1 2938 76 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 2 4437 50 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 3 1975 27 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 4 563 42 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 5 2015 32 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 6 562 28 BARRETT ESOPHAGUS: HISTORY, DEFINITION AND ETIOPATHOGENY. THE INJURY OF THE ESOPHAGEAL EPITHELIUM MAY BE DETERMINED BY THE REFLUX OF THE GASTRIC ACID IN THE ESOPHAGUS. BARRETT'S ESOPHAGUS (BE) IS CHARACTERIZED BY THE REPLACEMENT OF THE NORMAL SQUAMOUS EPITHELIUM WITH THE COLUMNAR EPITHELIUM, WHEN THE HEALING OF THE LESION OCCURS. ACCORDING TO SOME STUDIES, THE INCIDENCE OF THE ESOPHAGEAL ADENOCARCINOMA IN PATIENTS WITH BE IS OF ABOUT 0,5% PER YEAR. THE TERM BARRETT'S ESOPHAGUS IS SUBJECTED TO INTERPRETATION NOWADAYS, SO IT LACKS THE CLARITY NEEDED FOR THE CLINICAL AND SCIENTIFIC COMMUNICATION ON THE SUBJECT OF COLUMNAR METAPLASIA OF THE ESOPHAGEAL MUCOSA. THE MAJOR PATHOGENETIC FACTOR IN THE DEVELOPMENT OF BE IS REPRESENTED BY THE REFLUX DISEASE. THE CELLULAR ORIGIN OF BE IS CONTROVERSIAL AND IT REPRESENTS AN ISSUE THAT NEEDS TO BE RESOLVED BECAUSE IT WILL HAVE IMPLICATIONS IN THE PUTATIVE MOLECULAR MECHANISMS UNDERLYING THE METAPLASTIC PROCESS. THE EPIGENETIC OR GENETIC CHANGES, WHICH ALTER PROTEIN EXPRESSION, FUNCTION, AND/ OR ACTIVITY, IN POST-MITOTIC CELLS TO DRIVE TRANSDIFFERENTIATION OR IN STEM/ PROGENITOR CELLS SUCH THAT THEY ARE REPROGRAMMED TO DIFFERENTIATE INTO COLUMNAR RATHER THAN SQUAMOUS CELLS, ARE DRIVEN BY THE INFLAMMATORY ENVIRONMENT CREATED BY CHRONIC REFLUX. IN ORDER TO BE ABLE TO DEVELOP BETTER THERAPEUTIC STRATEGIES FOR THE PATIENTS WITH THIS DISEASE, AN INCREASING INTEREST IN UNDERSTANDING THE PATHOGENESIS OF BE AT THE CELLULAR AND MOLECULAR LEVEL PRESENTS THESE DAYS. 2014 7 196 24 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 8 4438 28 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 9 5180 20 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 10 4733 28 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 11 2994 28 GENETIC PATHOGENESIS OF INFLAMMATION-ASSOCIATED CANCERS IN DIGESTIVE ORGANS. EPIDEMIOLOGICAL, CLINICAL, AND BIOLOGICAL STUDIES CONVINCINGLY DEMONSTRATE THAT CHRONIC INFLAMMATION PREDISPOSES TO THE DEVELOPMENT OF HUMAN CANCERS. IN DIGESTIVE ORGANS, INFLAMMATION-ASSOCIATED CANCERS INCLUDE COLITIS-ASSOCIATED COLORECTAL CANCERS, HELICOBACTER PYLORI-ASSOCIATED GASTRIC CANCER, AS WELL AS BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA ASSOCIATED WITH CHRONIC