1 5181 85 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 2 2938 26 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 3 5180 31 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 4 196 31 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 5 563 39 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 6 4232 29 METHYLATION OF RUNX3 IN VARIOUS TYPES OF HUMAN CANCERS AND PREMALIGNANT STAGES OF GASTRIC CARCINOMA. ACCUMULATING EVIDENCE HAS IDENTIFIED A MECHANISM POTENTIALLY RESPONSIBLE FOR THE INACTIVATION OF TUMOR SUPPRESSOR GENES, NAMELY TRANSCRIPTIONAL SILENCING BY ABERRANT METHYLATION OF CPG ISLANDS. A PREVIOUS STUDY HAS SHOWN THE LOSS OF RUNX3 EXPRESSION, DUE TO ABERRANT METHYLATION OF ITS CPG ISLAND, IN GASTRIC CANCER CELL LINES, SUGGESTING THAT RUNX3 IS A TARGET FOR EPIGENETIC GENE SILENCING IN GASTRIC CARCINOGENESIS. HOWEVER, THERE ARE LIMITED DATA ON THE METHYLATION STATUS OF RUNX3 IN THE NEOPLASTIC AND NON-NEOPLASTIC TISSUES IN VARIOUS TYPES OF HUMAN CANCERS, INCLUDING GASTRIC CANCER. HERE, WE REPORT THAT 60% OF GASTRIC CANCER CELL LINES AND 64% OF PRIMARY GASTRIC CARCINOMAS (N=75) WERE METHYLATED AT THE RUNX3 CPG ISLAND. RUNX3 METHYLATION WAS ALSO DETECTED IN HEPATOCELLULAR CARCINOMAS (73%, N=48), LARYNX CANCERS (62%, N=37), LUNG CANCERS (46%, N=24), BREAST CANCERS (25%, N=25), PROSTATE CANCERS (23%, N=44), ENDOMETRIAL CANCERS (12.5%, N=24), COLON CANCERS (4.9%, N=61) AND UTERINE CERVICAL CANCERS (2.5%, N=40), SHOWING THAT RUNX3 METHYLATION IS NOT RESTRICTED TO GASTRIC CANCER. INTERESTINGLY, THE RUNX3 METHYLATION WAS ESPECIALLY FREQUENT IN TUMORS FROM TISSUES OF A FOREGUT DERIVATIVE, THAT IS, THE STOMACH, LIVER, LARYNX AND LUNG. NEXT, THE METHYLATION STATUS OF RUNX3 IN VARIOUS NON-NEOPLASTIC TISSUES WAS EXAMINED, INCLUDING THE PREMALIGNANT LESIONS OF GASTRIC CARCINOMAS. THE RUNX3 METHYLATION WAS FOUND IN 8.1% OF CHRONIC GASTRITIS (N=99), 28.1% OF INTESTINAL METAPLASIA (N=32), 27.3% OF GASTRIC ADENOMAS (N=77) AND 64% OF GASTRIC CARCINOMAS (N=75), BUT NOT IN CHRONIC HEPATITIS B, NORMAL PROSTATE AND COLON MUCOSA, EVEN THOUGH IN CASES OF CHRONIC HEPATITIS, THE METHYLATION FREQUENCY OF ITS NEOPLASTIC TISSUES WAS VERY HIGH. IN CONCLUSION, RUNX3 METHYLATION IS FREQUENTLY FOUND IN HUMAN CANCERS, INCLUDING GASTRIC CANCER, AND IS MOSTLY CANCER SPECIFIC, WITH THE EXCEPTION OF THE STOMACH, AND THUS, MIGHT BE USEFUL AS A POTENTIAL DIAGNOSTIC BIOMARKER OF CANCER. 2004 7 1975 26 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 8 3232 26 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY. 2015 9 4437 25 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 10 5182 32 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 11 4438 25 MOLECULAR FINDINGS IN BARRETT'S EPITHELIUM. BARRETT'S METAPLASIA IS A PREMALIGNANT CONDITION AND REMAINS THE NUMBER ONE RISK FACTOR FOR DEVELOPING ADENOCARCINOMA. THE HISTOLOGIC CHANGES LEADING TO ADENOCARCINOMA ARE ACCOMPANIED BY GENETIC DISTURBANCES OF THE EPITHELIAL CELLS ITSELF AS WELL AS THE SURROUNDING STROMA. GENETIC AND EPIGENETIC EVENTS AFFECT THE CELL CYCLE, LEADING TO GROWTH SELF-SUFFICIENCY AND IGNORATION