1 562 125 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 2 1975 28 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 3 563 36 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 4437 38 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 5 2015 40 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 4733 32 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 7 2994 34 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 8 2658 37 EPITHELIAL METAPLASIA: ADULT STEM CELL REPROGRAMMING AND (PRE)NEOPLASTIC TRANSFORMATION MEDIATED BY INFLAMMATION? THROUGHOUT ADULT LIFE, NEW DEVELOPMENTAL COMMITMENT OF ADULT STEM CELLS CAUSES METAPLASTIC CONVERSIONS TO OCCUR FREQUENTLY IN SOME ORGANS. THESE REVERSIBLE EPITHELIAL REPLACEMENTS ARE ALMOST ALWAYS OBSERVED IN ASSOCIATION WITH CHRONIC INFLAMMATION AND PERSISTENT IRRITATION. ALTHOUGH METAPLASIA IS NOT SYNONYMOUS WITH DYSPLASIA, CLINICAL SURVEILLANCE HAS DEMONSTRATED THAT THESE ADAPTIVE PROCESSES HAVE AN INCREASED SUSCEPTIBILITY TO EVOLVE INTO CANCER. WE PROPOSE THAT CYTOKINES AND OTHER SOLUBLE FACTORS RELEASED BY BOTH EPITHELIAL AND INFLAMMATORY CELLS MIGHT ALTER THE TRANSCRIPTION-FACTOR EXPRESSION PROFILE OF STEM CELLS AND LEAD TO THE DEVELOPMENT OF METAPLASIA. FURTHERMORE, INFLAMMATORY MEDIATORS MIGHT ALSO PROMOTE THE MALIGNANT TRANSFORMATION OF EPITHELIAL METAPLASIA BY INDUCING GENETIC AND EPIGENETIC CHANGES AND BY PREVENTING THE IMMUNE SYSTEM FROM MOUNTING AN EFFICIENT ANTI-TUMOUR IMMUNE RESPONSE. A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS LEADING TO METAPLASIA MIGHT HELP IN THE DESIGN OF NEW THERAPIES FOR NEOPLASTIC AND DEGENERATIVE DISEASES. 2009 9 4479 35 MOLECULAR PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR THERAPY. THE DEVELOPMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC) IS A MULTISTEP PROCESS REQUIRING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS, INFLUENCED BY A PATIENT'S GENETIC PREDISPOSITION AS WELL AS BY ENVIRONMENTAL INFLUENCES, INCLUDING TOBACCO, ALCOHOL, CHRONIC INFLAMMATION, AND VIRAL INFECTION. TUMORIGENIC GENETIC ALTERATIONS CONSIST OF TWO MAJOR TYPES: TUMOR SUPPRESSOR GENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN INACTIVATED; AND ONCOGENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN ACTIVATED. TUMOR SUPPRESSOR GENES CAN BE INACTIVATED THROUGH GENETIC EVENTS SUCH AS MUTATION, LOSS OF HETEROZYGOSITY, OR DELETION, OR BY EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION OR CHROMATIN REMODELING. ONCOGENES CAN BE ACTIVATED THROUGH OVEREXPRESSION DUE TO GENE AMPLIFICATION, INCREASED TRANSCRIPTION, OR CHANGES IN STRUCTURE DUE TO MUTATIONS THAT LEAD TO INCREASED TRANSFORMING ACTIVITY. THIS REVIEW FOCUSES ON THE MOLECULAR MECHANISMS OF ORAL CARCINOGENESIS AND THE USE OF BIOLOGIC THERAPY TO SPECIFICALLY TARGET MOLECULES ALTERED IN OSCC. THE RAPID PROGRESS THAT HAS BEEN MADE IN OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS CONTRIBUTING TO THE DEVELOPMENT OF OSCC IS LEADING TO IMPROVEMENTS IN THE EARLY DIAGNOSIS OF TUMORS AND THE REFINEMENT OF BIOLOGIC TREATMENTS INDIVIDUALIZED TO THE SPECIFIC CHARACTERISTICS OF A PATIENT'S TUMOR. 