1 1435 177 DIFFERENTIAL METHYLATION LANDSCAPE OF PANCREATIC DUCTAL ADENOCARCINOMA AND ITS PRECANCEROUS LESIONS. BACKGROUND: PANCREATIC CANCER IS ONE OF THE MOST LETHAL DISEASES WITH AN INCIDENCE ALMOST EQUAL TO THE MORTALITY. IN ADDITION TO HAVING GENETIC CAUSES, CANCER CAN ALSO BE CONSIDERED AN EPIGENETIC DISEASE. DNA METHYLATION IS THE PREMIER EPIGENETIC MODIFICATION AND PATTERNS OF ABERRANT DNA METHYLATION ARE RECOGNIZED TO BE A COMMON HALLMARK OF HUMAN TUMOR. IN THE MULTISTAGE CARCINOGENESIS OF PANCREAS STARTING FROM PRECANCEROUS LESIONS TO PANCREATIC DUCTAL ADENOCARCINOMA (PDAC), THE EPIGENETIC CHANGES PLAY A SIGNIFICANT ROLE. DATA SOURCES: RELEVANT STUDIES FOR THIS REVIEW WERE DERIVED VIA AN EXTENSIVE LITERATURE SEARCH IN PUBMED VIA USING VARIOUS KEYWORDS SUCH AS PANCREATIC DUCTAL ADENOCARCINOMA, PRECANCEROUS LESIONS, METHYLATION PROFILE, EPIGENETIC BIOMARKERS THAT ARE RELEVANT DIRECTLY OR CLOSELY ASSOCIATED WITH THE CONCERNED AREA OF OUR INTEREST. THE LITERATURE SEARCH WAS INTENSIVELY DONE CONSIDERING A TIME FRAME OF 20 YEARS (1998-2018). RESULT: IN THIS REVIEW WE HAVE HIGHLIGHTED THE HYPERMETHYLATION AND HYPOMETHYLATION OF THE PRECANCEROUS PDAC LESIONS (PANCREATIC INTRA-EPITHELIAL NEOPLASIA, INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM, MUCINOUS CYSTIC NEOPLASM AND CHRONIC PANCREATITIS) AND PDAC ALONG WITH THE POTENTIAL BIOMARKERS. WE HAVE ALSO ACHIEVED THE EARLY EPIGENETIC DRIVER THAT LEADS TO PROGRESSION FROM PRECANCEROUS LESIONS TO PDAC. A BUNCH OF EPIGENETIC DRIVER GENES LEADS TO PROGRESSION OF PRECANCEROUS LESIONS TO PDAC (PPENK, APC, P14/5/16/17, HMLH1 AND MGMT) ARE ALSO DOCUMENTED. WE SUMMARIZED THE IMPORTANCE OF THESE OBSERVATIONS IN THERAPEUTICS AND DIAGNOSIS OF PDAC HENCE IDENTIFYING THE POTENTIAL USE OF EPIGENETIC BIOMARKERS IN EPIGENETIC TARGETED THERAPY. EPIGENETIC INACTIVATION OCCURS BY HYPERMETHYLATION OF CPG ISLANDS IN THE PROMOTER REGIONS OF TUMOR SUPPRESSOR GENES. WE LISTED ALL HYPER- AND HYPOMETHYLATION OF CPG ISLANDS OF SEVERAL GENES IN PDAC INCLUDING ITS PRECANCEROUS LESIONS. CONCLUSIONS: THE CONCEPT OF THE REVIEW WOULD HELP TO UNDERSTAND THEIR BIOLOGICAL EFFECTS, AND TO DETERMINE WHETHER THEY MAY BE SUCCESSFULLY COMBINED WITH OTHER EPIGENETIC DRUGS. HOWEVER, WE NEED TO CONTINUE OUR RESEARCH TO DEVELOP MORE SPECIFIC DNA-DEMETHYLATING AGENTS, WHICH ARE THE TARGETS FOR HYPERMETHYLATED CPG METHYLATION SITES. 2020 2 3686 41 INFLAMMATION-RELATED ABERRANT PATTERNS OF DNA METHYLATION: DETECTION AND ROLE IN EPIGENETIC DEREGULATION OF CANCER CELL TRANSCRIPTOME. IT IS NOW APPARENT THAT EPIGENETIC ABNORMALITIES, IN PARTICULAR ALTERED DNA METHYLATION, PLAY A CRUCIAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF HUMAN CANCERS. DNA HYPERMETHYLATION AT PROMOTER CPG ISLANDS IS NOW RECOGNIZED AS A THIRD MECHANISM BY WHICH INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS. ABERRANT CPG ISLAND HYPERMETHYLATION IS ALSO