1 4479 109 MOLECULAR PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR THERAPY. THE DEVELOPMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC) IS A MULTISTEP PROCESS REQUIRING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS, INFLUENCED BY A PATIENT'S GENETIC PREDISPOSITION AS WELL AS BY ENVIRONMENTAL INFLUENCES, INCLUDING TOBACCO, ALCOHOL, CHRONIC INFLAMMATION, AND VIRAL INFECTION. TUMORIGENIC GENETIC ALTERATIONS CONSIST OF TWO MAJOR TYPES: TUMOR SUPPRESSOR GENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN INACTIVATED; AND ONCOGENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN ACTIVATED. TUMOR SUPPRESSOR GENES CAN BE INACTIVATED THROUGH GENETIC EVENTS SUCH AS MUTATION, LOSS OF HETEROZYGOSITY, OR DELETION, OR BY EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION OR CHROMATIN REMODELING. ONCOGENES CAN BE ACTIVATED THROUGH OVEREXPRESSION DUE TO GENE AMPLIFICATION, INCREASED TRANSCRIPTION, OR CHANGES IN STRUCTURE DUE TO MUTATIONS THAT LEAD TO INCREASED TRANSFORMING ACTIVITY. THIS REVIEW FOCUSES ON THE MOLECULAR MECHANISMS OF ORAL CARCINOGENESIS AND THE USE OF BIOLOGIC THERAPY TO SPECIFICALLY TARGET MOLECULES ALTERED IN OSCC. THE RAPID PROGRESS THAT HAS BEEN MADE IN OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS CONTRIBUTING TO THE DEVELOPMENT OF OSCC IS LEADING TO IMPROVEMENTS IN THE EARLY DIAGNOSIS OF TUMORS AND THE REFINEMENT OF BIOLOGIC TREATMENTS INDIVIDUALIZED TO THE SPECIFIC CHARACTERISTICS OF A PATIENT'S TUMOR. 2008 2 2975 58 GENETIC AND MOLECULAR ALTERATIONS ASSOCIATED WITH ORAL SQUAMOUS CELL CANCER (REVIEW). THE DEVELOPMENT OF ORAL SQUAMOUS CELL CANCER (OSCC) IS A MULTISTEP PROCESS INVOLVING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS MODULATED BY GENETIC PRE-DISPOSITION AND ENVIRONMENTAL INFLUENCES SUCH AS TOBACCO AND ALCOHOL USE, CHRONIC INFLAMMATION, AND VIRAL INFECTIONS. ALL OF THESE FACTORS CAN LEAD TO A WIDE RANGE OF GENETIC AND MOLECULAR ALTERATIONS THAT CAN BE DETECTED USING A RANGE OF MOLECULAR STUDIES. THE ALTERATIONS MOSTLY AFFECT TWO LARGE GROUPS OF GENES: ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH CAN BE EITHER INACTIVATED OR OVEREXPRESSED THROUGH MUTATIONS, LOSS OF HETEROZYGOSITY, DELETIONS, OR EPIGENETIC MODIFICATIONS SUCH AS METHYLATION. OTHER MOLECULES THAT ARE CLOSELY ASSOCIATED WITH TUMOR PATHOGENESIS AND PROGNOSIS ALSO EXIST AND WARRANT FURTHER STUDY. IMPORTANT ADVANCES IN MOLECULAR BIOLOGY ARE HELPING TO SHED LIGHT ON ORAL CANCER AND THUS AIDING IN THE EARLY DIAGNOSIS AND DEVELOPMENT OF NEW PERSONALIZED TREATMENT APPROACHES. THE PURPOSE OF THE REVIEW IS TO EXPLORE THE GENETIC AND MOLECULAR ALTERATIONS ASSOCIATED WITH OSCC. 2009 3 5291 46 PROSTATE CARCINOGENESIS: INSIGHTS IN RELATION TO EPIGENETICS AND INFLAMMATION. PROSTATE