1 5180 74 PREMALIGNANT CONDITIONS OF GASTRIC CANCER. PREMALIGNANT LESIONS OF GASTRIC CANCER ENCOMPASS A VARIETY OF CONDITIONS SUCH AS CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA, IN WHICH ELEVATED RISK OF DEVELOPING GASTRIC CANCER HAVE BEEN DOCUMENTED. AMONG THEM, INTESTINAL METAPLASIA IS FREQUENTLY ENCOUNTERED IN OUR DAILY ENDOSCOPIC EXAMINATION, YET ITS CLINICAL SIGNIFICANCE IS OFTEN UNDERESTIMATED DESPITE OF A NUMBER OF REPORTS DEMONSTRATING GENETIC AND EPIGENETIC ALTERATIONS IN THE INTESTINAL METAPLASTIC MUCOSA. IN THIS REVIEW, I WILL DESCRIBE THE MOLECULAR MECHANISMS OF PHENOTYPIC CHANGES FROM GASTRIC MUCOSA TO INTESTINAL METAPLASIA BASED ON OUR ANALYSIS OF MOUSE MODEL OF INTESTINAL METAPLASIA GENERATED BY ECTOPIC EXPRESSION OF CDX2 IN CONJUNCTION WITH THE STUDIES WITH HUMAN INTESTINAL METAPLASIA. 2013 2 5181 31 PREMALIGNANT LESIONS IN GASTRIC CANCER. DESPITE A PLATEAU IN INCIDENCE, GASTRIC CANCER IS ONE OF THE MOST COMMON CANCERS WORLDWIDE AND CAUSES CONSIDERABLE MORBIDITY AND MORTALITY. PREMALIGNANT GASTRIC LESIONS ARE WELL KNOWN RISK FACTORS FOR THE DEVELOPMENT OF INTESTINAL-TYPE GASTRIC ADENOCARCINOMAS. IN THIS MULTISTEP MODEL OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI CAUSES CHRONIC ACTIVE INFLAMMATION OF THE GASTRIC MUCOSA, WHICH SLOWLY PROGRESSES THROUGH THE PREMALIGNANT STAGES OF ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND ADENOMA/DYSPLASIA TO GASTRIC CARCINOMA. THIS PROGRESSION IS PARALLELED BY A STEPWISE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. DETECTION, TREATMENT, AND MOLECULAR ANALYSES OF PREMALIGNANT LESIONS MAY THUS PROVIDE A BASIS FOR GASTRIC CANCER PREVENTION. THIS REVIEW DESCRIBES AN OVERVIEW OF CURRENT KNOWLEDGE ON PREMALIGNANT GASTRIC LESIONS. IT ALSO REVIEWS THE ISSUE OF SURVEILLANCE OF PATIENTS WITH PREMALIGNANT LESIONS IN ORDER TO IMPROVE THE SURVIVAL OF PATIENTS WITH GASTRIC CANCER. 2010 3 563 29 BARRETT'S ESOPHAGUS: CAN BIOMARKERS PREDICT PROGRESSION TO MALIGNANCY? BARRETT'S ESOPHAGUS (BE) IS ONE OF THE MOST COMMON PREMALIGNANT LESIONS AND CAN PROGRESS TO ESOPHAGEAL ADENOCARCINOMA. IT IS CHARACTERIZED HISTOLOGICALLY BY A SPECIALIZED INTESTINAL METAPLASIA THAT REPLACES THE SQUAMOUS EPITHELIUM OF THE DISTAL ESOPHAGUS, AND IS ASSOCIATED WITH CHRONIC GASTROESOPHAGEAL REFLUX DISEASE AND OBESITY. SIMILAR TO THE ADENOMA-CARCINOMA SEQUENCE OF COLORECTAL CARCINOMAS, ESOPHAGEAL ADENOCARCINOMA DEVELOPS THROUGH PROGRESSION FROM BE TO LOW- AND HIGH-GRADE DYSPLASIA, THEN TO ADENOCARCINOMA WITH ACCUMULATION OF GENETIC AND EPIGENETIC ABNORMALITIES. THE EXACT MALIGNANCY POTENTIAL OF BE IS UNCERTAIN. DYSPLASIA IS THE MOST PREDICTIVE MARKER FOR RISK OF ESOPHAGEAL ADENOCARCINOMA, WHEREAS ENDOSCOPIC AND HISTOLOGICAL DIAGNOSES ARE STILL THE GOLD STANDARD FOR SURVEILLANCE OF PATIENTS WITH BE. HOWEVER, BOTH ARE LIMITED, EITHER BY SAMPLING ERRORS IN BIOPSIES OR BY DIFFERENCES IN HISTOLOGICAL INTERPRETATION. SEVERAL STUDIES HAVE IDENTIFIED CANDIDATE BIOMARKERS THAT MAY HAVE PREDICTIVE VALUE AND MAY SERVE AS ADDITIONAL FACTORS FOR THE RISK ASSESSMENT OF ESOPHAGEAL ADENOCARCINOMA. THIS REVIEW DISCUSSES THE ROLE OF BIOMARKERS IN THE PROGRESSION FROM BE TO ADENOCARCINOMA, FOCUSING ON CLINICAL AND MOLECULAR MARKERS. 