and KRAS genes are associated with the progression of polyps to cancer. This review surveys the research done at the cellular and molecular level aimed at finding specific alternative therapeutic targets for fighting colorectal cancer.

• adenoma
• colorectal cancer
• familial adenomatous polyposis
• hereditary non-polyposis colorectal cancer
• metastasis
• microsatellite instability
• proto-oncogenes
• tumour suppressor genes

• DNA methylation
• cancer diagnosis
• epigenomics
• microarray
• sequencing

• DNA methylation
• colon cancer

Colorectal cancer is ranked third both in incidence and mortality rate among malignant tumor diseases worldwide, posing a serious threat to human health. The improvement of people's living standards and changes in dietary habits and structure have led to a rapid increase in the incidence and mortality rate of colorectal cancer. The methylation of tumor suppressor genes (TSGs) participates in the genesis and progression of colorectal cancer and has become a hotspot in colorectal cancer research in recent years. Elucidation of the clinical significance of methylation of TSG can be helpful in the early screening and diagnosis, recurrence and metastasis monitoring, effective treatment, and evaluation of prognosis of this malignancy. This article reviews the recent progress in understanding the relationship between TSG methylation and colorectal cancer.

• Tumor suppressor genes
• Methylation
• Colorectal cancer
• CIMP
• Clinical significance