FREQUENTLY OBSERVED IN CHRONIC INFLAMMATION AND PRECANCEROUS LESIONS, WHICH SUGGESTS THAT IT IS AN EARLY EVENT IN TUMORIGENESIS THAT COULD SERVE AS A USEFUL TUMOR MARKER. A VARIETY OF SCREENING TECHNIQUES HAVE BEEN DEVELOPED FOR GENOME-WIDE SCREENING OF METHYLATION STATUS. OF THOSE, TRANSCRIPTOME ANALYSIS COUPLED WITH PHARMACOLOGICAL UNMASKING HAS EMERGED AS A POWERFUL TOOL FOR REVEALING DNA METHYLATION PATTERNS IN CANCER CELLS AND IDENTIFYING NEW TUMOR MARKER CANDIDATES. 2009 3 342 50 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS. 2007 4 2122 44 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 5 3067 47 GENOME-WIDE DNA METHYLATION PROFILES IN PRECANCEROUS CONDITIONS AND CANCERS. ALTERATIONS OF DNA METHYLATION, WHICH RESULT IN CHROMOSOMAL INSTABILITY AND SILENCING OF TUMOR-RELATED GENES, ARE AMONG THE MOST CONSISTENT EPIGENETIC CHANGES OBSERVED IN HUMAN CANCERS. ANALYSIS OF TISSUE SPECIMENS HAS REVEALED THAT DNA METHYLATION ALTERATIONS PARTICIPATE IN MULTISTAGE CARCINOGENESIS, EVEN FROM THE EARLY AND PRECANCEROUS STAGES, ESPECIALLY IN ASSOCIATION WITH CHRONIC INFLAMMATION AND/OR PERSISTENT VIRAL INFECTION, SUCH AS CHRONIC HEPATITIS OR LIVER CIRRHOSIS RESULTING FROM INFECTION WITH HEPATITIS B OR C VIRUS. DNA METHYLATION ALTERATIONS CAN ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY, BUT IS SIGNIFICANTLY CORRELATED WITH ACCUMULATION OF DNA HYPERMETHYLATION IN CPG ISLANDS OF TUMOR-RELATED GENES. ALTERATION OF DNA METHYLTRANSFERASE 3B SPLICING MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION IN PERICENTROMERIC SATELLITE REGIONS. GENOME-WIDE ANALYSIS OF DNA METHYLATION STATUS HAS REVEALED THAT THE DNA METHYLATION PROFILE AT THE PRECANCEROUS STAGE IS BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. DNA METHYLATION STATUS IS NOT SIMPLY ALTERED AT THE PRECANCEROUS STAGE; RATHER, DNA METHYLATION ALTERATIONS AT THE PRECANCEROUS STAGE MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. THEREFORE, GENOME-WIDE DNA METHYLATION PROFILING MAY PROVIDE OPTIMAL INDICATORS FOR CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION, AND THUS PROVIDE AN AVENUE FOR CANCER PREVENTION AND THERAPY ON AN INDIVIDUAL BASIS. 2010 6 1582 39 DNA METHYLATION PROFILES IN PRECANCEROUS TISSUE AND CANCERS: CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION BASED ON DNA METHYLATION STATUS. ALTERATIONS IN DNA METHYLATION, WHICH ARE ASSOCIATED WITH DNA METHYLTRANSFERASE ABNORMALITIES AND RESULT IN SILENCING OF TUMOR-RELATED GENES AND CHROMOSOMAL INSTABILITY, ARE INVOLVED EVEN IN PRECANCEROUS CHANGES IN VARIOUS ORGANS. DNA METHYLATION ALTERATIONS ALSO ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. THEREFORE, WE HAVE ANALYZED DNA METHYLATION ON A GENOME-WIDE SCALE IN CLINICAL TISSUE SAMPLES. OUR APPROACH USING THE BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION METHOD HAS REVEALED THAT DNA METHYLATION ALTERATIONS CORRELATED