2008 4 4960 24 PATHOGENESIS OF PRE-NEOPLASTIC LESIONS OF THE STOMACH: TARGETS FOR PREVENTION. GASTRIC ATROPHY AND INTESTINAL METAPLASIA ARE GENERALLY CONSIDERED TO BE PRECANCEROUS LESIONS OF THE STOMACH. CHRONIC HELICOBACTER PYLORI INFECTION IS ONE THE MOST IMPORTANT FACTORS IN THE DEVELOPMENT OF THESE PRE-MALIGNANT GASTRIC LESIONS. IN ADDITION TO BACTERIAL FACTORS, POLYMORPHISMS IN THE CYTOKINE GENES OF THE HOST THAT MODULATE INFLAMMATORY RESPONSES ARE FOUND TO HAVE A SYNERGISTIC EFFECT IN THE DEVELOPMENT OF GASTRIC CANCER AS WELL AS PRE-NEOPLASTIC LESIONS. RECENTLY, INAPPROPRIATE ACTIVATION OF THE INTESTINE-SPECIFIC TRANSCRIPTION FACTOR LIKE THE HOMEOBOX GENE COMPLEX CDX1 AND CDX2 ARE FOUND TO BE AN IMPORTANT CONTRIBUTING FACTOR IN THE INDUCTION OF INTESTINAL METAPLASIA IN THE STOMACH. ABERRANT EXPRESSION OF CYCLOOXYGENASE-2 AND EPIGENETIC CHANGES ARE ALSO FREQUENTLY DETECTED IN PRE-NEOPLASTIC GASTRIC LESIONS. ONE OF THE MOST IMPORTANT QUESTIONS RELATING TO THESE PRE-NEOPLASTIC GASTRIC LESIONS IS THAT WHETHER H. PYLORI ERADICATION COULD REVERSE THESE CHANGES. HOWEVER, MOST CONTROLLED STUDIES SHOWED NO OR JUST MODEST IMPROVEMENT IN INTESTINAL METAPLASIA AFTER H. PYLORI ERADICATION. FURTHER STUDIES SHOULD EVALUATE THE ROLE OF OTHER CHEMOPREVENTIVE AGENTS, PARTICULARLY CYCLOOXYGENASE-2 INHIBITOR, ON REGRESSION OF PRE-NEOPLASTIC LESIONS. 2004 5 1435 29 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 6 4437 28 MOLECULAR EVOLUTION OF METAPLASIA TO ADENOCARCINOMA IN THE ESOPHAGUS. ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPS FROM BARRETT'S ESOPHAGUS (BE), A CONDITION WHERE THE NORMAL SQUAMOUS EPITHELIA IS REPLACED BY SPECIALIZED INTESTINAL METAPLASIA IN RESPONSE TO CHRONIC GASTROESOPHAGEAL ACID REFLUX. IN A MINORITY OF INDIVIDUALS, BE CAN PROGRESS TO LOW- AND HIGH-GRADE DYSPLASIA AND EVENTUALLY TO INTRA-MUCOSAL AND THEN INVASIVE CARCINOMA. BE PROVIDES RESEARCHERS WITH A UNIQUE MODEL TO CHARACTERIZE THE PROCESS BY WHICH A CARCINOMA ARISES FROM ITS PRECURSOR LESION. MOLECULAR STUDIES OF BE HAVE DEMONSTRATED THAT IT IS NOT SIMPLY A METAPLASTIC TISSUE, BUT RATHER IT HARBORS FREQUENT ALTERATIONS THAT ARE ALSO PRESENT IN DYSPLASTIC BE AND IN EAC. BOTH BE AND EAC ARE CHARACTERIZED BY LOSS OF HETEROZYGOSITY, ANEUPLOIDY, SPECIFIC GENETIC MUTATIONS, AND CLONAL DIVERSITY. EPIGENETIC ABNORMALITIES, PRIMARY ALTERATIONS IN DNA METHYLATION, ARE ALSO FREQUENTLY SEEN IN BE AND EAC. CANDIDATE GENE AND ARRAY-BASED APPROACHES HAVE DEMONSTRATED THAT NUMEROUS TUMOR SUPPRESSOR GENES EXHIBIT ABERRANT PROMOTER METHYLATION, AND SOME OF THESE ALTERED GENES ARE ASSOCIATED WITH THE NEOPLASTIC PROGRESSION OF BE. IT HAS ALSO BEEN SHOWN THAT THE BE AND EAC EPIGENOMES ARE CHARACTERIZED BY HYPOMETHYLATION OF INTRAGENIC AND NON-CODING REGIONS RECENT STUDIES HAVE ALSO PROVIDED NEW INSIGHT INTO THE EVOLUTIONARY FORCES UNDERLYING THE MOLECULAR ALTERATIONS SEEN IN BE AND EAC AND INTO THE MOLECULAR PATHOGENESIS OF EAC. 2018 7 5182 24 PREMALIGNANT LESIONS OF SQUAMOUS CELL CARCINOMA OF THE LUNG: THE MOLECULAR MAKE-UP AND FACTORS AFFECTING THEIR PROGRESSION. SQUAMOUS CELL CARCINOMA (SCC), ONE OF THE MOST