CANCER IS A MULTIFACTORIAL DISEASE THAT MAINLY OCCURS DUE TO THE ACCUMULATION OF SOMATIC, GENETIC, AND EPIGENETIC CHANGES, RESULTING IN THE INACTIVATION OF TUMOR-SUPPRESSOR GENES AND ACTIVATION OF ONCOGENES. MUTATIONS IN GENES, SPECIFICALLY THOSE THAT CONTROL CELL GROWTH AND DIVISION OR THE REPAIR OF DAMAGED DNA, MAKE THE CELLS GROW AND DIVIDE UNCONTROLLABLY TO FORM A TUMOR. THE RISK OF DEVELOPING PROSTATE CANCER DEPENDS UPON THE GENE THAT HAS UNDERGONE THE MUTATION. IDENTIFYING SUCH GENETIC RISK FACTORS FOR PROSTATE CANCER POSES A CHALLENGE FOR THE RESEARCHERS. BESIDES GENETIC MUTATIONS, MANY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS (METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION) NUCLEOSOMAL REMODELING, AND CHROMOSOMAL LOOPING, HAVE SIGNIFICANTLY CONTRIBUTED TO THE ONSET OF PROSTATE CANCER AS WELL AS THE PROGNOSIS, DIAGNOSIS, AND TREATMENT OF PROSTATE CANCER. CHRONIC INFLAMMATION ALSO PLAYS A MAJOR ROLE IN THE ONSET AND PROGRESSION OF HUMAN CANCER, VIA MODIFICATIONS IN THE TUMOR MICROENVIRONMENT BY INITIATING EPITHELIALMESENCHYMAL TRANSITION AND REMODELING THE EXTRACELLULAR MATRIX. IN THIS ARTICLE, THE AUTHORS PRESENT A BRIEF HISTORY OF THE MECHANISMS AND POTENTIAL LINKS BETWEEN THE GENETIC ABERRATIONS, EPIGENETIC CHANGES, INFLAMMATION, AND INFLAMMASOMES THAT ARE KNOWN TO CONTRIBUTE TO THE PROGNOSIS OF PROSTATE CANCER. FURTHERMORE, THE AUTHORS EXAMINE AND DISCUSS THE CLINICAL POTENTIAL OF PROSTATE CARCINOGENESIS IN RELATION TO EPIGENETICS AND INFLAMMATION FOR ITS DIAGNOSIS AND TREATMENT.. 2021 4 2970 46 GENETIC AND EPIGENETIC SIGNATURES IN HUMAN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD MOST COMMON CAUSE OF CANCER DEATHS WORLDWIDE, AND THE INCIDENCE OF THIS FATAL DISEASE IS STILL ON RISE. THE MAJORITY OF HCCS EMERGE IN THE BACKGROUND OF A CHRONIC LIVER DISEASE, SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS. THE CURRENT UNDERSTANDING IS THAT MAJORITY OF HCCS EVOLVE AS A CONSEQUENCE OF CHRONIC INFLAMMATION AND DUE TO THE PRESENCE OF INFECTION WITH HEPATITIS VIRUSES. THESE UNDERLYING PATHOGENIC STIMULI SUBSEQUENTLY INDUCE A SPECTRUM OF GENETIC AND EPIGENETIC ALTERATIONS IN SEVERAL CANCER-RELATED GENES, WHICH ARE INVOLVED IN CELL-CYCLE REGULATION, CELL GROWTH AND ADHESION. SUCH WIDESPREAD GENOMIC ALTERATIONS CAUSE DISRUPTION OF NORMAL CELLULAR SIGNALING AND FINALLY LEAD TO THE ACQUISITION OF A MALIGNANT PHENOTYPE IN HCC. IN GENERAL, THE TYPE OF GENE ALTERATIONS, SUCH AS POINT MUTATIONS, DELETION OF CHROMOSOMAL REGIONS AND ABNORMAL METHYLATION OF GENE PROMOTERS DIFFER ACCORDING TO THE INDIVIDUAL TARGETED GENE. IN HCC, INCIDENCE OF GENETIC ALTERATIONS IS RELATIVELY RARE AND IS LIMITED TO A SUBSET OF FEW CANCER-SPECIFIC GENES, SUCH AS THE TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS THE CTNNB1. IN CONTRAST, EPIGENETIC CHANGES THAT INVOLVE ABERRANT METHYLATION OF GENES AND OTHER POST-TRANSCRIPTIONAL HISTONE MODIFICATIONS OCCUR FAR MORE FREQUENTLY, AND SOME OF THESE EPIGENETIC ALTERATIONS ARE NOW BEING EXPLOITED FOR THE DEVELOPMENT OF MOLECULAR DIAGNOSTIC SIGNATURES FOR HCC. IN ADDITION, RECENT FINDINGS OF UNIQUE MICRORNA EXPRESSION PROFILES ALSO PROVIDE AN EVIDENCE FOR THE EXISTENCE OF NOVEL MECHANISMS FOR GENE EXPRESSION REGULATION IN HCC. IN THIS REVIEW ARTICLE, WE WILL REVIEW THE CURRENT STATE OF KNOWLEDGE ON THE ACTIVATION OF VARIOUS ONCOGENIC PATHWAYS AND THE INACTIVATION OF TUMOR SUPPRESSOR PATHWAYS IN HCC THAT RESULT IN THE DISRUPTION OF CANCER-RELATED GENE FUNCTION. IN ADDITION, WE WILL SPECIFICALLY EMPHASIZE THE CLINICAL IMPLICATION OF SOME OF THESE GENETIC AND EPIGENETIC ALTERATIONS IN THE MANAGEMENT OF HEPATOCARCINOGENESIS. 2011 5 4539 40 MULTISTAGE CARCINOGENESIS IN MOUSE SKIN. THE MOUSE SKIN MODEL OF MULTISTAGE CARCINOGENESIS HAS FOR MANY YEARS PROVIDED A CONCEPTUAL FRAMEWORK FOR STUDYING CARCINOGENESIS MECHANISMS AND POTENTIAL MEANS FOR INHIBITING SPECIFIC STAGES OF CARCINOGENESIS. THE PROCESS OF SKIN CARCINOGENESIS INVOLVES THE STEPWISE ACCUMULATION OF GENETIC CHANGE ULTIMATELY LEADING TO MALIGNANCY. INITIATION, THE FIRST STEP IN MULTISTAGE SKIN CARCINOGENESIS INVOLVES CARCINOGEN-INDUCED GENETIC CHANGES. A TARGET GENE IDENTIFIED FOR SOME SKIN TUMOR INITIATORS IS C-HA-RAS. THE SECOND STEP, THE PROMOTION STAGE, INVOLVES PROCESSES WHEREBY INITIATED CELLS UNDERGO SELECTIVE CLONAL EXPANSION TO FORM VISIBLE PREMALIGNANT LESIONS TERMED PAPILLOMAS. THE PROCESS OF TUMOR PROMOTION INVOLVES THE PRODUCTION AND MAINTENANCE OF A SPECIFIC AND CHRONIC HYPERPLASIA CHARACTERIZED BY A SUSTAINED CELLULAR PROLIFERATION OF EPIDERMAL CELLS. THESE CHANGES ARE BELIEVED TO RESULT FROM EPIGENETIC MECHANISMS SUCH AS ACTIVATION OF THE CELLULAR RECEPTOR, PROTEIN KINASE C, BY SOME CLASSES OF TUMOR PROMOTERS. THE PROGRESSION STAGE INVOLVES THE CONVERSION OF PAPILLOMAS TO MALIGNANT TUMORS, SQUAMOUS CELL CARCINOMAS. THE ACCUMULATION OF ADDITIONAL GENETIC CHANGES IN CELLS COMPRISING PAPILLOMAS HAS BEEN CORRELATED WITH TUMOR PROGRESSION, INCLUDING TRISOMIES OF CHROMOSOMES 6 AND 7 AND LOSS OF HETEROZYGOSITY. THE CURRENT REVIEW FOCUSES ON THE MECHANISMS INVOLVED IN MULTISTAGE SKIN CARCINOGENESIS, A SUMMARY OF KNOWN INHIBITORS OF SPECIFIC STAGES AND THEIR PROPOSED MECHANISMS OF ACTION, AND THE RELEVANCE OF THIS MODEL SYSTEM TO HUMAN CANCER. 