WITH THE FUTURE DEVELOPMENT OF MORE MALIGNANT CANCERS ARE ALREADY ACCUMULATED AT THE PRECANCEROUS STAGE IN THE KIDNEY, LIVER AND URINARY TRACT. DNA METHYLATION PROFILES AT PRECANCEROUS STAGES ARE BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. SUCH DNA METHYLATION ALTERATIONS MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. ON THE BASIS OF BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION DATA, INDICATORS FOR CARCINOGENETIC RISK ESTIMATION HAVE BEEN ESTABLISHED USING LIVER TISSUE SPECIMENS FROM PATIENTS WITH HEPATITIS VIRUS INFECTION, CHRONIC HEPATITIS AND LIVER CIRRHOSIS OR HISTOLOGICALLY NORMAL UROTHELIA, AND FOR PROGNOSTICATION USING BIOPSY OR SURGICALLY RESECTED SPECIMENS FROM PATIENTS WITH RENAL CELL CARCINOMA, HEPATOCELLULAR CARCINOMA AND UROTHELIAL CARCINOMA. SUCH GENOME-WIDE DNA METHYLATION PROFILING HAS NOW FIRMLY ESTABLISHED THE CLINICAL RELEVANCE OF TRANSLATIONAL EPIGENETICS. 2010 7 4733 40 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 8 606 53 BEYOND GENETICS--THE EMERGING ROLE OF EPIGENETIC CHANGES IN HEMATOPOIETIC MALIGNANCIES. THE TERM EPIGENETIC REFERS TO A HERITABLE CHANGE IN GENE EXPRESSION THAT IS MEDIATED BY MECHANISMS OTHER THAN ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. DNA METHYLATION AT CYTOSINE BASES THAT ARE LOCATED 5' TO GUANOSINE WITHIN A CPG DINUCLEOTIDE IS THE MAIN EPIGENETIC MODIFICATION IN HUMANS. PATTERNS OF DNA METHYLATION ARE PROFOUNDLY DERANGED IN HUMAN CANCER AND COMPRISE GENOME-WIDE LOSSES AS WELL AS REGIONAL GAINS IN DNA METHYLATION. HYPERMETHYLATION OF CPG ISLANDS WITHIN GENE PROMOTER REGIONS IS ASSOCIATED WITH TRANSCRIPTIONAL INACTIVATION AND REPRESENTS, IN ADDITION TO GENETIC ABERRATIONS, AN IMPORTANT MECHANISM OF GENE SILENCING IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THIS EPIGENETIC PHENOMENON ACTS AS AN ALTERNATIVE TO MUTATIONS AND DELETIONS TO DISRUPT TUMOR SUPPRESSOR GENE FUNCTION. A LARGE NUMBER OF GENES INVOLVING FUNDAMENTAL CELLULAR PATHWAYS MAY BE AFFECTED IN VIRTUALLY ALL TYPES OF HUMAN CANCER BY ABERRANT CPG ISLAND METHYLATION IN ASSOCIATION WITH TRANSCRIPTIONAL SILENCING. ALTERED METHYLATION PATTERNS CAN BE USED AS BIOMARKERS FOR CANCER DETECTION, ASSESSMENT OF PROGNOSIS, AND PREDICTION OF RESPONSE TO ANTITUMOR TREATMENT. FURTHERMORE, CLINICAL TRIALS USING EPIGENETICALLY TARGETED THERAPIES HAVE YIELDED PROMISING RESULTS FOR ACUTE AND CHRONIC LEUKEMIAS AS WELL AS FOR MYELODYSPLASTIC SYNDROMES. THE EXPLORATION OF OUR GROWING KNOWLEDGE ABOUT EPIGENETIC ABERRATIONS MAY HELP DEVELOP NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES IN THE FUTURE. 