COMMON FORMS OF LUNG CANCER, SHOWS ACCELERATED PROGRESSION AND AGGRESSIVE GROWTH AND USUALLY IS OBSERVED AT ADVANCED STAGES. SCC ORIGINATES FROM MORPHOLOGICAL CHANGES IN THE BRONCHIAL EPITHELIUM THAT OCCUR DURING CHRONIC INFLAMMATION: BASAL CELL HYPERPLASIA, SQUAMOUS METAPLASIA, AND DYSPLASIA I-III. HOWEVER, THE PROCESS IS NOT INEVITABLE; IT CAN BE STOPPED AT ANY STAGE, REMAIN IN THE STABLE STATE INDEFINITELY AND EITHER PROGRESS OR REGRESS. THE REASONS AND MECHANISMS OF DIFFERENT SCENARIOS OF THE EVOLUTION OF PREMALIGNANT LESIONS IN THE RESPIRATORY EPITHELIUM ARE NOT FULLY UNDERSTOOD. IN THIS REVIEW, WE SUMMARIZED THE LITERATURE DATA (INCLUDING OUR OWN DATA) REGARDING GENETIC, EPIGENETIC, TRANSCRIPTOMIC AND PROTEOMIC PROFILES OF THE PREMALIGNANT LESIONS AND HIGHLIGHTED FACTORS (ENVIRONMENTAL CAUSES, INFLAMMATION, AND GENE POLYMORPHISM) THAT MAY GOVERN THEIR PROGRESSION OR REGRESSION. IN CONCLUSION, WE REVIEWED STRATEGIES FOR LUNG CANCER PREVENTION AND PROPOSED NEW MODELS AND RESEARCH DIRECTIONS FOR STUDYING PREMALIGNANT LESIONS AND DEVELOPING NEW TOOLS TO PREDICT THE RISK OF THEIR MALIGNANT TRANSFORMATION. 2019 8 196 27 ACID REFLUX AND OESOPHAGEAL CANCER. BARRETT'S METAPLASIA IS ONE OF THE COMMONEST PREMALIGNANT LESIONS IN THE WESTERN WORLD FOLLOWING COLORECTAL ADENOMAS. ONE IN 50 OF THE ADULT POPULATION DEVELOPS BARRETT'S AS A CONSEQUENCE OF CHRONIC GASTRO-OESOPHAGEAL REFLUX. THE MUCOSAL INFLAMMATION SEEN WITHIN PATIENTS WITH GASTRO-OESOPHAGEAL REFLUX SEEMS LIKELY TO DRIVE THE GROWTH OF THE METAPLASTIC MUCOSA AND ALSO HELP DIRECT FURTHER ONCOLOGICAL CHANGE, YET THE MOLECULAR EVENTS THAT CHARACTERIZE THE PATHWAY FROM INFLAMMATION TO METAPLASIA TO DYSPLASIA AND ADENOCARCINOMA ARE POORLY UNDERSTOOD. THERE IS HOPE THAT UNDERSTANDING THE ROLE OF OESOPHAGEAL INFLAMMATION WILL PROVIDE IMPORTANT INSIGHT INTO THE DEVELOPMENT OF BARRETT'S METAPLASIA AND OESOPHAGEAL CANCER. THIS CHAPTER WILL DISCUSS THE INFLAMMATION SEEN WITHIN CONTEXT OF BARRETT'S OESOPHAGUS AND ALSO CLINICAL TRIALS WHICH HOPE TO ADDRESS THIS COMMON PREMALIGNANT DISEASE. THERE ARE SEVERAL ONGOING CLINICAL TRIALS WHICH ARE AIMING TO PROVIDE DATA USING ANTI-INFLAMMATORY THERAPIES TO TACKLE THIS IMPORTANT PREMALIGNANT CONDITION. THERE IS NEW DATA PRESENTED WHICH SUGGESTS THAT DATA FROM THE ASPIRIN ESOMEPRAZOLE CHEMOPREVENTION TRIAL (ASPECT) MAY HOLD THE CLUE TO DISEASE TREATMENT AND THAT THE CYTOKINE TNF-ALPHA SEEMS TO BE A KEY SIGNALLING MOLECULE IN THE METAPLASIA-DYSPLASIA-CARCINOMA SEQUENCE. SPECIFICALLY IT APPEARS THAT BOTH EPIGENETIC AND INHERITED GENETICS COOPERATE TO MODULATE THE PROGNOSIS. 2011 9 4733 24 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 10 6824 27 [GENETIC ALTERATIONS IN PRENEOPLASTIC AND NEOPLASTIC INJURIES OF THE GALLBLADDER]. THIS ARTICLE AIMS TO REVIEW THE MOST RELEVANT MORPHOLOGICAL AND MOLECULAR ASPECTS INVOLVED IN GALLBLADDER (GB) CANCER. IN CHILE, GALLBLADDER CANCER IS THE MAIN CAUSE OF DEATH DUE TO CANCER, AMONG WOMEN OLDER THAN 40 YEARS. HOWEVER, THERE IS ALMOST NONE INFORMATION ABOUT THE MORPHOLOGICAL CHANGES AND THE GENETIC ALTERATIONS INVOLVED IN THE BEGINNING AND DEVELOPMENT OF THIS NEOPLASIA. TWO CARCINOGENIC WAYS HAVE BEEN