2008 10 4429 29 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 11 1522 35 DNA METHYLATION CHANGE PROFILING OF COLORECTAL DISEASE: SCREENING TOWARDS CLINICAL USE. COLON CANCER REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. TRANSFORMATION OF COLON EPITHELIAL CELLS INTO INVASIVE ADENOCARCINOMAS HAS BEEN WELL KNOWN TO BE DUE TO THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC CHANGES. IN THE PAST DECADE, THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) WHICH IS CHARACTERIZED BY CHRONIC INFLAMMATION OF THE INTESTINAL MUCOSA, WAS ONLY PARTIALLY EXPLAINED BY GENETIC STUDIES PROVIDING SUSCEPTIBILITY LOCI, BUT RECENTLY EPIGENETIC STUDIES HAVE PROVIDED CRITICAL EVIDENCES AFFECTING IBD PATHOGENESIS. OVER THE PAST DECADE, A DEEP UNDERSTANDING OF EPIGENETICS ALONG WITH TECHNOLOGICAL ADVANCES HAVE LED TO IDENTIFYING NUMEROUS GENES THAT ARE REGULATED BY PROMOTER DNA HYPERMETHYLATION IN COLORECTAL DISEASES. RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN COLORECTAL DISEASES COULD IMPROVE A MULTITUDE OF POWERFUL DNA METHYLATION-BASED BIOMARKERS, PARTICULARLY FOR USE AS DIAGNOSIS, PROGNOSIS, AND PREDICTION FOR THERAPEUTIC APPROACHES. THIS REVIEW FOCUSES ON THE EMERGING POTENTIAL FOR TRANSLATIONAL RESEARCH OF EPIGENETIC ALTERATIONS INTO CLINICAL UTILITY AS MOLECULAR BIOMARKERS. MOREOVER, THIS REVIEW DISCUSSES RECENT PROGRESS REGARDING THE IDENTIFICATION OF UNKNOWN HYPERMETHYLATED GENES IN COLON CANCERS AND IBD, AS WELL AS THEIR POSSIBLE ROLE IN CLINICAL PRACTICE, WHICH WILL HAVE IMPORTANT CLINICAL SIGNIFICANCE, PARTICULARLY IN THE ERA OF THE PERSONALIZED MEDICINE. 2021 12 2975 27 GENETIC AND MOLECULAR ALTERATIONS ASSOCIATED WITH ORAL SQUAMOUS CELL CANCER (REVIEW). THE DEVELOPMENT OF ORAL SQUAMOUS CELL CANCER (OSCC) IS A MULTISTEP PROCESS INVOLVING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS MODULATED BY GENETIC PRE-DISPOSITION AND ENVIRONMENTAL INFLUENCES SUCH AS TOBACCO AND ALCOHOL USE, CHRONIC INFLAMMATION, AND VIRAL INFECTIONS. ALL OF THESE FACTORS CAN LEAD TO A WIDE RANGE OF GENETIC AND MOLECULAR ALTERATIONS THAT CAN BE DETECTED USING A RANGE OF MOLECULAR STUDIES. THE ALTERATIONS MOSTLY AFFECT TWO LARGE GROUPS OF GENES: ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH CAN BE EITHER INACTIVATED OR OVEREXPRESSED THROUGH MUTATIONS, LOSS OF HETEROZYGOSITY, DELETIONS, OR EPIGENETIC MODIFICATIONS SUCH AS METHYLATION. OTHER MOLECULES THAT ARE CLOSELY ASSOCIATED WITH TUMOR PATHOGENESIS AND PROGNOSIS ALSO EXIST AND WARRANT FURTHER STUDY. IMPORTANT ADVANCES IN MOLECULAR BIOLOGY ARE HELPING TO SHED LIGHT ON ORAL CANCER AND THUS AIDING IN THE EARLY DIAGNOSIS AND DEVELOPMENT OF NEW PERSONALIZED TREATMENT APPROACHES. THE PURPOSE OF THE REVIEW IS TO EXPLORE THE GENETIC AND MOLECULAR ALTERATIONS ASSOCIATED WITH OSCC. 2009 13 5182 31 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 14 5742 23 SMOKING MOLECULAR DAMAGE IN BRONCHIAL EPITHELIUM. OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LUNG CANCER IS ADVANCING RAPIDLY WITH SEVERAL SPECIFIC GENES AND CHROMOSOMAL REGIONS BEING IDENTIFIED. LUNG CANCER APPEARS TO REQUIRE MANY MUTATIONS IN BOTH DOMINANT AND RECESSIVE ONCOGENES TO POSSESS MALIGNANT PHENOTYPES. SEVERAL GENETIC AND EPIGENETIC CHANGES ARE COMMON TO ALL LUNG CANCER HISTOLOGIC TYPES, WHILE OTHERS APPEAR TO BE CELL TYPE SPECIFIC. HOWEVER, SPECIFIC ROLES OF THE GENES UNDERGOING MUTATIONS AND THE ORDER OF CUMULATIVE MOLECULAR CHANGES THAT LEAD TO THE DEVELOPMENT OF EACH LUNG TUMOR HISTOLOGIC TYPE REMAIN TO BE FULLY ELUCIDATED. RECENT FINDINGS OF MOLECULAR ABNORMALITIES IN NORMAL APPEARING AND PRENEOPLASTIC BRONCHIAL EPITHELIUM FROM PATIENTS WITH LUNG CANCER AND CHRONIC SMOKERS SUGGEST THAT GENETIC CHANGES MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS, RISK ASSESSMENT AND MONITORING RESPONSE TO CHEMOPREVENTION. 