1992 6 928 30 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. CHRONIC INFLAMMATION OFTEN PRECEDES OR ACCOMPANIES A SUBSTANTIAL NUMBER OF CANCERS. INDEED, ANTI-INFLAMMATORY THERAPIES HAVE SHOWN EFFICACY IN CANCER PREVENTION AND TREATMENT. THE EXACT MECHANISMS THAT TURN A WOUND HEALING PROCESS INTO A CANCER PRECURSOR ARE TOPICS OF INTENSE RESEARCH. A PATHOGENIC LINK HAS BEEN IDENTIFIED BETWEEN INFLAMMATORY MEDIATORS, INFLAMMATION RELATED GENE POLYMORPHISMS AND CARCINOGENESIS. ANIMAL MODELS OF CANCER HAVE BEEN INSTRUMENTAL IN DEMONSTRATING THE DIVERSITY OF MECHANISMS THROUGH WHICH EVERY TUMOR COMPARTMENT AND TUMOR STAGE MAY BE AFFECTED BY THE UNDERLYING INFLAMMATORY PROCESS. IN THIS REVIEW, WE FOCUS ON THE INTERACTION BETWEEN CHRONIC INFLAMMATION, TUMOR STEM CELLS AND THE TUMOR MICROENVIRONMENT. WE SUMMARIZE THE PROPOSED MECHANISMS THAT LEAD TO THE RECRUITMENT OF BONE MARROW DERIVED CELLS AND EXPLORE THE GENETIC AND EPIGENETIC ALTERATIONS THAT MAY OCCUR IN INFLAMMATION ASSOCIATED CANCERS. 2009 7 2335 35 EPIGENETIC REGULATION OF INFLAMMATORY CYTOKINES AND ASSOCIATED GENES IN HUMAN MALIGNANCIES. INFLAMMATION IS A MULTIFACETED DEFENSE RESPONSE OF IMMUNE SYSTEM AGAINST INFECTION. CHRONIC INFLAMMATION HAS BEEN IMPLICATED AS AN IMMINENT THREAT FOR MAJOR HUMAN MALIGNANCIES AND IS DIRECTLY LINKED TO VARIOUS STEPS INVOLVED IN TUMORIGENESIS. INFLAMMATORY CYTOKINES, INTERLEUKINS, INTERFERONS, TRANSFORMING GROWTH FACTORS, CHEMOKINES, AND ADHESION MOLECULES HAVE BEEN ASSOCIATED WITH CHRONIC INFLAMMATION. NUMEROUS CYTOKINES ARE REPORTED TO BE ABERRANTLY REGULATED BY DIFFERENT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS IN TUMOR TISSUES, CONTRIBUTING TO PATHOGENESIS OF TUMOR IN MULTIPLE WAYS. SOME OF THESE CYTOKINES ALSO WORK AS EPIGENETIC REGULATORS OF OTHER CRUCIAL GENES IN TUMOR BIOLOGY, EITHER DIRECTLY OR INDIRECTLY. SUCH REGULATIONS ARE REPORTED IN LUNG, BREAST, CERVICAL, GASTRIC, COLORECTAL, PANCREATIC, PROSTATE, AND HEAD AND NECK CANCERS. EPIGENETICS OF INFLAMMATORY MEDIATORS IN CANCER IS CURRENTLY SUBJECT OF EXTENSIVE RESEARCH. THESE INVESTIGATIONS MAY HELP IN UNDERSTANDING CANCER BIOLOGY AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES. THE PURPOSE OF THIS PAPER IS TO HAVE A BRIEF VIEW OF THE ABERRANT REGULATION OF INFLAMMATORY CYTOKINES IN HUMAN MALIGNANCIES. 2015 8 1232 40 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 9 6710 37 VIRAL-INDUCED HUMAN CARCINOGENESIS: AN OXIDATIVE STRESS PERSPECTIVE. ONCOGENIC TRANSFORMATION OCCURS VIA MANY DIFFERENT MECHANISMS. ALTERATIONS IN THE EXPRESSION OF CERTAIN KEY GENES (ONCOGENES AND/OR TUMOR SUPPRESSOR GENES) CONTRIBUTE TO THE DEVELOPMENT OF THE TUMORIGENIC STATE OF UNCONTROLLED CELL PROLIFERATION. TUMOR VIRUSES' STUDIES HAVE CONTRIBUTED OVER THE LAST 2 DECADES SIGNIFICANTLY IN CANCER ETIOLOGY, FIRST BY PROVIDING VALUABLE INFORMATION ON THE MECHANISMS AND DISSECTION OF CELL SIGNALING AND GROWTH CONTROL PATHWAYS AND SECOND BY BEING CAUSATIVE AGENTS OF HUMAN NEOPLASIA. VIRUSES CONTRIBUTE TO THE DEVELOPMENT OF THE