DESCRIBED. THE SEQUENCE ADENOMA-CARCINOMA IS ACCEPTED TO BE LESS FREQUENT AND IMPORTANT. THE MOST IMPORTANT IS THE SEQUENCE WHERE A METAPLASIA EVOLVES TO DISPLASIA THAT PROGRESSES TO CARCINOMA IN SITU AND FINALLY IT BECOMES INVASIVE. THIS PROGRESS REQUIRES 10 TO 15 YEARS APPROXIMATELY. DURING THIS TIME, A CONTINUE PROGRESSION OF INJURIES HAVE BEEN DESCRIBED. MOLECULAR RESEARCH STUDIES SHOW GENETIC ANOMALIES IN SOME GENES WHICH ARE TEMPORARY EVENTS IN PRENEOPLASTIC INJURIES OF THE GALLBLADDER. SOME OF THEM EVEN EXIST BEFORE THE FIRST MORPHOLOGICAL CHANGES, WHILE THE EXPRESSION OF TUMOR SUPPRESSOR GENES LIKE P53, ADHESION MOLECULES AND ONCOGENES, AMONG OTHERS, CAN BE RELATED TO LATE GB CARCINOGENESIS. THE K-RAS GENE SEEMS TO PLAY A ROLE IN THIS NEOPLASIA, MAINLY IN THOSE THAT PRESENT AN ABNORMAL BILIOPANCREATIC UNION. THE MICROSATELITAL INSTABILITY HAS BEEN FOUND IN A SMALL SUBSET OF PRENEOPLASTIC AND NEOPLASTIC LESIONS. THE EXISTENCE OF METHYLATION IN THE PROMOTOR GENE AREAS HAS BEEN RELATED TO THE CELLULAR PROLIFERATION, INVASION AND METASTASIS AND ALSO IN CASES OF CHRONIC CHOLECYSTITIS, SUGGESTING THAT THIS EPIGENETIC PHENOMENON REPRESENTS A CRUCIAL EARLY EVENT IN GB CARCINOGENESIS. 2010 11 2938 20 GENETIC AND EPIGENETIC ALTERATIONS IN BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA. ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPS FROM BARRETT'S ESOPHAGUS (BE), WHEREIN NORMAL SQUAMOUS EPITHELIA IS REPLACED BY SPECIALIZED INTESTINAL METAPLASIA IN RESPONSE TO CHRONIC GASTROESOPHAGEAL ACID REFLUX. BE CAN PROGRESS TO LOW- AND HIGH-GRADE DYSPLASIA, INTRAMUCOSAL, AND INVASIVE CARCINOMA. BOTH BE AND EAC ARE CHARACTERIZED BY LOSS OF HETEROZYGOSITY, ANEUPLOIDY, SPECIFIC GENETIC MUTATIONS, AND CLONAL DIVERSITY. GIVEN THE LIMITATIONS OF HISTOPATHOLOGY, GENOMIC AND EPIGENOMIC ANALYSES MAY IMPROVE THE PRECISION OF RISK STRATIFICATION. ASSAYS TO DETECT MOLECULAR ALTERATIONS ASSOCIATED WITH NEOPLASTIC PROGRESSION COULD BE USED TO IMPROVE THE PATHOLOGIC ASSESSMENT OF BE/EAC AND TO SELECT HIGH-RISK PATIENTS FOR MORE INTENSIVE SURVEILLANCE. 2015 12 4957 20 PATHOGENESIS OF ENDOMETRIOSIS: THE GENETIC/EPIGENETIC THEORY. OBJECTIVE: TO STUDY THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. DESIGN: OVERVIEW OF OBSERVATIONS ON ENDOMETRIOSIS. SETTING: NOT APPLICABLE. PATIENT(S): NONE. INTERVENTIONS(S): NONE. MAIN OUTCOME MEASURE(S): THE HYPOTHESIS IS COMPATIBLE WITH ALL OBSERVATIONS. RESULT(S): ENDOMETRIOSIS, ENDOMETRIUM-LIKE TISSUE OUTSIDE THE UTERUS, HAS A VARIABLE MACROSCOPIC APPEARANCE AND A POORLY UNDERSTOOD NATURAL HISTORY. IT IS A HEREDITARY AND HETEROGENEOUS DISEASE WITH MANY BIOCHEMICAL CHANGES IN THE LESIONS, WHICH ARE CLONAL IN ORIGIN. IT IS ASSOCIATED WITH PAIN, INFERTILITY, ADENOMYOSIS, AND CHANGES IN THE JUNCTIONAL ZONE, PLACENTATION, IMMUNOLOGY, PLASMA, PERITONEAL FLUID, AND CHRONIC INFLAMMATION OF THE PERITONEAL CAVITY. THE SAMPSON HYPOTHESIS OF IMPLANTED ENDOMETRIAL CELLS FOLLOWING RETROGRADE MENSTRUATION, ANGIOGENIC SPREAD, LYMPHOGENIC SPREAD, OR THE METAPLASIA THEORY CANNOT EXPLAIN ALL OBSERVATIONS IF METAPLASIA IS DEFINED AS CELLS WITH REVERSIBLE CHANGES AND AN ABNORMAL BEHAVIOR/MORPHOLOGY DUE TO THE