1 1544 141 DNA METHYLATION IN HUMAN GASTRIC EPITHELIAL CELLS DEFINES REGIONAL IDENTITY WITHOUT RESTRICTING LINEAGE PLASTICITY. BACKGROUND: EPIGENETIC MODIFICATIONS IN MAMMALIAN DNA ARE COMMONLY MANIFESTED BY DNA METHYLATION. IN THE STOMACH, ALTERED DNA METHYLATION PATTERNS HAVE BEEN OBSERVED FOLLOWING CHRONIC HELICOBACTER PYLORI INFECTIONS AND IN GASTRIC CANCER. IN THE CONTEXT OF EPIGENETIC REGULATION, THE REGIONAL NATURE OF THE STOMACH HAS BEEN RARELY CONSIDERED IN DETAIL. RESULTS: HERE, WE ESTABLISH GASTRIC MUCOSA DERIVED PRIMARY CELL CULTURES AS A RELIABLE SOURCE OF NATIVE HUMAN EPITHELIUM. WE DESCRIBE THE DNA METHYLATION LANDSCAPE ACROSS THE PHENOTYPICALLY DIFFERENT REGIONS OF THE HEALTHY HUMAN STOMACH, I.E., ANTRUM, CORPUS, FUNDUS TOGETHER WITH THE CORRESPONDING TRANSCRIPTOMES. WE SHOW THAT STABLE REGIONAL DNA METHYLATION DIFFERENCES TRANSLATE TO A LIMITED EXTENT INTO REGULATION OF THE TRANSCRIPTOMIC PHENOTYPE, INDICATING A LARGELY PERMISSIVE EPIGENETIC REGULATION. WE IDENTIFY A SMALL NUMBER OF TRANSCRIPTION FACTORS WITH NOVEL REGION-SPECIFIC ACTIVITY AND LIKELY EPIGENETIC IMPACT IN THE STOMACH, INCLUDING GATA4, IRX5, IRX2, PDX1 AND CDX2. DETAILED ANALYSIS OF THE WNT PATHWAY REVEALS DIFFERENTIAL REGULATION ALONG THE CRANIOCAUDAL AXIS, WHICH INVOLVES NON-CANONICAL WNT SIGNALING IN DETERMINING CELL FATE IN THE PROXIMAL STOMACH. BY EXTENDING OUR ANALYSIS TO PRE-NEOPLASTIC LESIONS AND GASTRIC CANCERS, WE CONCLUDE THAT EPIGENETIC DYSREGULATION CHARACTERIZES INTESTINAL METAPLASIA AS A FOUNDING BASIS FOR FUNCTIONAL CHANGES IN GASTRIC CANCER. WE PRESENT INSIGHTS INTO THE DYNAMICS OF DNA METHYLATION ACROSS ANATOMICAL REGIONS OF THE HEALTHY STOMACH AND PATTERNS OF ITS CHANGE IN DISEASE. FINALLY, OUR STUDY PROVIDES A WELL-DEFINED RESOURCE OF REGIONAL STOMACH TRANSCRIPTION AND EPIGENETICS. 2022 2 4114 31 MECHANISMS FOR THE INDUCTION OF GASTRIC CANCER BY HELICOBACTER PYLORI INFECTION: ABERRANT DNA METHYLATION PATHWAY. MULTIPLE PATHOGENIC MECHANISMS BY WHICH HELICOBACTER PYLORI INFECTION INDUCES GASTRIC CANCER HAVE BEEN ESTABLISHED IN THE LAST TWO DECADES. IN PARTICULAR, ABERRANT DNA METHYLATION IS INDUCED IN MULTIPLE DRIVER GENES, WHICH INACTIVATES THEM. METHYLATION PROFILES IN GASTRIC CANCER ARE ASSOCIATED WITH SPECIFIC SUBTYPES, SUCH AS MICROSATELLITE INSTABILITY. RECENT COMPREHENSIVE AND INTEGRATED ANALYSES SHOWED THAT MANY CANCER-RELATED PATHWAYS ARE MORE FREQUENTLY ALTERED BY ABERRANT DNA METHYLATION THAN BY MUTATIONS. ABERRANT DNA METHYLATION CAN EVEN BE PRESENT IN NONCANCEROUS GASTRIC MUCOSAE, PRODUCING AN "EPIGENETIC FIELD FOR CANCERIZATION." MECHANISTICALLY, H. PYLORI-INDUCED CHRONIC INFLAMMATION, BUT NOT H. PYLORI ITSELF, PLAYS A DIRECT ROLE IN THE INDUCTION OF ABERRANT DNA METHYLATION. THE EXPRESSION OF THREE INFLAMMATION-RELATED GENES, IL1B, NOS2, AND TNF, IS HIGHLY ASSOCIATED WITH THE INDUCTION OF ABERRANT DNA METHYLATION. IMPORTANTLY, THE DEGREE OF ACCUMULATED ABERRANT DNA METHYLATION IS STRONGLY CORRELATED WITH GASTRIC CANCER RISK. A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THE UTILITY OF EPIGENETIC CANCER RISK DIAGNOSIS FOR METACHRONOUS GASTRIC CANCER. SUPPRESSION OF ABERRANT DNA METHYLATION BY A DEMETHYLATING AGENT WAS SHOWN TO INHIBIT GASTRIC CANCER DEVELOPMENT IN AN ANIMAL MODEL. INDUCTION OF ABERRANT DNA METHYLATION IS THE MAJOR PATHWAY BY WHICH H. PYLORI INFECTION INDUCES GASTRIC CANCER, AND THIS CAN BE UTILIZED FOR TRANSLATIONAL OPPORTUNITIES. 