• Cell dedifferentiation
• Epigenetic remodeling
• Metabolic reprogramming
• Metabolic therapy
• Mitochondrial dynamics
• Mitochondrial dysfunction
• Mitochondrial-nuclear communication
• Warburg effect

• DNA methylation
• cell differentiation
• epigenetic modifications
• facilitated diffusion
• polymer physics modeling

• Humans
• DNA Methylation
• Epigenesis, Genetic
• Neoplasms/genetics
• CpG Islands
• DNA (Cytosine-5-)-Methyltransferases/metabolism
• DNA (Cytosine-5-)-Methyltransferases/genetics
• Cell Line, Tumor
• Models, Genetic

• PHY-2102726 National Science Foundation (NSF)

• Humans
• DNA Methylation
• Neoplasms/genetics
• Neoplasms/pathology
• Epigenesis, Genetic/physiology
• Biomarkers, Tumor/genetics
• CpG Islands/genetics
• Gene Expression Regulation, Neoplastic

• DNA methylation
• Gene expression
• Liver cancer
• Tumor-specific markers

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• DNA Methylation
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Humans
• CpG Islands
• Gene Expression Regulation, Neoplastic
• Epigenesis, Genetic
• Promoter Regions, Genetic
• Computer Simulation
• Liver/metabolism
• Liver/pathology

• BES-2017-079883 Ministerio de Ciencia e Innovación
• RYC2018-024475-1 Ministerio de Ciencia e Innovación
• PI19/00613 Instituto de Salud Carlos III (SCIII) cofinanced by 'Fondo Europeo de Desarrollo Regional' (FEDER) 'Una Manera de Hacer Europa'
• INVES223049AREC Fundación Científica Asociación Española Contra el Cáncer
• Instituto de Salud Carlos III (SCIII) cofinanced by ‘Fondo Europeo de Desarrollo Regional’ (FEDER) ‘Una Manera de Hacer Europa’
• Universidad de Navarra

• Colon cancer
• Epigenetic diagnosis
• Liquid biopsy
• Postoperative monitoring
• ctDNA

• Humans
• Colonic Neoplasms/genetics
• Colonic Neoplasms/diagnosis
• Colonic Neoplasms/blood
• DNA Methylation/genetics
• Circulating Tumor DNA/genetics
• Circulating Tumor DNA/blood
• Female
• Male
• Middle Aged
• Liquid Biopsy/methods
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/blood
• Aged
• Early Detection of Cancer/methods
• Epigenesis, Genetic
• Case-Control Studies
• Sensitivity and Specificity
• Cell-Free Nucleic Acids/genetics
• Cell-Free Nucleic Acids/blood
• Adult
• Prognosis

• Early diagnosis
• PRKY
• Promoter methylation
• Prostate cancer
• Y-chromosome

• Aged
• Humans
• Male
• Middle Aged
• Biomarkers, Tumor/genetics
• Chromosomes, Human, Y/genetics
• DNA Methylation
• Early Detection of Cancer
• Gene Expression Regulation, Neoplastic
• Promoter Regions, Genetic
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/diagnosis

• 81773221 National Natural Science Foundation of China

• chromatin
• colorectal cancer
• epigenetics
• intestinal stem cells

• Humans
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/metabolism
• Epigenesis, Genetic
• Stem Cells/metabolism
• Animals
• Intestines/pathology
• Cell Differentiation/genetics

• MR/X008517/1 Medical Research Council
• RG\R1\241024 Royal Society
• Leukaemia & Lymphoma
• Leukaemia & Lymphoma

• Humans
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/mortality
• DNA Methylation
• Prognosis
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/mortality
• Male
• Female
• Biomarkers, Tumor/genetics
• Isocitrate Dehydrogenase/genetics
• Mutation
• Gene Expression Regulation, Neoplastic
• Middle Aged
• Whole Genome Sequencing/methods
• Aged
• Tumor Suppressor Proteins/genetics
• Ubiquitin Thiolesterase/genetics
• Gene Expression Profiling