ABNORMAL ENVIRONMENT. WE PROPOSE A POLYGENETIC/POLYEPIGENETIC MECHANISM. THE SET OF GENETIC AND EPIGENETIC INCIDENTS TRANSMITTED AT BIRTH COULD EXPLAIN THE HEREDITARY ASPECTS, THE PREDISPOSITION, AND THE ENDOMETRIOSIS-ASSOCIATED CHANGES IN THE ENDOMETRIUM, IMMUNOLOGY, AND PLACENTATION. TO DEVELOP TYPICAL, CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS, A VARIABLE SERIES OF ADDITIONAL TRANSMISSIBLE GENETIC AND EPIGENETIC INCIDENTS ARE REQUIRED TO OCCUR IN A CELL WHICH MAY VARY FROM ENDOMETRIAL TO STEM CELLS. SUBTLE LESIONS ARE VIEWED AS ENDOMETRIUM IN A DIFFERENT ENVIRONMENT UNTIL ADDITIONAL INCIDENTS OCCUR. TYPICAL CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS ARE HETEROGENEOUS AND REPRESENT THREE DIFFERENT DISEASES. CONCLUSION(S): THE GENETIC EPIGENETIC THEORY IS COMPATIBLE WITH ALL OBSERVATIONS ON ENDOMETRIOSIS. IMPLICATIONS FOR TREATMENT AND PREVENTION ARE DISCUSSED. 2019 13 3683 29 INFLAMMATION, MICROBIOTA, AND PROSTATE CANCER. CONTEXT: CHRONIC INFLAMMATION OF THE PROSTATE HAS BEEN ASSOCIATED WITH PRENEOPLASTIC LESIONS AND CANCER DEVELOPMENT. MULTIPLE CAUSES HAVE BEEN CONSIDERED FOR CHRONIC INFLAMMATION OF THE PROSTATE. INFLAMMATORY CYTOKINES SUCH AS INTERLEUKINS ARE IMPLICATED IN PROSTATE CARCINOGENESIS AND DEVELOPMENT. OBJECTIVE: TO EVALUATE LITERATURE PUBLISHED ON ETIOLOGICAL FACTORS, URINARY MICROBIOTA, MORPHOLOGICAL FEATURES OF PROLIFERATIVE INFLAMMATORY ATROPHY AND HIGH-GRADE PROSTATE INTRAEPITHELIAL NEOPLASIA, GENETIC POLYMORPHISMS, INFLAMMATORY STRESS, AND CYTOKINE SIGNALING. EVIDENCE ACQUISITION: WE SEARCHED LITERATURE FROM PUBMED FROM 2010 AND ALSO INCLUDED THE MOST IMPORTANT PUBLICATIONS FROM THE PREVIOUS PERIOD. EVIDENCE SYNTHESIS: PROSTATE CANCER INFLAMMATION AND PREMALIGNANT LESIONS HAVE BEEN FREQUENTLY DISCUSSED IN SCIENTIFIC LITERATURE. A LIMITED NUMBER OF MODELS ARE AVAILABLE FOR STUDYING INFLAMMATION AND PREMALIGNANT LESIONS. HOWEVER, MORPHOLOGICAL PATHOLOGY COULD BE COMPLEMENTED BY ANALYSIS OF GENE POLYMORPHISMS IN THESE PATIENTS AND APPROPRIATE FUNCTIONAL STUDIES. CONCLUSIONS: PROSTATITIS COULD BE CAUSED BY BACTERIAL OR VIRAL INFECTIONS, DIETARY COMPOUNDS, AND CHANGES IN TESTOSTERONE:ESTRADIOL RATIO. IN SOME CASES, THE MICROBIOTA CAN EXERT DIRECT EFFECTS ON CANCER DEVELOPMENT. PROSTATE INFLAMMATORY ATROPHY OR HIGH GRADE PROSTATE INTRAEPITHELIAL NEOPLASIA HAVE BEEN ASSOCIATED WITH RESPONSE TO CELLULAR STRESS AND HAVE BEEN DISCUSSED IN CONNECTION TO EARLY CANCER DEVELOPMENT. A LARGE NUMBER OF GENETIC POLYMORPHISMS HAVE BEEN IDENTIFIED IN INFLAMMATORY PROSTATE. GENETIC AND EPIGENETIC ALTERATIONS MAY BE A CONSEQUENCE OF THE PROINFLAMMATORY STRESS IN THE PROSTATE. PROINFLAMMATORY CYTOKINES INTERLEUKIN-6 AND -8 CONTRIBUTE TO PROSTATE MALIGNANCY; HOWEVER, THEIR FUNCTION WAS MORE FREQUENTLY INVESTIGATED IN CANCER TISSUE RATHER THAN IN INFLAMMATION. PATIENT SUMMARY: WE PERFORMED A REVIEW OF RECENT LITERATURE RELATED TO PROSTATE INFLAMMATION, MICROBIOTA, AND PROSTATE CANCER. NEW FUNCTIONAL APPROACHES ARE REQUIRED FOR A BETTER UNDERSTANDING OF THE ROLE OF INFLAMMATION AND CANCER DEVELOPMENT. 