2004 9 4334 31 MICRORNAS: NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS FOR PANCREATIC DUCTAL ADENOCARCINOMA? PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS KNOWN FOR ITS VERY POOR OVERALL PROGNOSIS, MAKING TOOLS FOR EARLY DIAGNOSIS AND NEW THERAPEUTIC MODALITIES URGENTLY NEEDED. MICRORNAS (MIRNAS), ENDOGENOUS NONCODING RNA MOLECULES OF APPROXIMATELY 22 NT, HAVE GAINED ATTENTION AS AN EPIGENETIC COMPONENT INVOLVED IN THE DEVELOPMENT OF MANY CANCERS, INCLUDING PDAC. MIRNA EXPRESSION PROFILES OF VARYING PANCREATIC TISSUES HAVE IDENTIFIED A NUMBER OF DIFFERENTIALLY EXPRESSED MIRNAS AND SEEM TO BE ABLE TO DIFFERENTIATE BETWEEN THREE TISSUES OF CLINICAL IMPORTANCE: NORMAL PANCREAS, CHRONIC PANCREATITIS, AND PDAC. THIS ARTICLE GATHERS OUR CURRENT KNOWLEDGE OF DIFFERENTIALLY EXPRESSED MIRNAS IN PANCREATIC TISSUES WITH RELEVANCE TO PDAC AND PRESENTS POTENTIAL DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES. 2009 10 1280 52 DECIPHERING DNA METHYLATION SIGNATURES OF PANCREATIC CANCER AND PANCREATITIS. BACKGROUND: CHRONIC PANCREATITIS PRESENTS A HIGH RISK OF INFLAMMATION-RELATED PROGRESSION TO PANCREATIC CANCER. PANCREATIC CANCER IS THE FOURTH LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE HIGH MORTALITY RATE IS DIRECTLY RELATED TO THE DIFFICULTY IN PROMPTLY DIAGNOSING THE DISEASE, WHICH OFTEN PRESENTS AS OVERT AND ADVANCED. HENCE, EARLY DIAGNOSIS FOR PANCREATIC CANCER BECOMES CRUCIAL, PROPELLING RESEARCH INTO THE MOLECULAR AND EPIGENETIC LANDSCAPE OF THE DISEASE. MAIN BODY: RECENT STUDIES HAVE SHOWN THAT CELL-FREE DNA METHYLATION PROFILES FROM INFLAMMATORY DISEASES OR CANCER CAN VARY, THUS OPENING A NEW VENUE FOR THE DEVELOPMENT OF BIOMARKERS FOR EARLY DIAGNOSIS. IN PARTICULAR, CELL-FREE DNA METHYLATION COULD BE EMPLOYED IN THE IDENTIFICATION OF PRE-NEOPLASTIC SIGNATURES IN INDIVIDUALS WITH SUSPECTED PANCREATIC CONDITIONS, REPRESENTING A SPECIFIC AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PANCREATIC CANCER. IN THIS REVIEW, WE DESCRIBE THE MOLECULAR DETERMINANTS OF PANCREATIC CANCER AND HOW THESE ARE RELATED TO CHRONIC PANCREATITIS. WE WILL THEN PRESENT AN OVERVIEW OF DIFFERENTIAL METHYLATED GENES IN THE TWO CONDITIONS, HIGHLIGHTING THEIR DIAGNOSTIC OR PROGNOSTIC POTENTIAL. CONCLUSION: EXPLOITING THE RELATION BETWEEN ABNORMALLY METHYLATED CELL-FREE DNA AND PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS MAY BECOME A GAME-CHANGING APPROACH FOR THE DEVELOPMENT OF TOOLS FOR THE EARLY DIAGNOSIS OF PANCREATIC CANCER. 2019 11 4531 47 MULTILAYER-OMICS ANALYSES OF HUMAN CANCERS: EXPLORATION OF BIOMARKERS AND DRUG TARGETS BASED ON THE ACTIVITIES OF THE INTERNATIONAL HUMAN EPIGENOME CONSORTIUM. EPIGENETIC ALTERATIONS CONSISTING MAINLY OF DNA METHYLATION ALTERATIONS AND HISTONE MODIFICATION ALTERATIONS ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS FREQUENTLY ASSOCIATED WITH TUMOR AGGRESSIVENESS AND POOR PATIENT OUTCOME. RECENTLY, EPIGENOME ALTERATIONS HAVE BEEN ATTRACTING A GREAT DEAL OF ATTENTION FROM RESEARCHERS WHO ARE FOCUSING ON NOT ONLY CANCERS BUT ALSO NEURONAL, IMMUNE AND METABOLIC DISORDERS. IN ORDER TO ACCURATELY IDENTIFY DISEASE-SPECIFIC EPIGENOME PROFILES THAT COULD BE POTENTIALLY APPLICABLE FOR