• TJZ202104 National Health Commission of the People's Republic of China (NHC)
• 82202260 National Natural Science Foundation of China (NSFC)
• 82173248 National Natural Science Foundation of China (NSFC)
• 82373400 National Natural Science Foundation of China (NSFC)
• 82372660 National Natural Science Foundation of China (NSFC)
• 82272685 National Natural Science Foundation of China (NSFC)
• 82002967 National Natural Science Foundation of China (NSFC)
• BX20200225 National Postdoctoral Program for Innovative Talents (Postdoctoral Innovation Talent Support Program of China)
• 2022TQ0221 China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)
• 2022ZDZX0019 Science and Technology Department of Sichuan Province (SPDST)
• 2023NSFSC1874 Science and Technology Department of Sichuan Province (SPDST)
• ZYJC18008 West China Hospital, Sichuan University (WCH)
• 10822041A2103 Sichuan University (SCU)

• cns cancer
• paediatric cancer
• dna methylation
• cancer genomics
• tumour heterogeneity

• Humans
• DNA Methylation
• Central Nervous System Neoplasms/genetics
• Central Nervous System Neoplasms/metabolism
• Central Nervous System Neoplasms/pathology
• Child
• Gene Expression Regulation, Neoplastic
• Epigenesis, Genetic
• Histone Deacetylases/metabolism
• Histone Deacetylases/genetics
• Epigenomics/methods
• Repressor Proteins/metabolism
• Repressor Proteins/genetics
• Single-Cell Analysis
• Transcription, Genetic
• Cytosine/metabolism

• S10 OD030242 NIH HHS
• P20 GM130454 NIGMS NIH HHS
• S10 OD025235 NIH HHS
• R01 CA216265 NCI NIH HHS
• R01 CA253976 NCI NIH HHS
• Wellcome Trust
• P20 GM104416 NIGMS NIH HHS
• P30 CA023108 NCI NIH HHS
• United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• U.S. Department of Health & Human Services | National Institutes of Health (NIH)
• U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
• Alex's Lemonade Stand Foundation; Burroughs-Wellcome Fund: Big Data in the Life Sciences at Dartmouth; S.M. Tenney Fellowship at Dartmouth

• cancer metastasis
• epigenetics
• tumor microenvironment
• tumorigenesis

• National Natural Science Foundation of China

• Bivalent promoters
• Cancer
• DNA methylation
• H3K4me1
• LSD1
• Promoter CGIs

• 2020M683073 China Postdoctoral Science Foundation
• 201904010007 Guangzhou Science Technology Project
• 81872299 National Natural Science Foundation of China grants
• JCYJ20190807160011600 Shenzhen Science and Technology Program

• S10 OD030242 NIH HHS
• P20 GM130454 NIGMS NIH HHS
• S10 OD025235 NIH HHS
• P30 CA023108 NCI NIH HHS
• R01 CA216265 NCI NIH HHS
• R01 CA253976 NCI NIH HHS
• Wellcome Trust
• P20 GM104416 NIGMS NIH HHS

• CpG islands
• DNA methylation
• Epigenetics
• Follicular thyroid cancer
• Multinodular goiter
• Papillary thyroid cancer
• Sodium/iodide symporter

Multifocal colorectal cancer (CRC) comprises both clonally independent primary tumors caused by inherited predisposition and clonally related tumors mainly due to intraluminal spreading along an intact basement membrane. The distinction between these multifocal CRCs is essential because therapeutic strategies vary according to the clonal association of multiple tumor masses. Here, we report one unique case of synchronous intestinal cancer (SIC) with tumors occurring along the entire bowel tract, including the small intestine. We established six patient-derived organoids (PDOs), and patient-derived cell lines (PDCs) from each site of the SIC, which were subjected to extensive genomic, transcriptomic, and epigenomic sequencing. We also estimated the drug responses of each multifocal SIC to 25 clinically relevant therapeutic compounds to validate how the clinically actionable alternations between SICs were associated with drug sensitivity. Our data demonstrated distinct clonal associations across different organs, which were consistently supported by multi-omics analysis, as well as the accordant responses to various therapeutic compounds. Our results indicated the imminent drawback of a single tumor-based diagnosis of multifocal CRC and suggested the necessity of an in-depth molecular analysis of all tumor regions to avoid unexpected resistance to the currently available targeted therapies.