2016 14 3803 28 INTESTINAL METAPLASIA OF THE STOMACH. A STATUS REPORT. INTESTINAL METAPLASIA IN THE STOMACH INCREASES THE RISK OF GASTRIC CANCER, AND THE INCREASED RISK IS PROPORTIONAL TO THE EXTENT OF THE METAPLASIA. THIS RISK COULD BE GENERATED BY ONE OR MORE MECHANISMS: (1) THE METAPLASTIC TISSUE IS AN EARLY STEP IN A MULTISTEP INDUCTION PROCESS; (2) THE METAPLASTIC TISSUE IS AN EPIGENETIC CHANGE THAT RAISES THE PH OF GASTRIC JUICE BY REPLACING OXYNTIC MUCOSA, FAVORING THE GROWTH OF A BACTERIA CAPABLE OF GENERATING ENDOGENOUS MUTAGENS; AND/OR (3) THE METAPLASIA IS ONLY A MARKER FOR CHRONIC GASTRITIS DUE TO H. PYLORI INFECTION OR PERNICIOUS ANEMIA. WITH THE LAST MECHANISM, THE INFLAMMATORY RESPONSE FAVORS INTRAMURAL MUTAGENESIS THAT MIGHT RESULT IN METAPLASIA OR NEOPLASIA AS INDEPENDENT EVENTS. FINDING GENE REARRANGEMENTS COMMON TO BOTH METAPLASTIC AND NEOPLASTIC TISSUE MAY ESTABLISH A DIRECT LINK BETWEEN THEM, BUT TOO FEW HAVE BEEN IDENTIFIED TO ACCOUNT FOR THE LARGE NUMBER OF STOMACH CANCERS THAT DEVELOP IN HIGH RISK POPULATIONS. HISTOCHEMICAL AND IMMUNOCHEMICAL STAINS THAT IDENTIFY ENZYMES OR MUCOSUBSTANCES MAY SUGGEST THAT METAPLASTIC EPITHELIAL CELLS RESEMBLE SMALL OR LARGE INTESTINAL CELLS, BUT THEY ARE DISTINCTLY DIFFERENT FROM BOTH. MOREOVER, THESE STAINS DO NOT INDICATE WHETHER A GIVEN CYTOLOGIC CHANGE IS GENETIC OR EPIGENETIC; THEREFORE, THEY CANNOT BE USED TO DEFINE THE RELATIONSHIP BETWEEN METAPLASIA AND NEOPLASIA. IT IS UNNECESSARY FOR PRACTICING PHYSICIANS TO AWAIT RESOLUTION OF THIS QUESTION. IT CAN BE ASSUMED THAT ANY PERSON WITH EXTENSIVE METAPLASIA IS AT HIGH RISK FOR GASTRIC CANCER AND SHOULD BE SUBJECT TO PERIODIC SCREENING. THE EXTENT OF THE METAPLASTIC PROCESS IS PROBABLY MORE IMPORTANT THAN THE METAPLASTIC SUBTYPE. 1994 15 3222 30 HELICOBACTER PYLORI ASSOCIATED CHRONIC GASTRITIS, CLINICAL SYNDROMES, PRECANCEROUS LESIONS, AND PATHOGENESIS OF GASTRIC CANCER DEVELOPMENT. HELICOBACTER PYLORI (H. PYLORI) INFECTION IS WELL KNOWN TO BE ASSOCIATED WITH THE DEVELOPMENT OF PRECANCEROUS LESIONS SUCH AS CHRONIC ATROPHIC GASTRITIS (AG), OR GASTRIC INTESTINAL METAPLASIA (GIM), AND CANCER. VARIOUS MOLECULAR ALTERATIONS ARE IDENTIFIED NOT ONLY IN GASTRIC CANCER (GC) BUT ALSO IN PRECANCEROUS LESIONS. H. PYLORI TREATMENT SEEMS TO IMPROVE AG AND GIM, BUT STILL REMAINS CONTROVERSIAL. IN CONTRAST, MANY STUDIES, INCLUDING META-ANALYSIS, SHOW THAT H. PYLORI ERADICATION REDUCES GC. MOLECULAR MARKERS DETECTED BY GENETIC AND EPIGENETIC ALTERATIONS RELATED TO CARCINOGENESIS REVERSE FOLLOWING H. PYLORI ERADICATION. THIS INDICATES THAT THESE CHANGES MAY BE AN IMPORTANT FACTOR IN THE IDENTIFICATION OF HIGH RISK PATIENTS FOR CANCER DEVELOPMENT. PATIENTS WHO UNDERWENT ENDOSCOPIC TREATMENT OF GC ARE AT HIGH RISK FOR DEVELOPMENT OF METACHRONOUS GC. A RANDOMIZED CONTROLLED TRIAL FROM JAPAN CONCLUDED THAT PROPHYLACTIC ERADICATION OF H. PYLORI AFTER ENDOSCOPIC RESECTION SHOULD BE USED TO PREVENT THE DEVELOPMENT OF METACHRONOUS GC, BUT RECENT RETROSPECTIVE STUDIES DID NOT SHOW THE TENDENCY. PATIENTS WITH PRECANCEROUS LESIONS (MOLECULAR ALTERATIONS) THAT DO NOT REVERSE AFTER H. PYLORI TREATMENT, REPRESENT THE "POINT OF NO RETURN" AND MAY BE AT HIGH RISK FOR THE DEVELOPMENT OF GC. THEREFORE, EARLIER H. PYLORI ERADICATION SHOULD BE CONSIDERED FOR PREVENTING GC DEVELOPMENT PRIOR TO THE APPEARANCE OF PRECANCEROUS LESIONS. 