DUODENOGASTRIC-ESOPHAGEAL REFLUX. CANCER IS A GENOMIC DISEASE, AND STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR-RELATED GENES LEADS TO THE DEVELOPMENT OF TUMOR CELLS. RECENT GENOME ANALYSES SHOW THAT GENETIC ALTERATIONS, WHICH ARE EVOKED BY INFLAMMATION, ARE LATENTLY ACCUMULATED IN INFLAMED EPITHELIAL CELLS OF DIGESTIVE ORGANS. PRODUCTION OF REACTIVE OXYGEN AND ABERRANT EXPRESSION OF ACTIVATION-INDUCED CYTIDINE DEAMINASE, A NUCLEOTIDE-EDITING ENZYME, COULD BE INDUCED IN INFLAMED GASTROINTESTINAL EPITHELIAL CELLS AND PLAY A ROLE AS A GENOMIC MODULATOR OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. UNDERSTANDING THE MOLECULAR LINKAGE BETWEEN INFLAMMATION AND GENETIC ALTERATIONS WILL OPEN UP A NEW FIELD OF TUMOR BIOLOGY AND PROVIDE A NOVEL STRATEGY FOR THE PREVENTION OF INFLAMMATION-ASSOCIATED TUMORIGENESIS. 2021 12 5181 26 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 13 5211 27 PRENEOPLASTIC LESIONS IN HUMAN HEPATOCARCINOGENESIS. THE EARLY STAGES OF HEPATOCARCINOGENESIS IN HUMAN CHRONIC LIVER DISEASES ARE CHARACTERIZED BY THE EMERGENCE OF PRENEOPLASTIC LESIONS OF WHICH SOME WILL EVENTUALLY DEVELOP INTO HEPATOCELLULAR CARCINOMA (HCC). BASIC STUDIES ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THESE PRENEOPLASTIC LESIONS MAY EVENTUALLY LEAD TO NEW THERAPEUTIC STRATEGIES. CLINICOPATHOLOGICAL STUDIES ARE ALSO IMPORTANT IN ORDER TO DETERMINE OPTIMAL MANAGEMENT OF PATIENTS WITH A PRENEOPLASTIC LESION. THIS ARTICLE AIMS TO PROVIDE A COMPREHENSIVE REVIEW OF THE CURRENT CONCEPTS OF PRENEOPLASTIC LESION IN CHRONIC LIVER DISEASES. THE MICROSCOPICAL SMALL-CELL DYSPLASTIC FOCUS IS THE SMALLEST MORPHOLOGICALLY RECOGNIZABLE PRECURSOR LESION OF HCC AND THEREFORE IS A LOGICAL TARGET OF STUDY TO ELUCIDATE THE EARLIEST EVENTS IN HEPATOCARCINOGENESIS. IN CONTRAST, LARGE-CELL DYSPLASIA IS NOT A PRECURSOR LESION, BUT APPEARS TO BE OF CLINICAL VALUE BECAUSE OF ITS GOOD PREDICTIVE VALUE FOR DEVELOPMENT OF HCC. DYSPLASTIC NODULES (DNS) ARE MACROSCOPICALLY RECOGNIZABLE PRECURSOR LESIONS OF HCC AND HIGH-GRADE DNS (HGDNS) HAVE A RISK OF MALIGNANT TRANSFORMATION. DETECTION OF DNS AND CORRECT DIFFERENTIATION FROM SMALL HCC (<2 CM) IS SOMETIMES DIFFICULT, ESPECIALLY WHEN ONLY IMAGING TECHNIQUES ARE USED. ADDITIONAL CLINICOPATHOLOGICAL STUDIES ON IDENTIFICATION AND OPTIMAL TREATMENT OF DNS ARE NECESSARY. MOLECULAR STUDIES ON HGDNS AND SMALL HCCS MAY YIELD MUCH INFORMATION ON THE GENETIC MECHANISMS INVOLVED IN THE TRANSITION FROM SEVERE DYSPLASIA TO EARLY MALIGNANCY. IN CONTRAST, CURRENTLY AVAILABLE DATA INDICATE THAT (LARGE) REGENERATIVE NODULES DO NOT REPRESENT A DISTINCT STEP IN HEPATOCARCINOGENESIS. ANIMAL MODELS WILL BE HELPFUL IN THE FURTHER UNRAVELLING OF HUMAN HCC DEVELOPMENT, PROVIDED THAT STUDIES ARE PERFORMED ON MODELS THAT ARE GOOD REPRESENTATIVES OF HUMAN HEPATOCARCINOGENESIS. WE PROPOSE THREE CRITERIA BY WHICH GOOD MIMICKERS CAN BE IDENTIFIED. 