DISEASE PREVENTION, DIAGNOSIS AND THERAPY, STRICT COMPARISON WITH STANDARD EPIGENOME PROFILES OF NORMAL TISSUES IS INDISPENSABLE. HOWEVER, EPIGENOME MECHANISMS SHOW HETEROGENEITY AMONG TISSUES AND CELL LINEAGES. THEREFORE, IT IS NOT EASY TO OBTAIN A COMPREHENSIVE PICTURE OF STANDARD EPIGENOME PROFILES OF NORMAL TISSUES. IN 2010, THE INTERNATIONAL HUMAN EPIGENOME CONSORTIUM (IHEC) WAS ESTABLISHED TO COORDINATE THE PRODUCTION OF REFERENCE MAPS OF HUMAN EPIGENOMES FOR KEY CELLULAR STATES. IN ORDER TO GAIN SUBSTANTIAL COVERAGE OF THE HUMAN EPIGENOME, THE IHEC HAS SET AN AMBITIOUS GOAL TO DECIPHER AT LEAST 1000 EPIGENOMES WITHIN THE NEXT 7-10 YEARS. WE CONSIDER THAT PATHWAY ANALYSIS USING GENES SHOWING MULTILAYER-OMICS ABNORMALITIES, INCLUDING GENOME, EPIGENOME, TRANSCRIPTOME, PROTEOME AND METABOLOME ABNORMALITIES, MAY BE USEFUL FOR ELUCIDATING THE MOLECULAR BACKGROUND OF PATHOGENESIS AND FOR EXPLORING POSSIBLE THERAPEUTIC TARGETS FOR EACH DISEASE. 2014 12 2483 38 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 13 2033 44 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 14 778 44 CELL-FREE DNA METHYLATION: THE NEW FRONTIERS OF PANCREATIC CANCER BIOMARKERS' DISCOVERY. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS AMONG THE MOST LETHAL CANCER TYPES WORLD-WIDE. ITS HIGH MORTALITY IS RELATED TO THE DIFFICULTY IN THE DIAGNOSIS, WHICH OFTEN OCCURS WHEN THE DISEASE IS ALREADY ADVANCED. AS OF TODAY, NO EARLY DIAGNOSTIC TESTS ARE AVAILABLE, WHILE ONLY A LIMITED NUMBER OF PROGNOSTIC TESTS HAVE REACHED CLINICAL PRACTICE. THE MAIN REASON IS THE LACK OF RELIABLE BIOMARKERS THAT ARE ABLE TO CAPTURE THE EARLY DEVELOPMENT OR THE PROGRESSION OF THE DISEASE. HENCE, THE DISCOVERY OF BIOMARKERS FOR EARLY DIAGNOSIS OR PROGNOSIS OF PDAC REMAINS, DE FACTO, AN UNMET NEED. AN INCREASING NUMBER OF STUDIES HAS SHOWN THAT CELL-FREE DNA (CFDNA) METHYLATION ANALYSIS REPRESENTS A PROMISING NON-INVASIVE APPROACH FOR THE DISCOVERY OF BIOMARKERS WITH DIAGNOSTIC OR PROGNOSTIC POTENTIAL. IN PARTICULAR, CFDNA METHYLATION COULD BE UTILIZED FOR THE IDENTIFICATION OF DISEASE-SPECIFIC SIGNATURES IN PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS (CP), REPRESENTING A SENSITIVE AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PDAC. IN THIS REVIEW, WE WILL DISCUSS THE ADVANTAGES AND PITFALLS OF CFDNA METHYLATION STUDIES. FURTHER, WE WILL PRESENT THE CURRENT ADVANCES IN THE DISCOVERY OF PANCREATIC CANCER BIOMARKERS WITH EARLY DIAGNOSTIC OR PROGNOSTIC POTENTIAL, FOCUSING ON PANCREAS-SPECIFIC (E.G., CUX2 OR REG1A) OR ABNORMAL (E.G., ADAMTS1 OR BNC1) CFDNA METHYLATION SIGNATURES IN HIGH RISK PRE-NEOPLASTIC CONDITIONS AND PDAC. 2019 15 332 52 ALTERATION OF EPIGENETIC PROFILE IN HUMAN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL IMPLICATIONS. HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON CANCER WORLDWIDE AND DEVELOPS AGAINST A BACKGROUND OF CHRONIC LIVER