2014 16 1028 25 CIRCULATING MIRNAS RELATED TO EPITHELIAL-MESENCHYMAL TRANSITIONS (EMT) AS THE NEW MOLECULAR MARKERS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC GYNECOLOGICAL DISEASE DEFINED BY THE PRESENCE OF ENDOMETRIAL-LIKE TISSUE FOUND OUTSIDE THE UTERUS, MOST COMMONLY IN THE PERITONEAL CAVITY. ENDOMETRIOSIS LESIONS ARE HETEROGENOUS BUT USUALLY CONTAIN ENDOMETRIAL STROMAL CELLS AND EPITHELIAL GLANDS, IMMUNE CELL INFILTRATES AND ARE VASCULARIZED AND INNERVATED BY NERVES. THE COMPLEX ETIOPATHOGENESIS AND HETEROGENITY OF THE CLINICAL SYMPTOMS, AS WELL AS THE LACK OF A SPECIFIC NON-INVASIVE DIAGNOSTIC BIOMARKERS, UNDERLINE THE NEED FOR MORE ADVANCED DIAGNOSTIC TOOLS. UNFORTUNATELY, THE CONTRIBUTION OF ENVIRONMENTAL, HORMONAL AND IMMUNOLOGICAL FACTORS IN THE DISEASE ETIOLOGY IS INSUFFICIENT, AND THE CONTRIBUTION OF GENETIC/EPIGENETIC FACTORS IS STILL FRAGMENTARY. THEREFORE, THERE IS A NEED FOR MORE FOCUSED STUDY ON THE MOLECULAR MECHANISMS OF ENDOMETRIOSIS AND NON-INVASIVE DIAGNOSTIC MONITORING SYSTEMS. MICRORNAS (MIRNAS) DEMONSTRATE HIGH STABILITY AND TISSUE SPECIFICITY AND PLAY A SIGNIFICANT ROLE IN MODULATING A RANGE OF MOLECULAR PATHWAYS, AND HENCE MAY BE SUITABLE DIAGNOSTIC BIOMARKERS FOR THE ORIGIN AND DEVELOPMENT OF ENDOMETRIOSIS. OF THESE, THE MOST FREQUENTLY STUDIED ARE THOSE RELATED TO ENDOMETRIOSIS, INCLUDING THOSE INVOLVED IN EPITHELIAL-MESENCHYMAL TRANSITION (EMT), WHOSE EXPRESSION IS ALTERED IN PLASMA OR ENDOMETRIOTIC LESION BIOPSIES; HOWEVER, THE RESULTS ARE AMBIGUOUS. SPECIFIC MIRNAS EXPRESSED IN ENDOMETRIOSIS MAY SERVE AS DIAGNOSTICS MARKERS WITH PROGNOSTIC VALUE, AND THEY HAVE BEEN PROPOSED AS MOLECULAR TARGETS FOR TREATMENT. THE AIM OF THIS REVIEW IS TO PRESENT SELECTED MIRNAS ASSOCIATED WITH EMT KNOWN TO HAVE EXPERIMENTALLY CONFIRMED SIGNIFICANCE, AND DISCUSS THEIR UTILITY AS BIOMARKERS IN ENDOMETRIOSIS. 2021 17 1582 26 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 18 2015 31 EPIGENETIC BIOMARKERS IN ESOPHAGEAL CANCER. THE ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES IS WELL DOCUMENTED IN ESOPHAGEAL CANCER, INCLUDING ADENOCARCINOMA (EAC) AND SQUAMOUS CELL CARCINOMA (ESCC) AS WELL AS IN BARRETT'S ESOPHAGUS (BE), A PRE-MALIGNANT CONDITION THAT IS ASSOCIATED WITH CHRONIC ACID REFLUX. BE IS A WELL-RECOGNIZED RISK FACTOR FOR THE DEVELOPMENT OF EAC, AND CONSEQUENTLY THE STANDARD OF CARE IS FOR INDIVIDUALS WITH BE TO BE PLACED IN ENDOSCOPIC SURVEILLANCE PROGRAMS AIMED AT DETECTING EARLY HISTOLOGIC CHANGES THAT ASSOCIATE WITH AN INCREASED RISK OF DEVELOPING EAC. YET BECAUSE THE ABSOLUTE RISK OF EAC IN INDIVIDUALS WITH BE IS MINIMAL, A CLINICAL NEED IN THE MANAGEMENT OF BE IS THE IDENTIFICATION OF ADDITIONAL RISK MARKERS THAT WILL INDICATE INDIVIDUALS WHO ARE AT A SIGNIFICANT ABSOLUTE RISK OF EAC SO THAT THEY MAY BE SUBJECTED TO MORE INTENSIVE SURVEILLANCE. THE BEST CURRENTLY AVAILABLE RISK MARKER IS THE DEGREE OF DYSPLASIA IN ENDOSCOPIC BIOPSIES FROM THE ESOPHAGUS; HOWEVER, THIS MARKER IS SUBOPTIMAL FOR A VARIETY OF REASONS. TO DATE, THERE ARE NO MOLECULAR BIOMARKERS THAT HAVE BEEN TRANSLATED