NEOPLASTIC STATE THROUGH MANY MECHANISMS: INACTIVATION OF TUMOR SUPPRESSOR GENES, HYPERSTIMULATION OF CELLULAR PROTO-ONCOGENE TRANSCRIPTION, OR BY VIRAL PROTEIN INTERFERENCE WITH THE CELLULAR TRANSCRIPTION, SIGNAL TRANSDUCTION, DNA REPAIR AND APOPTOSIS PATHWAYS AND INDUCTION OF CHRONIC OXIDATIVE STRESS. ON THE OTHER HAND, ONLY RECENTLY RESEARCH HAS PROVIDED EVIDENCE OF THE EPIGENETIC PATHWAY INVOLVEMENT AND ESPECIALLY THE DNA METHYLATION MACHINERY. TO THIS END, BOTH HYPOMETHYLATION-INDUCED ONCOGENIC ACTIVATION AND/OR HYPERMETHYLATION-INDUCED TUMOR SUPPRESSOR GENE SILENCING ARE LINKED WITH VIRAL-INDUCED CARCINOGENESIS. IN THIS REVIEW, WE DISCUSS THE CURRENT STATUS OF KNOWLEDGE ON VIRAL-ASSOCIATED CARCINOGENESIS WITH EMPHASIS ON THE MECHANISMS OF OXIDATIVE STRESS AND DNA DAMAGE INDUCTION IN HUMANS BY VIRUSES AS WELL AS IMPLICATIONS IN CANCER TREATMENT. 2010 10 4429 45 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 11 2122 34 EPIGENETIC IMPACT OF INFECTION ON CARCINOGENESIS: MECHANISMS AND APPLICATIONS. VIRAL AND BACTERIAL INFECTIONS ARE INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS, SUCH AS LIVER, NASOPHARYNGEAL, CERVICAL, HEAD AND NECK, AND GASTRIC CANCERS. ABERRANT DNA METHYLATION IS FREQUENTLY PRESENT IN THESE CANCERS, AND SOME OF THE ABERRANTLY METHYLATED GENES ARE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. NOTABLY, ABERRANT DNA METHYLATION CAN BE PRESENT EVEN IN NON-CANCEROUS OR PRECANCEROUS TISSUES, AND ITS LEVELS CORRELATE WITH THE RISK OF CANCER DEVELOPMENT, PRODUCING A SO-CALLED 'EPIGENETIC FIELD FOR CANCERIZATION'. MECHANISTICALLY, MOST VIRAL OR BACTERIAL INFECTIONS INDUCE DNA METHYLATION INDIRECTLY VIA CHRONIC INFLAMMATION, BUT RECENT STUDIES HAVE INDICATED THAT SOME VIRUSES HAVE DIRECT EFFECTS ON THE EPIGENETIC MACHINERY OF HOST CELLS. FROM A TRANSLATIONAL VIEWPOINT, A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THAT ASSESSMENT OF THE EXTENT OF ALTERATIONS IN DNA METHYLATION IN NON-CANCEROUS TISSUES CAN BE USED TO PREDICT CANCER RISK. FURTHERMORE, SUPPRESSION OF ABERRANT DNA METHYLATION WAS SHOWN TO BE A USEFUL STRATEGY FOR CANCER PREVENTION IN AN ANIMAL MODEL. HERE, WE REVIEW THE INVOLVEMENT OF ABERRANT DNA METHYLATION IN VARIOUS TYPES OF INFECTION-ASSOCIATED CANCERS, ALONG WITH INDIVIDUAL INDUCTION MECHANISMS, AND WE DISCUSS THE APPLICATION OF THESE FINDINGS FOR CANCER PREVENTION, DIAGNOSIS, AND THERAPY. 