DAMAGE. A VARIETY OF HCC-RELATED GENES ARE KNOWN TO BE ALTERED BY GENETIC AND EPIGENETIC MECHANISMS. THEREFORE, INFORMATION REGARDING ALTERATION OF THE GENETIC AND EPIGENETIC PROFILES IN HCC IS ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF THIS TYPE OF TUMOR. METHYLATION AT CPG SITES IN GENE PROMOTERS IS KNOWN TO AFFECT THE TRANSCRIPTION OF THE CORRESPONDING GENES. ABNORMAL REGIONAL HYPERMETHYLATION IS OBSERVED IN THE 5' REGION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) IN HCC, AND THIS HYPERMETHYLATION MAY PROMOTE CARCINOGENESIS THROUGH THE TRANSCRIPTIONAL INACTIVATION OF DOWNSTREAM TSGS. THE DNA DAMAGE INDUCED BY OXIDATION IS A TRIGGER OF ABNORMAL DNA METHYLATION AND INACTIVATION OF TSGS THROUGH RECRUITMENT OF THE POLYCOMB REPRESSIVE COMPLEX TO THE PROMOTER SEQUENCE. THUS, OXIDATIVE STRESS MAY BE RESPONSIBLE FOR THE EMERGENCE OF HCC FROM CHRONIC HEPATITIS AND LIVER CIRRHOSIS THROUGH THE EPIGENETIC ALTERATION OF TSGS. THERE HAVE BEEN SEVERAL ATTEMPTS TO APPLY EPIGENETIC INFORMATION TO THE DIAGNOSIS AND TREATMENT OF HCC. THE PREDICTIVE VALUE OF SELECTED METHYLATION EVENTS ON SURVIVAL IN HCC PATIENTS HAS BEEN REPORTED, AND THE METHYLATION PROFILE OF BACKGROUND LIVER COULD BE ASSOCIATED WITH RECURRENCE-FREE SURVIVAL OF HCC PATIENTS WHO HAVE UNDERGONE HEPATECTOMY. ANOTHER STUDY DETECTED METHYLATED DNA FROM HCC CELLS IN SERUM, AND THE CIRCULATING TUMOR DNA WAS REGARDED AS A POTENTIAL TUMOR MARKER. IN ADDITION, SEVERAL TRIALS OF HCC THERAPY HAVE TARGETED THE EPIGENETIC MACHINERY AND WERE BASED UPON COMPREHENSIVE ANALYSES OF DNA METHYLATION OF THIS TYPE OF TUMOR. HERE, WE PRESENT AN OVERVIEW OF RESEARCH REGARDING DNA METHYLATION STATUS IN HUMAN HCC AND DESCRIBE THE CLINICAL APPLICATION OF EPIGENETIC INFORMATION TO HCC. 2014 16 5276 50 PROMOTER METHYLATION OF TUMOR-RELATED GENES IN GASTRIC CARCINOGENESIS. ABERRANT PROMOTER METHYLATION AND SUBSEQUENT SILENCING OF CANCER-RELATED GENES HAS BEEN RECOGNIZED AS AN IMPORTANT PATHWAY INVOLVED IN GASTRIC CARCINOGENESIS. IN FACT, SEVERAL FACTORS ARE BELIEVED TO CONTRIBUTE TO ITS INDUCTION IN GASTRIC EPITHELIA, INCLUDING AGING, DIET, CHRONIC INFLAMMATION AND INFECTION OF HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV). HOWEVER, THE UNDERLING MECHANISMS ARE NOT COMPLETELY IDENTIFIED, DESPITE THE BELIEF THAT INCREASED EXPRESSION OR ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), OR DECREASED DEMETHYLATION ACTIVITY MAY CONTRIBUTE TO THE EXCESSIVE METHYLATION. A GREAT NUMBER OF GENES WITH PROMOTER METHYLATION HAVE BEEN OBSERVED IN GASTRIC CANCER (GC), AMONG WHICH P16INK4A (P16), MUT L HOMOLOGUE 1 (MLH1), EPITHELIAL-CADHERIN (E-CADHERIN), RUNT-RELATED TRANSCRIPTION FACTOR 3 (RUNX3), ADENOMATOUS POLYPOSIS COLI (APC), O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT), RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) AND DEATH-ASSOCIATED PROTEIN KINASE (DAPK) HAVE BEEN EXTENSIVELY