TO WIDESPREAD CLINICAL PRACTICE. THE SEARCH FOR BIOMARKERS, INCLUDING HYPERMETHYLATED GENES, FOR EITHER THE DIAGNOSIS OF BE, EAC, OR ESCC OR FOR RISK STRATIFICATION FOR THE DEVELOPMENT OF EAC IN THOSE WITH BE IS CURRENTLY AN AREA OF ACTIVE RESEARCH. IN THIS REVIEW, WE SUMMARIZE THE STATUS OF IDENTIFIED CANDIDATE EPIGENETIC BIOMARKERS FOR BE, EAC, AND ESCC. MOST OF THESE ABERRANTLY METHYLATED GENES HAVE BEEN DESCRIBED IN THE CONTEXT OF EARLY DETECTION OR DIAGNOSTIC MARKERS; OTHERS MIGHT PROVE USEFUL FOR ESTIMATING PROGNOSIS OR PREDICTING RESPONSE TO TREATMENT. FINALLY, SPECIAL ATTENTION WILL BE PAID TO SOME OF THE CHALLENGES THAT MUST BE OVERCOME IN ORDER TO DEVELOP CLINICALLY USEFUL ESOPHAGEAL CANCER BIOMARKERS. 2014 19 3170 27 GUT INFLAMMATION AND TUMORIGENESIS: EVERY SITE HAS A DIFFERENT TALE TO TELL. GUT INFLAMMATION HAS BEEN CORRELATED WITH CANCEROGENESIS BY DISRUPTING GASTROINTESTINAL HOMEOSTASIS. NUMEROUS CHRONIC INFLAMMATORY DISORDERS OF THE TUBULAR GASTROINTESTINAL TRACT (E.G., GASTROESOPHAGEAL REFLUX DISEASE, HELICOBACTER PYLORI-INDUCED AND AUTOIMMUNE CHRONIC GASTRITIS, CELIAC DISEASE, AND INFLAMMATORY BOWEL DISEASES) HAVE BEEN VARIABLY ASSOCIATED WITH AN INCREASED NEOPLASTIC RISK. GASTROINTESTINAL INFLAMMATION-INDUCED NEOPLASMS INCLUDE EPITHELIAL TUMORS (ESOPHAGEAL SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA, GASTRIC ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, SMALL BOWEL ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, AND COLORECTAL CANCER) AND LYMPHOMAS (SUCH AS GASTRIC MARGINAL ZONE LYMPHOMAS AND ENTEROPATHY-ASSOCIATED T CELL LYMPHOMA). IN THE LAST DECADES, NUMEROUS STUDIES HAVE INVESTIGATED THE PATHOGENETIC MECHANISMS AND THE MICROENVIRONMENTAL/MICROBIOME CHANGES THAT TRIGGER GENETIC AND/OR EPIGENETIC ALTERATIONS EVENTUALLY LEADING TO TUMORIGENESIS, OFTEN THROUGH A HISTOLOGICALLY RECOGNIZABLE INFLAMMATION-DYSPLASIA-CARCINOMA CANCEROGENIC SEQUENCE. IN THE PRESENT REVIEW, AN OVERVIEW OF THE CURRENT KNOWLEDGE ON THE LINKS BETWEEN INFLAMMATORY DISEASES AND NEOPLASMS OF THE TUBULAR GI TRACT, APPLYING A SITE-BY-SITE APPROACH, IS PROVIDED. 2023 20 1975 24 EPIGENETIC ALTERATIONS FROM BARRETT'S ESOPHAGUS TO ESOPHAGEAL ADENOCARCINOMA. BARRETT'S ESOPHAGUS (BE) IS A DISEASE ENTITY THAT IS A SEQUELA OF CHRONIC GASTROESOPHAGEAL REFLUX DISEASE THAT MAY RESULT IN ESOPHAGEAL ADENOCARCINOMA (EAC) DUE TO COLUMNAR EPITHELIAL DYSPLASIA. THE HISTOLOGICAL DEGREE OF DYSPLASIA IS THE SOLE BIOMARKER FREQUENTLY UTILIZED BY CLINICIANS. HOWEVER, THE COST OF ENDOSCOPY AND THE FACT THAT THE DEGREE OF DYSPLASIA DOES NOT PROGRESS IN MANY PATIENTS WITH BE DIMINISH THE EFFECTIVENESS OF HISTOLOGICAL GRADING AS A PERFECT BIOMARKER. MULTIPLE OR MORE QUANTITATIVE BIOMARKERS ARE REQUIRED BY CLINICIANS SINCE EARLY DIAGNOSIS IS CRUCIAL IN ESOPHAGEAL ADENOCANCERS, WHICH HAVE A HIGH MORTALITY RATE. THE PRESENCE OF EPIGENETIC FACTORS IN THE EARLY STAGES OF THIS NEOPLASTIC TRANSFORMATION HOLDS PROMISE AS A PREDICTIVE BIOMARKER. IN THIS REVIEW, CURRENT STUDIES ON DNA METHYLATIONS, HISTONE MODIFICATIONS, AND NONCODING RNAS (MIRNAS) THAT HAVE BEEN DISCOVERED DURING THE PROGRESSION FROM BE DYSPLASIA TO EAC WERE COLLATED. 2023