2005 14 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 15 2852 28 FROM GASTRIC INFLAMMATION TO GASTRIC CANCER. THE MAJORITY OF GASTRIC ADENOCARCINOMAS ARE RELATED TO CHRONIC INFLAMMATION INDUCED BY HELICOBACTER PYLORI INFECTION. FOR INTESTINAL-TYPE GASTRIC CANCER, A MULTISTEP PROCESS OF MUCOSAL ALTERATIONS LEADING FROM GASTRITIS VIA GLANDULAR ATROPHY, INTESTINAL METAPLASIA AND DYSPLASIA TO INVASIVE CARCINOMA IS WELL RECOGNIZED. ONGOING CLINICAL STUDIES FOCUS ON A 'POINT OF NO RETURN'. IT IS DEFINED AS A SITUATION WHEN CERTAIN ALTERATIONS ARE NO LONGER REVERSIBLE BY H. PYLORI ERADICATION AND PROGRESSION TO GASTRIC CANCER MAY CONTINUE. H. PYLORI AFFECTS THE MUCOSAL AS WELL AS THE SYSTEMIC IMMUNE RESPONSE BY SECRETION OF CYTOKINES AND THE RECRUITMENT OF DISTINCT INFLAMMATORY CELLS. THE IMMUNE RESPONSE IS CHARACTERIZED BY A BALANCE BETWEEN A TH1-DOMINATED RESPONSE AND THE RECRUITMENT OF ANTIGEN-SPECIFIC REGULATORY T CELLS THAT ALLOW THE BACTERIA TO PERSIST IN HUMAN GASTRIC MUCOSA. BESIDES IMMUNE-MEDIATED EFFECTS, H. PYLORI INDUCES CELLULAR ALTERATIONS AS WELL AS GENETIC ALTERATIONS IN GENES THAT ARE ESSENTIAL FOR THE EPIGENETIC INTEGRITY AND MUCOSAL HOMEOSTASIS. THESE GENETIC ALTERATIONS DURING GASTRIC CANCER DEVELOPMENT ARE IN FOCUS OF INTENSIVE RESEARCH AND SHOULD ULTIMATELY ALLOW THE IDENTIFICATION OF RISK FACTORS INVOLVED IN GASTRIC CARCINOGENESIS. THE DETECTION OF INDIVIDUALS AT HIGH RISK FOR GASTRIC CANCER WOULD HELP TO DESIGN APPROPRIATE STRATEGIES FOR PREVENTION AND SURVEILLANCE. 2010 16 1099 28 COLONIC CARCINOGENESIS IN IBD: MOLECULAR EVENTS. PATIENTS WITH ULCERATIVE COLITIS (UC) AND CROHN'S DISEASE (CD) ARE AT INCREASED RISK OF DEVELOPING INTESTINAL CANCERS VIA MECHANISMS THAT REMAIN INCOMPLETELY UNDERSTOOD. SEVERAL EVIDENCES SUGGEST A CAUSAL LINK BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT OF CANCER IN THE GASTROINTESTINAL TRACT. IN FACT, PATIENTS WITH UC ARE EXPOSED TO REPEATED EPISODES OF INFLAMMATION THAT PREDISPOSE TO VARIOUS TUMORIGENIC EVENTS AND THE SEQUENCE OF THESE EVENTS ARE DIFFERENT FROM THOSE THAT CONTRIBUTE TO DEVELOP A SPORADIC COLORECTAL CANCER. IN UC CARCINOGENESIS THE EARLY EVENTS ARE REPRESENTED BY DNA METHYLATION THAT PRODUCE AN INHIBITION OF ONCO-SUPPRESSOR