2016 12 2036 34 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 13 3799 30 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 14 2854 31 FROM HEPATITIS TO HEPATOCELLULAR CARCINOMA: A PROPOSED MODEL FOR CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS. INFLAMMATION REPRESENTS THE BODY'S NATURAL RESPONSE TO TISSUE DAMAGE; HOWEVER, CHRONIC INFLAMMATION MAY ACTIVATE CELL PROLIFERATION AND INDUCE DEREGULATION OF CELL DEATH IN AFFECTED TISSUES. CHRONIC INFLAMMATION IS AN IMPORTANT FACTOR IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), ALTHOUGH THE PRECISE UNDERLYING MECHANISM REMAINS UNKNOWN. EPIGENETIC EVENTS, WHICH ARE CONSIDERED KEY MECHANISMS IN THE REGULATION OF GENE ACTIVITY STATES, ARE ALSO COMMONLY DEREGULATED IN HCC. HERE, WE REVIEW THE EVIDENCE THAT CHRONIC INFLAMMATION MIGHT DEREGULATE EPIGENETIC PROCESSES, THUS PROMOTING ONCOGENIC TRANSFORMATION, AND WE PROPOSE A WORKING HYPOTHESIS THAT EPIGENETIC DEREGULATION IS AN UNDERLYING MECHANISM BY WHICH INFLAMMATION MIGHT PROMOTE HCC DEVELOPMENT. IN THIS SCENARIO, DIFFERENT COMPONENTS OF THE INFLAMMATORY RESPONSE MIGHT DIRECTLY AND INDIRECTLY INDUCE CHANGES IN EPIGENETIC MACHINERIES ('EPIGENETIC SWITCH'), INCLUDING THOSE INVOLVED IN SETTING AND PROPAGATING NORMAL PATTERNS OF DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS IN HEPATOCYTES. WE DISCUSS THE POSSIBILITY THAT SELF-REINFORCING CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS MIGHT AMPLIFY INFLAMMATORY SIGNALS AND MAINTAIN A CHRONIC STATE OF INFLAMMATION CULMINATING IN CANCER DEVELOPMENT. THE POTENTIAL ROLE OF INFLAMMATION-EPIGENOME INTERACTIONS IN THE EMERGENCE AND MAINTENANCE OF CANCER STEM CELLS IS ALSO DISCUSSED. 2012 15 6428 36 THE TUMOR MICROENVIRONMENT AND METASTATIC DISEASE. THE MICROENVIRONMENT OF SOLID TUMORS IS A HETEROGENEOUS, COMPLEX MILIEU FOR TUMOR GROWTH AND SURVIVAL THAT INCLUDES FEATURES SUCH AS ACIDIC PH, LOW NUTRIENT LEVELS, ELEVATED INTERSTITIAL FLUID PRESSURE (IFP) AND CHRONIC AND FLUCTUATING LEVELS OF OXYGENATION THAT RELATE TO THE ABNORMAL VASCULAR NETWORK THAT EXISTS IN TUMORS. THE METASTATIC POTENTIAL OF TUMOR CELLS IS BELIEVED TO BE REGULATED BY INTERACTIONS BETWEEN THE TUMOR CELLS AND THEIR EXTRACELLULAR ENVIRONMENT (EXTRACELLULAR MATRIX (ECM)). THESE INTERACTIONS CAN BE MODIFIED BY THE ACCUMULATION OF GENETIC CHANGES AND BY THE TRANSIENT ALTERATIONS IN GENE EXPRESSION INDUCED BY THE LOCAL TUMOR MICROENVIRONMENT. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT ALTERED GENE EXPRESSION IN RESPONSE TO THE HYPOXIC MICROENVIRONMENT IS A CONTRIBUTING FACTOR TO INCREASED METASTATIC EFFICIENCY. A NUMBER OF GENES THAT HAVE BEEN IMPLICATED IN THE METASTATIC PROCESS, INVOLVING ANGIOGENESIS, INTRA/EXTRAVASATION, SURVIVAL AND GROWTH, HAVE BEEN FOUND TO BE HYPOXIA-RESPONSIVE. THE VARIOUS METASTATIC DETERMINANTS, GENETIC AND EPIGENETIC, SOMATIC AND INHERITED MAY SERVE AS PRECEDENTS FOR THE FUTURE IDENTIFICATION OF MORE GENES THAT ARE INVOLVED IN METASTASIS. MUCH RESEARCH HAS FOCUSED ON GENETIC AND MOLECULAR PROPERTIES OF THE TUMOR CELLS THEMSELVES. IN THE PRESENT REVIEW WE DISCUSS THE EPIGENETIC AND PHYSIOLOGICAL REGULATION OF METASTASIS AND EMPHASIZE THE NEED FOR FURTHER STUDIES ON THE INTERACTIONS BETWEEN THE PATHOPHYSIOLOGIC TUMOR MICROENVIRONMENT AND THE TUMOR EXTRACELLULAR MATRIX. 