STUDIED. UNLIKE THE DISTINCT METHYLATION CHARACTERIZATION IN SINGLE GENES, METHYLATION ANALYSIS OF MULTIPLE GENES MAY PROVIDE MORE INFORMATION IN RISK PREDICTION, EARLY DETECTION, PROGNOSIS ASSESSMENT AND CHEMOTHERAPY CHOICE FOR GC. SPECIFICALLY, PARTICULAR MONITORING AND SCREENING SHOULD BE PERFORMED ON THOSE OVER 45 YEARS OLD, WITH PRECANCEROUS GASTRIC DISEASE OR INFECTION OF H. PYLORI OR EBV. AS AN ALTERNATIVE TO TUMOR TISSUES, METHYLATION DETECTION IN PATIENT SERA OR GASTRIC WASHES MAY ALSO BE USED IN RISK PREDICTION AND EARLY DETECTION. HOWEVER, WHAT STILL POSES A GREAT CHALLENGE AS WELL AS A PUZZLE IS THE DETERMINATION OF THE VERY GENES THAT SHOULD BE USED IN METHYLATION ANALYSIS. BECAUSE EPIGENETIC ALTERATIONS ARE NORMALLY REVERSIBLE, DRUGS OR CHEMICAL COMPOUNDS WITH DEMETHYLATING ACTIVITY, SUCH AS 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) COULD BE USED IN THE TREATMENT OF PATIENTS WITH MULTIPLE GENE METHYLATION. IN VIEW OF THE ADVERSE EFFECTS OF 5-AZA-DC, DNMT-TARGETED STRATEGY HAS BEEN PROPOSED AND MAY PROVE TO BE MORE EFFECTIVE THAN DEMETHYLATING AGENTS. 2012 17 6539 39 TRANSCRIPTIONAL VARIATIONS IN THE WIDER PERITUMORAL TISSUE ENVIRONMENT OF PANCREATIC CANCER. TRANSCRIPTIONAL PROFILING WAS PERFORMED ON 452 RNA PREPARATIONS ISOLATED FROM VARIOUS TYPES OF PANCREATIC TISSUE FROM TUMOUR PATIENTS AND HEALTHY DONORS, WITH A PARTICULAR FOCUS ON PERITUMORAL SAMPLES. PANCREATIC DUCTAL ADENOCARCINOMAS (PDAC) AND CYSTIC TUMOURS WERE MOST DIFFERENT IN THESE NON-TUMOROUS TISSUES SURROUNDING THEM, WHEREAS THE ACTUAL TUMOURS EXHIBITED RATHER SIMILAR TRANSCRIPT PATTERNS. THE ENVIRONMENT OF CYSTIC TUMOURS WAS TRANSCRIPTIONALLY NEARLY IDENTICAL TO NORMAL PANCREAS TISSUE. IN CONTRAST, THE TISSUE AROUND PDAC BEHAVED A LOT LIKE THE TUMOUR, INDICATING SOME KIND OF FIELD DEFECT, WHILE SHOWING FAR LESS MOLECULAR RESEMBLANCE TO BOTH CHRONIC PANCREATITIS AND HEALTHY TISSUE. THIS SUGGESTS THAT THE MAJOR PATHOGENIC DIFFERENCE BETWEEN CYSTIC AND DUCTAL TUMOURS MAY BE DUE TO THEIR CELLULAR ENVIRONMENT RATHER THAN THE FEW VARIATIONS BETWEEN THE TUMOURS. LACK OF CORRELATION BETWEEN DNA METHYLATION AND TRANSCRIPT LEVELS MAKES IT UNLIKELY THAT THE OBSERVED FIELD DEFECT IN THE PERITUMORAL TISSUE OF PDAC IS CONTROLLED TO A LARGE EXTENT BY SUCH EPIGENETIC REGULATION. FUNCTIONALLY, A STRIKINGLY LARGE NUMBER OF AUTOPHAGY-RELATED TRANSCRIPTS WAS CHANGED IN BOTH PDAC AND ITS PERITUMORAL TISSUE, BUT NOT IN OTHER PANCREATIC TUMOURS. A TRANSCRIPTION SIGNATURE OF 15 AUTOPHAGY-RELATED GENES WAS ESTABLISHED THAT PERMITS A PROGNOSIS OF SURVIVAL WITH HIGH ACCURACY AND INDICATES THE ROLE OF AUTOPHAGY IN TUMOUR BIOLOGY. 