2002 15 928 28 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. CHRONIC INFLAMMATION OFTEN PRECEDES OR ACCOMPANIES A SUBSTANTIAL NUMBER OF CANCERS. INDEED, ANTI-INFLAMMATORY THERAPIES HAVE SHOWN EFFICACY IN CANCER PREVENTION AND TREATMENT. THE EXACT MECHANISMS THAT TURN A WOUND HEALING PROCESS INTO A CANCER PRECURSOR ARE TOPICS OF INTENSE RESEARCH. A PATHOGENIC LINK HAS BEEN IDENTIFIED BETWEEN INFLAMMATORY MEDIATORS, INFLAMMATION RELATED GENE POLYMORPHISMS AND CARCINOGENESIS. ANIMAL MODELS OF CANCER HAVE BEEN INSTRUMENTAL IN DEMONSTRATING THE DIVERSITY OF MECHANISMS THROUGH WHICH EVERY TUMOR COMPARTMENT AND TUMOR STAGE MAY BE AFFECTED BY THE UNDERLYING INFLAMMATORY PROCESS. IN THIS REVIEW, WE FOCUS ON THE INTERACTION BETWEEN CHRONIC INFLAMMATION, TUMOR STEM CELLS AND THE TUMOR MICROENVIRONMENT. WE SUMMARIZE THE PROPOSED MECHANISMS THAT LEAD TO THE RECRUITMENT OF BONE MARROW DERIVED CELLS AND EXPLORE THE GENETIC AND EPIGENETIC ALTERATIONS THAT MAY OCCUR IN INFLAMMATION ASSOCIATED CANCERS. 2009 16 4539 26 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 17 1844 45 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 18 2122 27 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 19 6809 32 [EPIGENETICS IN INFLAMMATORY SYSTEMIC DISEASES]. IN ADDITION TO ANALYSIS OF THE GENETIC CODE, IN RECENT YEARS MORE AND MORE STUDIES HAVE CONCENTRATED ON CHANGES IN THE EPIGENETIC CODE. EPIGENETIC MECHANISMS DETERMINE WHICH GENES IN A CELL ARE TRANSCRIBED AND THUS FORM THE PHENOTYPE OF A CELL. THE EPIGENETIC CODE CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES, WHICH ALLOWS CELLS TO ADAPT TO LONGSTANDING CHANGES IN THE ENVIRONMENT. THEREFORE, IT IS FEASIBLE TO ASSUME THAT EPIGENETIC CHANGES ARE THE MOLECULAR BASIS FOR LONG-TERM EFFECTS OF THE ENVIRONMENT ON DISEASE DEVELOPMENT. IN PARTICULAR IN TUMORS AND CHRONIC INFLAMMATORY DISEASES EPIGENETIC CHANGES WERE FOUND TO CORRELATE WITH DISEASE SEVERITY AND PROGRESSION. KNOWLEDGE ABOUT THESE EPIGENETIC CHANGES MIGHT HELP THAT EPIGENETIC MODIFICATIONS CAN BE USED IN THE FUTURE AS BIOMARKERS, PROGNOSTIC FACTORS AND THERAPEUTIC TARGETS. 2014 20 186 25 ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL CELLS AND CANCER RISK. CANCERS DEVELOP DUE TO THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. GENETIC ALTERATIONS ARE INDUCED BY AGING, MUTAGENIC CHEMICALS, ULTRAVIOLET LIGHT, AND OTHER FACTORS; WHEREAS, EPIGENETIC ALTERATIONS ARE MAINLY BY AGING AND CHRONIC INFLAMMATION. THE ACCUMULATION AND PATTERNS OF ALTERATIONS IN NORMAL CELLS REFLECT OUR PAST EXPOSURE LEVELS AND LIFE HISTORY. MOST ACCUMULATED ALTERATIONS ARE CONSIDERED AS PASSENGERS, BUT THEIR ACCUMULATION IS CORRELATED WITH CANCER DRIVERS. THIS HAS BEEN SHOWN FOR ABERRANT DNA METHYLATION BUT HAS ONLY BEEN SPECULATED FOR GENETIC ALTERATIONS. HOWEVER, RECENT TECHNOLOGICAL ADVANCEMENTS HAVE ENABLED MEASUREMENT OF RARE POINT MUTATIONS, AND STUDIES HAVE SHOWN THAT THEIR ACCUMULATION LEVELS ARE INDEED CORRELATED WITH CANCER RISK. WHEN THE ACCUMULATION LEVELS OF ABERRANT DNA METHYLATION AND POINT MUTATIONS ARE COMBINED, RISK PREDICTION BECOMES EVEN MORE ACCURATE. WHEN HIGH LEVELS OF ALTERATIONS ACCUMULATE, THE TISSUE HAS A HIGH RISK OF DEVELOPING CANCER OR EVEN MULTIPLE CANCERS AND IS CONSIDERED AS A "CANCERIZATION FIELD", WITH OR WITHOUT EXPANSION OF PHYSIOLOGICAL PATCHES OF CLONAL CELLS. IN THIS REVIEW, WE DESCRIBE THE FORMATION OF A CANCERIZATION FIELD AND HOW WE CAN APPLY ITS DETECTION IN PRECISION CANCER RISK DIAGNOSIS. 2019