2009 16 4733 37 NOVEL BIOMARKERS FOR THE IDENTIFICATION AND TARGETED THERAPY OF GASTRIC CANCER. GASTRIC CANCER DEVELOPMENT FOLLOWS THE PATHOLOGIC PATTERN SUCH THAT CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA PROGRESSIVELY TRANSFORMS NORMAL MUCOSA INTO ATROPHY, INTESTINAL METAPLASIA, ADENOMA/DYSPLASIA AND EVENTUALLY INVASIVE AND METASTATIC TUMORS. THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS LEADS TO THE DYSREGULATION OF ONCOGENES AND TUMOR SUPPRESSORS, WHICH WAS CONSIDERED AS THE DRIVER BEHIND EVENTS DURING THE TUMORIGENESIS. ALMOST ALL GASTRIC CANCERS ARE ADENOCARCINOMAS, WHICH SHARE CONSIDERABLE HETEROGENEITY WITH DISTINCT MORPHOLOGY, PATHOGENESIS AND CLINICAL BEHAVIOR. THEREFORE, IDENTIFYING SUBTYPES OF GASTRIC CANCERS WITH MOLECULAR AND GENETIC FEATURES WILL BE BENEFICIAL FOR THE EARLY IDENTIFICATION AND SELECTION OF NEW EFFECTIVE AGENTS FOR TARGETED TREATMENT. HIGH-THROUGHPUT SEQUENCING TECHNIQUES SUCH AS WHOLE GENOMIC, EPIGENOME AND TRANSCRIPTOME SEQUENCING AND PROTEOMICS PLATFORMS HAVE IDENTIFIED MAJOR GENOMIC CHARACTERISTICS THAT EXHIBIT IDENTIFICATION AND PROGNOSTIC IMPACTS AND DISTINCT RESPONSE PATTERNS. IN THIS ARTICLE, THE AUTHORS AIM TO SUMMARIZE THE INFORMATION REGARDING THE MOST PROMISING MOLECULES THAT MAY HAVE CLINICAL APPLICATION AS NON-INVASIVE BIOMARKERS AND THERAPY TARGETS. 2015 17 733 41 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 18 2166 39 EPIGENETIC MECHANISMS IN HEPATOCELLULAR CARCINOMA: HOW ENVIRONMENTAL FACTORS INFLUENCE THE EPIGENOME. EPIGENETIC MECHANISMS MAINTAIN HERITABLE CHANGES IN GENE EXPRESSION AND CHROMATIN ORGANIZATION OVER MANY CELL GENERATIONS. IMPORTANTLY, DEREGULATED EPIGENETIC MECHANISMS PLAY A KEY ROLE IN A WIDE RANGE OF HUMAN MALIGNANCIES, INCLUDING LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC), WHICH ORIGINATES FROM THE HEPATOCYTES, IS BY FAR THE MOST COMMON LIVER CANCER, WITH RATES AND AETIOLOGY THAT SHOW CONSIDERABLE GEOGRAPHIC VARIATION. VARIOUS ENVIRONMENTAL AGENTS AND LIFESTYLES KNOWN TO BE RISK FACTORS FOR HCC (SUCH AS INFECTION BY HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), CHRONIC ALCOHOL INTAKE, AND AFLATOXINS) ARE SUSPECTED TO PROMOTE ITS DEVELOPMENT BY ELICITING EPIGENETIC CHANGES, HOWEVER THE PRECISE GENE TARGETS AND UNDERLYING MECHANISMS HAVE NOT BEEN ELUCIDATED. MANY RECENT STUDIES HAVE EXPLOITED CONCEPTUAL AND TECHNOLOGICAL ADVANCES IN EPIGENETICS AND EPIGENOMICS TO INVESTIGATE THE ROLE OF EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN HCC TUMORS AND NON-TUMOR PRECANCEROUS (CIRRHOTIC) LESIONS. THESE STUDIES HAVE IDENTIFIED A