• Methionine
• cancer therapy
• epigenetics
• metabolism
• nutrition
• one-carbon
• oxidative stress

The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.

The cellular origin of lung adenocarcinoma remains a focus of intense research efforts. The marked cellular heterogeneity and plasticity of the lungs, as well as the vast variety of molecular subtypes of lung adenocarcinomas perplex the field and account for the extensive variability of experimental results. While most experts would agree on the cellular origins of other types of thoracic tumours, great controversy exists on the tumour-initiating cells of lung adenocarcinoma, since this histologic subtype of lung cancer arises in the distal pulmonary regions where airways and alveoli converge, occurs in smokers as well as nonsmokers, is likely caused by various environmental agents, and is marked by vast molecular and pathologic heterogeneity. Alveolar type II, club, and their variant cells have all been implicated in lung adenocarcinoma progeny and the lineage hierarchies in the distal lung remain disputed. Here we review the relevant literature in this rapidly expanding field, including results from mouse models and human studies. In addition, we present a case for club cells as cells of origin of lung adenocarcinomas that arise in smokers.

Multiple lung epithelial cells are targets of carcinogenic hits. Club cells are such cells that can metabolically activate tobacco pre-carcinogens, being thus positioned as cells of origin of lung adenocarcinomas in smokers.https://bit.ly/3iOshcy

• colorectal cancer
• genome-wide methylation array
• metastasis
• methylation
• miRNA

• Adolescent
• Breast cancer
• Ewing-like sarcoma
• Metaplastic carcinoma
• Small blue round-cell tumor

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy in need of novel targeted therapies to prevent relapse and lessen treatment toxicity. We reveal frequent (∼88%) transcriptional silencing or repression of the tumor suppressor TET2 in T-ALL. We show that loss of TET2 in T-ALL is correlated with hypermethylation of the TET2 promoter and that TET2 expression can be rescued by treatment with the DNA demethylating agent, 5-azacytidine (5-aza). We further reveal that the TET2 cofactor vitamin C exerts a strong synergistic effect on global transcriptional changes when added to 5-aza treatment. Importantly, 5-aza treatment results in increased cell death, specifically in T-ALL cells lacking TET2. Thus, we clearly identify 5-aza as a potentially targeted therapy for TET2-silenced T-ALL.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methylation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improving prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respectively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Importantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2-silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous retroviruses (HERVs), which was further enhanced by the addition of physiological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2-silenced T-ALL.

• 5-azacytidine
• HERV
• T-ALL
• TET2
• vitamin C

• 5-methylcytosine
• DNA sequencing technologies
• N4-methylcytosine
• N6-methyladenine

Hydroxycarbamide (HC, hydroxyurea) is a cytoreductive drug inducing cell cycle blockade. However, emerging evidence suggests that HC plays a role in the modulation of transcription through the activity of transcription factors and DNA methylation. Examining the global mechanism of action of HC in the context of myeloproliferative neoplasms (MPNs), for which HC is the first-line treatment, will provide a better understanding of its molecular effects. To explore the effects of HC genome-wide, transcriptomic analyses were performed on two clinically relevant cell types at different stages of differentiation treated with HC in a murine MPN model. This study was replicated in MPN patients by profiling genome-wide gene expression and DNA methylation using patient blood samples collected longitudinally, before and following HC exposure. The effects of HC on the transcriptome were not only associated with cell cycle interruption but also with hematopoietic functions. Moreover, a group of genes were restored to normal expression levels in murine hematopoietic stem cells (HSCs) following drug treatment, including the master regulator of hematopoiesis, RUNX1. In humans, HC significantly modifies DNA methylation levels in HSCs at several distal regulatory regions, which we show to be associated with SPI1 binding sites and at the SPI1 locus itself. We have identified novel targets of HC that include pivotal transcription factors involved in hematopoiesis, and for the first time we report abnormal methylation patterns in MPN patients at the master regulator gene SPI1 and its distal binding sites, which HC is able to restore to normal levels.