GENES, MUTATION OF P53, ANEUPLOIDY AND MICROSATELLITE INSTABILITY. HYPERMETHYLATION OF TUMOR SUPPRESSORS AND DNA MISMATCH REPAIR GENE PROMOTER REGIONS, IS AN EPIGENETIC MECHANISM OF GENE SILENCING THAT CONTRIBUTES TO TUMORIGENESIS AND MIGHT REPRESENT THE FIRST STEP IN INFLAMMATORY CARCINOGENESIS. P53 IS FREQUENTLY MUTATED IN THE EARLY STAGES OF UC-ASSOCIATED CANCER, IN 33-67% OF PATIENTS WITH DYSPLASIA AND IN 83-95% OF UC RELATED CANCER PATIENTS. MOREOVER, ANEUPLOIDY IS AN INDEPENDENT RISK FACTOR FOR FORTHCOMING CARCINOGENESIS IN UC FINALLY, THE INCONSISTENCY BETWEEN THE HIGH CUMULATIVE RATE OF DYSPLASIA IN UC AND THE RELATIVELY LOWER INCIDENCE OF INVASIVE CANCER RAISES THE QUESTION ABOUT THE MECHANISMS OF IMMUNOSURVEILLANCE THAT MAY PREVENT MALIGNANT PROGRESSION OF NEOPLASM IN THE COLON IN MOST CASES. CO-STIMULATORY MOLECULE CD80 UP-REGULATION IN COLONIC MUCOSA IN UC DYSPLASIA MAY BE ONE OF THESE MECHANISM. 2011 17 3170 22 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 18 4316 24 MICRORNAS AS NON-INVASIVE DIAGNOSTIC BIOMARKERS FOR GASTRIC CANCER: CURRENT INSIGHTS AND FUTURE PERSPECTIVES. NON-INVASIVE DIAGNOSTIC BIOMARKERS MAY CONTRIBUTE TO AN EARLY IDENTIFICATION OF GASTRIC CANCER (GC) AND IMPROVE THE CLINICAL MANAGEMENT. UNFORTUNATELY, NO SENSITIVE AND SPECIFIC SCREENING BIOMARKERS ARE AVAILABLE YET AND THE CURRENTLY AVAILABLE APPROACHES ARE LIMITED BY THE NATURE OF THE DISEASE. GC IS A HETEROGENIC DISEASE WITH VARIOUS DISTINCT GENETIC AND EPIGENETIC EVENTS THAT OCCUR DURING THE MULTIFACTORIAL CASCADE OF CARCINOGENESIS. MICRORNAS (MIRNAS) ARE COMMONLY DEREGULATED IN GASTRIC MUCOSA DURING THE HELICOBACTER PYLORI INFECTION AND IN STEPWISE MANNER FROM CHRONIC GASTRITIS, THROUGH PRENEOPLASTIC CONDITIONS SUCH AS ATROPHIC GASTRITIS AND INTESTINAL METAPLASIA, TO EARLY DYSPLASIA AND INVASIVE CANCER. IDENTIFICATION OF MIRNAS IN BLOOD IN 2008 LED TO A GREAT INTEREST ON MIRNA-BASED DIAGNOSTIC, PROGNOSTIC BIOMARKERS IN GC. IN THIS REVIEW, WE PROVIDE THE MOST RECENT SYSTEMATIC REVIEW ON THE EXISTING STUDIES RELATED TO MIRNAS AS DIAGNOSTIC BIOMARKERS FOR GC. HERE, WE SYSTEMATICALLY EVALUATE 75 STUDIES RELATED TO DIFFERENTIAL EXPRESSION OF CIRCULATING MIRNAS IN GC PATIENTS AND PROVIDE NOVEL VIEW ON VARIOUS HETEROGENIC ASPECTS OF THE EXISTING DATA AND SUMMARIZE THE METHODOLOGICAL DIFFERENCES. FINALLY, WE HIGHLIGHT SEVERAL IMPORTANT ASPECTS CRUCIAL TO IMPROVE THE FUTURE TRANSLATIONAL AND CLINICAL RESEARCH IN THE FIELD. 2018 19 4539 22 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 20 3230 24 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