LARGE NUMBER OF GENES AND PATHWAYS THAT ARE TARGETED BY EPIGENETIC DEREGULATION (CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-MEDIATED GENE SILENCING) DURING THE DEVELOPMENT AND PROGRESSION OF HCC. FREQUENT IDENTIFICATION OF ABERRANT EPIGENETIC CHANGES IN SPECIFIC GENES IN CIRRHOTIC TISSUE IS CONSISTENT WITH THE NOTION THAT EPIGENETIC DEREGULATION OF SELECTED GENES IN PRE-MALIGNANT LESIONS PRECEDES AND PROMOTES THE DEVELOPMENT OF HCC. IN ADDITION, SEVERAL LINES OF EVIDENCE ARGUE THAT SOME ENVIRONMENTAL FACTORS (SUCH AS HBV VIRUS) MAY ABROGATE CELLULAR DEFENSE SYSTEMS, INDUCE SILENCING OF HOST GENES AND PROMOTE HCC DEVELOPMENT VIA AN "EPIGENETIC STRATEGY". FINALLY, PROFILING STUDIES REVEAL THAT HCC TUMORS AND PRE-CANCEROUS LESIONS MAY EXHIBIT EPIGENETIC SIGNATURES ASSOCIATED WITH SPECIFIC RISK FACTORS AND TUMOR PROGRESSION STAGE. TOGETHER, RECENT EVIDENCE UNDERSCORES THE IMPORTANCE OF ABERRANT EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN LIVER CANCER AND HIGHLIGHTS POTENTIAL TARGETS FOR BIOMARKER DISCOVERY AND FUTURE PREVENTIVE AND THERAPEUTIC STRATEGIES. 2011 19 5412 30 REGULATION OF ANTITUMOR IMMUNITY BY INFLAMMATION-INDUCED EPIGENETIC ALTERATIONS. CHRONIC INFLAMMATION PROMOTES TUMOR DEVELOPMENT, PROGRESSION, AND METASTATIC DISSEMINATION AND CAUSES TREATMENT RESISTANCE. THE ACCUMULATION OF GENETIC ALTERATIONS AND LOSS OF NORMAL CELLULAR REGULATORY PROCESSES ARE NOT ONLY ASSOCIATED WITH CANCER GROWTH AND PROGRESSION BUT ALSO RESULT IN THE EXPRESSION OF TUMOR-SPECIFIC AND TUMOR-ASSOCIATED ANTIGENS THAT MAY ACTIVATE ANTITUMOR IMMUNITY. THIS ANTAGONISM BETWEEN INFLAMMATION AND IMMUNITY AND THE ABILITY OF CANCER CELLS TO AVOID IMMUNE DETECTION AFFECT THE COURSE OF CANCER DEVELOPMENT AND TREATMENT OUTCOMES. WHILE INFLAMMATION, PARTICULARLY ACUTE INFLAMMATION, SUPPORTS T-CELL PRIMING, ACTIVATION, AND INFILTRATION INTO INFECTED TISSUES, CHRONIC INFLAMMATION IS MOSTLY IMMUNOSUPPRESSIVE. HOWEVER, THE MAIN MECHANISMS THAT DICTATE THE OUTCOME OF THE INFLAMMATION-IMMUNITY INTERPLAY ARE NOT WELL UNDERSTOOD. RECENT DATA SUGGEST THAT INFLAMMATION TRIGGERS EPIGENETIC ALTERATIONS IN CANCER CELLS AND COMPONENTS OF THE TUMOR MICROENVIRONMENT. THESE ALTERATIONS CAN AFFECT AND MODULATE NUMEROUS ASPECTS OF CANCER DEVELOPMENT, INCLUDING TUMOR GROWTH, THE METABOLIC STATE, METASTATIC SPREAD, IMMUNE ESCAPE, AND IMMUNOSUPPRESSIVE OR IMMUNOSUPPORTIVE LEUKOCYTE GENERATION. IN THIS REVIEW, WE DISCUSS THE ROLE OF INFLAMMATION IN INITIATING EPIGENETIC ALTERATIONS IN IMMUNE CELLS, CANCER-ASSOCIATED FIBROBLASTS, AND CANCER CELLS AND SUGGEST HOW AND WHEN EPIGENETIC INTERVENTIONS CAN BE COMBINED WITH IMMUNOTHERAPIES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 20 3659 36 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010