• DNA methylation
• DNA methyltransferase
• cancer
• histone modification

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group “subependymoma, posterior fossa” (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma–subependymoma morphology. Mixed ependymoma–subependymoma tumors varied in their extent of ependymoma differentiation (2–95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

• Chromosome 6
• DNA methylation
• Mixed ependymoma–subependymoma
• Subependymoma
• TERT

• Adult
• Aged
• Aged, 80 and over
• Chromosomes, Human, Pair 6/genetics
• DNA Methylation
• Ependymoma/classification
• Ependymoma/genetics
• Ependymoma/pathology
• Female
• Genetic Techniques
• Humans
• Infratentorial Neoplasms/classification
• Infratentorial Neoplasms/genetics
• Infratentorial Neoplasms/pathology
• Male
• Middle Aged
• Mutation
• Progression-Free Survival
• Promoter Regions, Genetic/genetics
• Telomerase/genetics

• Deutsches Krebsforschungszentrum
• Medizinische Fakultät, Westfälische Wilhelms-Universität Münster
• Charité (3093)

Aberrant methylation is common during the early stage of cancer development. This study was designed to investigate DNA methylation as biomarker for breast cancer.

Public database analysis and methylation-specific whole-gene sequencing were conducted to identify methylated biomarkers that would enable early non-invasive diagnosis of breast cancer. Firstly, the data was obtained from the TCGA Database and the Blueprint Epigenome Database. Secondly, methylation-specific whole-gene sequencing was conducted in 10 female patients with early-stage breast cancer and 10 healthy female volunteers from Nanfang Hospital of Southern Medical University between March 2018 and July 2018. Thirdly, the R language was used for data analysis, and KEGG and DAVID online tool was used for annotations.

We found that methylation levels at 13 cytosine-phosphate-guanine (CpG) sites (cg04066177, cg04281344, cg05995576, cg06221609, cg08642731, cg11388802, cg12665414, cg14557216, cg19404723, cg19457909, cg24570211, cg25818763, and cg26215982) in the malignant tissue DNA were highly comparable to those of circulating cell-free DNA (cfDNA) of breast cancer patients, but were significantly different from those of normal tissue DNA, cfDNA of healthy women, and leukocyte DNA. In addition, three CpG sites (cg04281344, cg24570211, and cg26215982) were confirmed in clinical research, which showed that the sensitivity and specificity of these CpGs as biomarkers for breast cancer were 69.4–83.7% and 85.7–88.6%, respectively.

New biomarkers were identified and confirmed for breast cancer by comparing the methylation of tumour tissues, leukocytes, and non-plasma DNA.

• Breast cancer
• biomarkers
• circulating cell-free DNA (cfDNA)
• database
• methylation

• cancer epigenetics
• epigenetics
• epigenomics
• dna methylation
• colorectal cancer

• Carcinogenesis/genetics
• Cell Line, Tumor
• Chromatin Immunoprecipitation Sequencing
• Colon/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• CpG Islands/genetics
• DNA (Cytosine-5-)-Methyltransferases/genetics
• DNA (Cytosine-5-)-Methyltransferases/metabolism
• DNA Methylation
• Datasets as Topic
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• Histone Code/genetics
• Histones/genetics
• Humans
• Promoter Regions, Genetic/genetics
• Transcription, Genetic

• 20837 Cancer Research UK
• C47648/A20837 Cancer Research UK
• Medical Research Council
• Cancer Research UK (CRUK)

• Adolescent
• Adult
• Aged
• Aging/genetics
• Biomarkers/metabolism
• Cell Line
• DNA Methylation/genetics
• Endometrium/metabolism
• Epigenesis, Genetic
• Female
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Pseudogenes/genetics
• Survival Analysis
• Young Adult