OF ANTIGROWTH SIGNALS. THE BALANCE OF CELL TURNOVER IS INSTABLE BY AVOIDANCE OF APOPTOSIS AND A GENERAL LIMITLESS OF THE REPLICATIVE POTENTIAL OF THE (MUTATED) STEM CELLS. SUSTAINED ANGIOGENESIS, NOT ONLY A CONSEQUENCE OF CHRONIC INFLAMMATION, MAY PRECEDE INVASION OF GENETICALLY INSTABLE (ANEUPLOID) CELLS. THE PRINCIPAL GENETIC CHANGES IN BARRETT'S CARCINOGENESIS ARE COMPARABLE TO THOSE KNOWN FROM OTHER EPITHELIAL MALIGNANCIES. LOSS OF P16 GENE EXPRESSION (BY DELETION OR HYPERMETHYLATION), THE LOSS OF P53 EXPRESSION (BY MUTATION AND DELETION), THE INCREASE IN CYCLIN EXPRESSION, AND THE LOSSES OF RB, APC AS WELL AS VARIOUS CHROMOSOMAL LOCI HAVE BEEN REPORTED. SINCE THESE GENETIC OR EPIGENETIC ALTERATIONS ARE NEITHER TUMOR NOR STAGE SPECIFIC, THEY COULD NOT GAIN DIAGNOSTIC SIGNIFICANCE AS BIOMARKERS UNTIL NOW. 2004 12 4984 37 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 13 2943 21 GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES IN GASTRIC CANCER. BOTH GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES INVOLVED IN THE PATHOGENESIS OF GASTRIC CANCER ARE REVIEWED HERE, AND MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS ARE PROPOSED. GASTRIC CARCINOMAS ARE BELIEVED TO EVOLVE FROM NATIVE GASTRIC MUCOSA OR INTESTINAL METAPLASTIC MUCOSA THAT UNDERGOES GENETIC AND EPIGENETIC ALTERATIONS INVOLVING EITHER THE SUPPRESSOR PATHWAY (DEFECTS IN TUMOR SUPPRESSOR GENES) OR MUTATOR PATHWAY (DEFECTS IN DNA MISMATCH REPAIR GENES). METHYLATION OF E-CADHERIN IN NATIVE GASTRIC MUCOSA RESULTS IN UNDIFFERENTIATED CARCINOMAS (SUPPRESSOR PATHWAY), WHILE METHYLATION OF HMLHI RESULTS IN DIFFERENTIATED FOVEOLAR-TYPE CARCINOMAS (MUTATOR PATHWAY). THE MAJORITY OF DIFFERENTIATED GASTRIC CARCINOMAS HOWEVER, ARISE FROM INTESTINAL METAPLASTIC MUCOSA AND EXHIBIT STRUCTURAL ALTERATIONS OF TUMOR SUPPRESSOR GENES, ESPECIALLY P53. THEY APPEAR TO BE RELATED TO CHRONIC INJURY, PERHAPS DUE TO HELICOBACTER PYLORI INFECTION. APPROXIMATELY 20% OF DIFFERENTIATED CARCINOMAS (ORDINARY-TYPE) HAVE EVIDENCE OF MUTATOR PATHWAY TUMORIGENESIS. MUTATIONS OF E-CADHERIN ARE MAINLY INVOLVED IN THE PROGRESSION OF DIFFERENTIATED CARCINOMAS TO UNDIFFERENTIATED TUMORS. THE MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS DEPEND ON THE HISTOLOGICAL BACKGROUND, AND GASTRIC CARCINOMAS SHOW DISTINCT BIOLOGICAL BEHAVIORS AS A RESULT OF DISCERNIBLE CELLULAR GENETIC AND EPIGENETIC ALTERATIONS. 2002 14 4960 29 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 15 3230 37 HELICOBACTER PYLORI-INDUCED INFLAMMATION AND EPIGENETIC CHANGES DURING GASTRIC CARCINOGENESIS. THE SEQUENCE OF EVENTS ASSOCIATED WITH THE DEVELOPMENT OF GASTRIC CANCER HAS BEEN DESCRIBED AS "THE GASTRIC PRECANCEROUS CASCADE". THIS CASCADE IS A DYNAMIC PROCESS THAT INCLUDES LESIONS, SUCH AS ATROPHIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA. ACCORDING TO THIS MODEL, HELICOBACTER PYLORI (H. PYLORI) INFECTION TARGETS THE NORMAL GASTRIC MUCOSA CAUSING NON-ATROPHIC GASTRITIS, AN INITIATING LESION THAT CAN BE CURED BY CLEARING H. PYLORI WITH ANTIBIOTICS OR THAT MAY THEN LINGER IN THE CASE OF CHRONIC INFECTION