2018 18 5360 43 RECENT ADVANCEMENTS IN COMPREHENSIVE GENETIC ANALYSES FOR HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) TYPICALLY DEVELOPS IN THE LIVER WITH CHRONIC HEPATITIS AND CIRRHOSIS, AND ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS DURING CARCINOGENESIS VIA GENETIC AND EPIGENETIC MECHANISMS. RECENT ADVANCEMENTS IN THE DEVELOPMENT OF ANALYSES FOR EXAMINING THE CANCER GENOME HAVE REVEALED INFORMATION REGARDING GENETIC ALTERATIONS IN HCC TISSUES. ACCORDING TO PREVIOUS STUDIES, THE INCIDENCE OF RECURRENT GENETIC ALTERATIONS IN INDIVIDUAL GENES WAS THOUGHT TO BE RELATIVELY RARE AND LIMITED TO A SUBSET OF A FEW CANCER-SPECIFIC GENES SUCH AS TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS CTNNB1. HOWEVER, RECENT WHOLE-GENOME ANALYSES AND EXOME SEQUENCING OF TUMOR DNA HAVE REVEALED NUMEROUS NOVEL ALTERATIONS OF CANCER-RELATED GENES AND PATHWAYS CRITICAL FOR HCC DEVELOPMENT. IN ADDITION, VARIOUS RISK FACTORS FOR HCC, SUCH AS THE PRESENCE OR ABSENCE OF HEPATITIS B AND C VIRUS, MAY AFFECT THE MUTATION PROFILE OF THE CORRESPONDING CANCER GENOME. ON THE OTHER HAND, GENOME-WIDE ASSOCIATION STUDIES HAVE ALSO IDENTIFIED IMPORTANT SINGLE-NUCLEOTIDE POLYMORPHISMS INVOLVED IN HCC DEVELOPMENT, WHICH MAY ALLOW DETECTION OF A GROUP AT HIGH RISK OF HCC EMERGENCE. SUCH ANALYSES WILL CLARIFY HOW THIS MALIGNANCY CAN BE TREATED, DIAGNOSED AND PREVENTED MORE EFFECTIVELY. 2013 19 3925 45 LIQUID BIOPSIES BASED ON DNA METHYLATION AS BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG CANCER. LUNG CANCER (LC) IS THE MAIN CAUSE OF CANCER-RELATED MORTALITY. MOST LC PATIENTS ARE DIAGNOSED IN AN ADVANCED STAGE WHEN THE SYMPTOMS ARE OBVIOUS, AND THE PROGNOSIS IS QUITE POOR. ALTHOUGH LOW-DOSE COMPUTED TOMOGRAPHY (LDCT) IS A ROUTINE CLINICAL EXAMINATION FOR EARLY DETECTION OF LC, THE FALSE-POSITIVE RATE IS OVER 90%. AS ONE OF THE INTENSELY STUDIED EPIGENETIC MODIFICATIONS, DNA METHYLATION PLAYS A KEY ROLE IN VARIOUS DISEASES, INCLUDING CANCER AND OTHER DISEASES. HYPERMETHYLATION IN TUMOR SUPPRESSOR GENES OR HYPOMETHYLATION IN ONCOGENES IS AN IMPORTANT EVENT IN TUMORIGENESIS. REMARKABLY, DNA METHYLATION USUALLY OCCURS IN THE VERY EARLY STAGE OF MALIGNANT TUMORS. THUS, DNA METHYLATION ANALYSIS MAY PROVIDE SOME USEFUL INFORMATION ABOUT THE EARLY DETECTION OF LC. IN RECENT YEARS, LIQUID BIOPSY HAS DEVELOPED RAPIDLY. LIQUID BIOPSY CAN DETECT AND MONITOR BOTH PRIMARY AND METASTATIC MALIGNANT TUMORS AND CAN REFLECT TUMOR HETEROGENEITY. MOREOVER, IT IS A MINIMALLY INVASIVE PROCEDURE, AND IT CAUSES LESS PAIN FOR PATIENTS. THIS REVIEW SUMMARIZED VARIOUS LIQUID BIOPSIES BASED ON DNA METHYLATION FOR LC. AT FIRST, WE BRIEFLY DISCUSSED SOME EMERGING TECHNOLOGIES FOR DNA METHYLATION ANALYSIS. SUBSEQUENTLY, WE OUTLINED CELL-FREE DNA (CFDNA), SPUTUM, BRONCHOALVEOLAR LAVAGE FLUID, BRONCHIAL ASPIRATES, AND BRONCHIAL WASHINGS DNA METHYLATION-BASED LIQUID BIOPSY FOR THE EARLY DETECTION OF LC. FINALLY, THE PROGNOSTIC VALUE OF DNA METHYLATION IN CFDNA AND SPUTUM AND THE DIAGNOSTIC VALUE OF OTHER DNA METHYLATION-BASED LIQUID BIOPSIES FOR LC WERE ALSO ANALYZED. 2022 20 1844 46 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016