• The Russian Science Foundation grant

• DNA methylation
• hepatocellular carcinoma
• lncRNAs
• survival analysis prognostic predictive model

• Biomarkers, Tumor
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/mortality
• Computational Biology/methods
• Databases, Genetic
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Liver Neoplasms/mortality
• Methylation
• Prognosis
• Proportional Hazards Models
• RNA Processing, Post-Transcriptional
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• ROC Curve
• Reproducibility of Results
• Transcriptome

• cancer
• pluripotency
• dna methylation
• embryonic stem cells
• reprogramming

• Animals
• Cell Line
• Cell Transformation, Neoplastic/genetics
• Cellular Reprogramming
• Coculture Techniques
• CpG Islands/genetics
• DNA (Cytosine-5-)-Methyltransferases/genetics
• DNA (Cytosine-5-)-Methyltransferases/metabolism
• DNA Methylation
• DNA Methyltransferase 3A
• Epigenesis, Genetic
• Fibroblasts
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• HEK293 Cells
• Histones/genetics
• Histones/metabolism
• Human Embryonic Stem Cells
• Humans
• Mice
• Mixed Function Oxygenases/genetics
• Mixed Function Oxygenases/metabolism
• Neoplasms/genetics
• Promoter Regions, Genetic/genetics
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• RNA, Small Interfering/metabolism

• 20837 Cancer Research UK
• MR/M01892X/1 Medical Research Council
• C47648/A20837 Cancer Research UK
• 1650326 Medical Research Council
• RCUK | Medical Research Council (MRC)

We have recently developed a highly accurate urine-based test, named Urodiag®, associating FGFR3 mutation and DNA methylation assays for recurrence surveillance in patients with low-, intermediate-, and high-risk NMIBC. Previously, the detection of four FGFR3 mutations (G372C, R248C, S249C and Y375C) required amplification steps and PCR products were analyzed by capillary electrophoresis (Allele Specific-PCR, AS-PCR), which was expensive and time-consuming. Here, we present the development a novel ultra-sensitive multiplex PCR assay as called “Mutated Allele Specific Oligonucleotide-PCR (MASO-PCR)”, generating a cost-effective, simple, fast and clinically applicable assay for the detection of FGFR3 mutations in voided urine.

Comparative clinical performances of MASO-PCR and AS-PCR technologies were performed from 263 urine DNA samples (87 FGFR3 mutated and 176 FGFR3 wild-type). In the development of Urodiag® PCR Kit, we studied the stability and reproducibility of each all-in-one PCR master mix (single reaction mixture including all the necessary PCR components) for MASO-PCR and QM-MSPCR (Quantitative Multiplex Methylation-Specific PCR to co-amplify SEPTIN9, HS3ST2 and SLIT2 methylated genes) assays.

Complete concordance (100%) was observed between the MASO-PCR and AS-PCR results. Each PCR master mix displayed excellent reproducibility and stability after 12 months of storage at − 20 °C, with intra-assay standard deviations lower than 0.3 Ct and coefficient of variations (CV) lower than 1%. The limit of detection (LoD) of MASO-PCR was 5% mutant detection in a 95% of wild-type background. The limit of quantification (LoQ) of QM-MSPCR was 10 pg of bisulfite-converted DNA.

We developed and clinically validated the MASO-PCR assay, generating cost-effective, simple, fast and clinically applicable assay for the detection of FGFR3 mutations in urine. We also designed the Urodiag® PCR Kit, which includes the MASO-PCR and QM-MSPCR assays. Adapted to routine clinical laboratory (simplicity, accuracy), the kit will be a great help to urologists for recurrence surveillance in patients at low-, intermediate- and high-risk NMIBC. Reducing the number of unnecessary cystoscopies, it will have extremely beneficial effects for patients (painless) and for the healthcare systems (low cost).