AND PROGRESS TO ATROPHIC GASTRITIS. THE PRESENCE OF VIRULENCE FACTORS IN THE INFECTING H. PYLORI DRIVES THE CARCINOGENESIS PROCESS. INDEPENDENT EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE CONFIRMED THE SEQUENTIAL PROGRESSION OF THESE PRECANCEROUS LESIONS. PARTICULARLY LONG-TERM FOLLOW-UP STUDIES ESTIMATED A RISK OF 0.1% FOR ATROPHIC GASTRITIS/INTESTINAL METAPLASIA AND 6% IN CASE OF DYSPLASIA FOR THE LONG-TERM DEVELOPMENT OF GASTRIC CANCER. WITH THIS IN MIND, A BETTER UNDERSTANDING OF THE GENETIC AND EPIGENETIC CHANGES ASSOCIATED WITH PROGRESSION OF THE CASCADE IS CRITICAL IN DETERMINING THE RISK OF GASTRIC CANCER ASSOCIATED WITH H. PYLORI INFECTION. IN THIS REVIEW, WE WILL SUMMARIZE SOME OF THE MOST RELEVANT MECHANISMS AND FOCUS PREDOMINANTLY BUT NOT EXCLUSIVELY ON THE DISCUSSION OF GENE PROMOTER METHYLATION AND MIRNAS IN THIS CONTEXT. 2015 16 5382 26 RECURRENT CHROMOSOMAL AND EPIGENETIC ALTERATIONS IN ORAL SQUAMOUS CELL CARCINOMA AND ITS PUTATIVE PREMALIGNANT CONDITION ORAL LICHEN PLANUS. HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AFFECTS ABOUT 700.000 INDIVIDUALS PER YEAR WORLDWIDE WITH ORAL SQUAMOUS CELL CARCINOMA (OSCC) AS A MAJOR SUBCATEGORY. DESPITE A COMPREHENSIVE TREATMENT CONCEPT INCLUDING SURGERY, RADIATION, AND CHEMOTHERAPY THE 5-YEAR SURVIVAL RATE IS STILL ONLY ABOUT 50 PERCENT. CHRONIC INFLAMMATION IS ONE OF THE HALLMARKS OF CARCINOGENESIS. UNTIL NOW, LITTLE IS KNOWN ABOUT THE PREMALIGNANT STATUS OF ORAL LICHEN PLANUS (OLP) AND MOLECULAR ALTERATIONS IN OLP ARE STILL POORLY CHARACTERIZED. OUR STUDY AIMS TO DELINEATE DIFFERENTIAL DNA METHYLATION PATTERNS IN OLP, OSCC, AND NORMAL ORAL MUCOSA. BY APPLYING A BEAD CHIP APPROACH, WE IDENTIFIED ALTERED CHROMOSOMAL PATTERNS CHARACTERISTIC FOR OSCC WHILE FINDING NO RECURRENT ALTERATIONS IN OLP. IN CONTRAST, WE IDENTIFIED NUMEROUS ALTERATIONS IN THE DNA METHYLATION PATTERN IN OLP, AS COMPARED TO NORMAL CONTROLS, THAT WERE ALSO PRESENT IN OSCC. OUR DATA SUPPORT THE HYPOTHESIS THAT OLP IS A PRECURSOR LESION OF OSCC SHARING MULTIPLE EPIGENETIC ALTERATIONS WITH OSCC. 2019 17 5277 29 PROMOTER METHYLATION PROFILE IN PRENEOPLASTIC AND NEOPLASTIC GALLBLADDER LESIONS. GALLBLADDER CARCINOMA (GBC) IS A HIGHLY MALIGNANT NEOPLASM AND REPRESENTS THE LEADING CAUSE OF CANCER DEATH IN CHILEAN WOMEN. IN ORDER TO DETERMINE THE POTENTIAL ROLE OF PROMOTER METHYLATION IN GALLBLADDER CARCINOGENESIS, WE INVESTIGATED THE FREQUENCY OF THIS EPIGENETIC MECHANISM BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) IN 35 CHRONIC CHOLECYSTITIS (CC, SEPARATED ACCORDING TO THE PRESENCE OR ABSENCE OF METAPLASIA), 19 EARLY CANCERS (MUCOSA OR MUSCULARIS PROPIA INVASION) AND 48 ADVANCED CARCINOMAS WITH INVASION OF THE GALLBLADDER SUBSEROSA (25 CASES) AND SEROSA (23 CASES). WE EXAMINED 14 GENES AND OBSERVED AN INCREASE OF MULTIGENIC METHYLATION DURING TUMORAL PROGRESSION WHICH WAS NOT SIGNIFICANTLY ASSOCIATED WITH THE PATIENT'S AGE. FOUR GENES (DAPK1, DLC1, TIMP3, AND RARBETA2) DISPLAYED A PROGRESSIVE INCREASE IN THEIR METHYLATION STATUS FROM CC WITHOUT METAPLASIA TO ADVANCED CARCINOMA INVADING THE SEROSA LAYER (P