• MASO-PCR
• Mutation and methylation markers
• NMIBC
• Surveillance
• Urine-based laboratory test
• Urodiag® PCR kit

• Bivalent
• Cancer
• Chromatin
• DNA methylation
• Development
• Epigenetic
• Polycomb
• Stem cells
• Trithorax

• Animals
• DNA Methylation
• Human Embryonic Stem Cells/metabolism
• Humans
• Mice
• Mouse Embryonic Stem Cells/metabolism
• Neoplasms/genetics
• Promoter Regions, Genetic

• MC_UU_00007/2 Medical Research Council
• MC_PC_U127574433 Medical Research Council
• MC_UU_00007/17 Medical Research Council
• MRF_C0396 MRF
• MC_UU_00007/7 Medical Research Council
• MR/J000914/1 Medical Research Council
• Medical Research Foundation

Co-occurrence and mutual exclusivity (COME) of DNA methylation refer to two or more genes that tend to be positively or negatively correlated in DNA methylation among different samples. Although COME of gene mutations in pan-cancer have been well explored, little is known about the COME of DNA methylation in pan-cancer. Here, we systematically explored the COME of DNA methylation profile in diverse human cancer. A total of 5,128,332 COME events were identified in 14 main cancers types in The Cancer Genome Atlas (TCGA). We also identified functional epigenetic modules of the zinc finger gene family in six cancer types by integrating the gene expression and DNA methylation data and the frequently occurred COME network. Interestingly, most of the genes in those functional epigenetic modules are epigenetically repressed. Strikingly, those frequently occurred COME events could be used to classify the patients into several subtypes with significant different clinical outcomes in six cancers as well as pan-cancer (p-value ≤ = 0.05). Moreover, we observed significant associations between different COME subtypes and clinical features (e.g., age, gender, histological type, neoplasm histologic grade, and pathologic stage) in distinct cancers. Taken together, we identified millions of COME events of DNA methylation in pan-cancer and detected functional epigenetic COME events that could separate tumor patients into different subtypes, which may benefit the diagnosis and prognosis of pan-cancer.

• DNA methylation
• cancer diagnosis
• co-methylation
• mutual exclusivity
• pan-cancer
• survival analysis

Current diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, resulting in overdiagnosis and overtreatment of clinically insignificant tumors. Thus, to improve the management of PC, novel biomarkers are urgently needed.

In this study, we integrated genome-wide methylome (Illumina 450K DNA methylation array (450K)) and RNA sequencing (RNAseq) data performed in a discovery set of 27 PC and 15 adjacent normal (AN) prostate tissue samples to identify candidate driver genes involved in PC development and/or progression. We found significant enrichment for homeobox genes among the most aberrantly methylated and transcriptionally dysregulated genes in PC. Specifically, homeobox gene MEIS2 (Myeloid Ecotropic viral Insertion Site 2) was significantly hypermethylated (p < 0.0001, Mann-Whitney test) and transcriptionally downregulated (p < 0.0001, Mann-Whitney test) in PC compared to non-malignant prostate tissue in our discovery sample set, which was also confirmed in an independent validation set including > 500 PC and AN tissue samples in total (TCGA cohort analyzed by 450K and RNAseq). Furthermore, in three independent radical prostatectomy (RP) cohorts (n > 700 patients in total), low MEIS2 transcriptional expression was significantly associated with poor biochemical recurrence (BCR) free survival (p = 0.0084, 0.0001, and 0.0191, respectively; log-rank test). Next, we analyzed another RP cohort consisting of > 200 PC, AN, and benign prostatic hyperplasia (BPH) samples by quantitative methylation-specific PCR (qMSP) and found that MEIS2 was significantly hypermethylated (p < 0.0001, Mann-Whitney test) in PC compared to non-malignant prostate tissue samples (AN and BPH) with an AUC > 0.84. Moreover, in this cohort, aberrant MEIS2 hypermethylation was significantly associated with post-operative BCR (p = 0.0068, log-rank test), which was subsequently confirmed (p = 0.0067; log-rank test) in the independent TCGA validation cohort (497 RP patients; 450K data).

To the best of our knowledge, this is the first study to investigate, demonstrate, and independently validate a prognostic biomarker potential for MEIS2 at the transcriptional expression level and at the DNA methylation level in PC.

• Biomarker
• DNA methylation
• Epigenetic silencing
• MEIS2
• Prognosis
• Prostate cancer
• RNA expression

In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation–dependent and –independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDH1) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation–independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.

Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation.

In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours.

Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers.

The online version of this article (10.1186/s13148-019-0695-0) contains supplementary material, which is available to authorized users.

• BTC
• Biliary tract cancer
• CLL
• CRA
• CRC
• CTCF
• Cancer methylation alteration
• Chronic lymphocytic leukemia
• Clustered PCDH
• Colorectal adenoma
• Colorectal carcinoma
• CpG islands
• GC
• Gastric cancer
• LGG
• Low grade glioma
• PA
• Pilocytic astrocytoma

• 5-hydroxymethylation
• BisChIP-seq
• CpG islands
• DNA methylation encroachment
• H3K4 monomethylation
• TAB-seq
• WGBS
• cancer
• hypermethylation

• 5-Methylcytosine/analogs & derivatives
• 5-Methylcytosine/metabolism
• Animals
• Cell Line, Tumor
• CpG Islands
• DNA Methylation
• DNA, Neoplasm/metabolism
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Histone-Lysine N-Methyltransferase/genetics
• Histone-Lysine N-Methyltransferase/metabolism
• Histones/genetics
• Histones/metabolism
• Humans
• Male
• Methylation
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid-Lymphoid Leukemia Protein/genetics
• Myeloid-Lymphoid Leukemia Protein/metabolism
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Promoter Regions, Genetic

DNA methylation is a form of epigenetic modification that has been shown to play a significant role in gene regulation. In cancer, DNA methylation plays an important role by regulating the expression of oncogenes. The role of DNA methylation in the onset and progression of various cancer types is now being elucidated as more large-scale data become available. The Cancer Genome Atlas (TCGA) provides a wealth of information for the analysis of various molecular aspects of cancer genetics. Gene expression data and DNA methylation data from TCGA have been used for a variety of studies. A traditional understanding of the effects of DNA methylation on gene expression has linked methylation of CpG sites in the gene promoter region with the decrease in gene expression. Recent studies have begun to expand this traditional role of DNA methylation.

Here we present a pan-cancer analysis of correlation patterns between CpG methylation and gene expression. Using matching patient data from TCGA, 33 cancer-specific correlations were calculated for each CpG site and the expression level of its corresponding gene. These correlations were used to identify patterns on a per-site basis as well as patterns of methylation across the gene body. Using these identified patterns, we found genes that contain conflicting methylation signals beyond the commonly accepted association between the promoter region methylation and silencing of gene expression. Beyond gene body methylation in whole, we examined individual CpG sites and show that, even in the same gene body, some sites can have a contradictory effect on gene expression in cancers.

We observed that within promoter regions there was a substantial amount of positive correlation between methylation and gene expression, which contradicts the commonly accepted association. We observed that the correlation between CpG methylation and gene expression does not exhibit in a tissue-specific manner, suggesting that the effects of methylation on gene expression are largely tissue independent. The analysis of correlation associated with the location of the CpG site in the gene body has led to the identification of several different methylation patterns that affect gene expression, and several examples of methylation activating gene expression were observed. Distinctly opposing or conflicting effects were seen in close proximity on the gene body, where negative and positive correlations were seen at the neighboring CpG sites.

• CpG methylation
• TCGA
• correlation
• epigenetics
• pan-cancer

• Aging/genetics
• Carcinogenesis/genetics
• Cell Division/genetics
• Chromatin/chemistry
• Chromosomes, Human
• DNA Methylation
• DNA Replication Timing
• Genes, Neoplasm
• Humans
• Neoplasms/genetics
• Organ Specificity
• Regulatory Sequences, Nucleic Acid