2017 3 4994 32 PERFORMANCE OF DNA METHYLATION ON THE MOLECULAR PATHOGENESIS OF HELICOBACTER PYLORI IN GASTRIC CANCER; TARGETED THERAPY APPROACH. GASTRIC CANCER (GC) IS A SIGNIFICANT CAUSE OF CANCER MORTALITY WHICH HAS LED TO FOCUSED EXPLORATION OF THE PATHOLOGY OF GC. THE ADVENT OF GENOME-WIDE ANALYSIS METHODS HAS MADE IT POSSIBLE TO UNCOVER GENETIC AND EPIGENETIC FLUCTUATION SUCH AS ABNORMAL DNA METHYLATION IN GENE PROMOTER REGIONS THAT IS EXPECTED TO PLAY A KEY ROLE IN GC. THE STUDY OF GASTRIC MALIGNANCIES REQUIRES AN ETIOLOGICAL PERSPECTIVE, AND HELICOBACTER PYLORI (H. PYLORI) WAS IDENTIFIED TO PLAY A ROLE IN GC. H. PYLORI INFECTION CAUSES CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM CAUSING ABNORMAL POLYCLONAL METHYLATION, WHICH MIGHT RAISE THE RISK OF GC. IN THE LAST TWO DECADES, VARIOUS PATHOGENIC FACTORS BY WHICH H. PYLORI INFECTION CAUSES GC HAVE BEEN DISCOVERED. ABNORMAL DNA METHYLATION IS TRIGGERED IN SEVERAL GENES, RENDERING THEM INACTIVE. IN GC, METHYLATION PATTERNS ARE LINKED TO CERTAIN SUBTYPES INCLUDING MICROSATELLITE INSTABILITY. MULTIPLE CANCER-RELATED PROCESSES ARE MORE USUALLY CHANGED BY ABNORMAL DNA METHYLATION THAN THROUGH MUTATIONS, ACCORDING TO CURRENT GENERAL AND COMBINED INVESTIGATIONS. FURTHERMORE, THE AMOUNT OF ACQUIRED ABNORMAL DNA METHYLATION IS HEAVILY LINKED TO THE CHANCES OF DEVELOPING GC. THEREFORE, WE INVESTIGATED ABNORMAL DNA METHYLATION IN GC AND THE LINK BETWEEN METHYLATION AND H. PYLORI INFECTION. 2022 4 925 33 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 5 4960 28 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 6 2033 39 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 7 2122 33 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 8 342 32 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS. 2007 9 3686 29 INFLAMMATION-RELATED ABERRANT PATTERNS OF DNA METHYLATION: DETECTION AND ROLE IN EPIGENETIC DEREGULATION OF CANCER CELL TRANSCRIPTOME. IT IS NOW APPARENT THAT EPIGENETIC ABNORMALITIES, IN PARTICULAR ALTERED DNA METHYLATION, PLAY A CRUCIAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF HUMAN CANCERS. DNA HYPERMETHYLATION AT PROMOTER CPG ISLANDS IS NOW RECOGNIZED AS A THIRD MECHANISM BY WHICH INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS. ABERRANT CPG ISLAND HYPERMETHYLATION IS ALSO FREQUENTLY OBSERVED IN CHRONIC INFLAMMATION AND PRECANCEROUS LESIONS, WHICH SUGGESTS THAT IT IS AN EARLY EVENT IN TUMORIGENESIS THAT COULD SERVE AS A USEFUL TUMOR MARKER. A VARIETY OF SCREENING TECHNIQUES HAVE BEEN DEVELOPED FOR GENOME-WIDE SCREENING OF METHYLATION STATUS. OF THOSE, TRANSCRIPTOME ANALYSIS COUPLED WITH PHARMACOLOGICAL UNMASKING HAS EMERGED AS A POWERFUL TOOL FOR REVEALING DNA METHYLATION PATTERNS IN CANCER CELLS AND IDENTIFYING NEW TUMOR MARKER CANDIDATES. 2009 10 3067 32 GENOME-WIDE DNA METHYLATION PROFILES IN PRECANCEROUS CONDITIONS AND CANCERS. ALTERATIONS OF DNA METHYLATION, WHICH RESULT IN CHROMOSOMAL INSTABILITY AND SILENCING OF TUMOR-RELATED GENES, ARE AMONG THE MOST CONSISTENT EPIGENETIC CHANGES OBSERVED IN HUMAN CANCERS. ANALYSIS OF TISSUE SPECIMENS HAS REVEALED THAT DNA METHYLATION ALTERATIONS PARTICIPATE IN MULTISTAGE CARCINOGENESIS, EVEN FROM THE EARLY AND PRECANCEROUS STAGES, ESPECIALLY IN ASSOCIATION WITH CHRONIC INFLAMMATION AND/OR PERSISTENT VIRAL INFECTION, SUCH AS CHRONIC HEPATITIS OR LIVER CIRRHOSIS RESULTING FROM INFECTION WITH HEPATITIS B OR C VIRUS. DNA METHYLATION ALTERATIONS CAN ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY, BUT IS SIGNIFICANTLY CORRELATED WITH ACCUMULATION OF DNA HYPERMETHYLATION IN CPG ISLANDS OF TUMOR-RELATED GENES. ALTERATION OF DNA METHYLTRANSFERASE 3B SPLICING MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION IN PERICENTROMERIC SATELLITE REGIONS. GENOME-WIDE ANALYSIS OF DNA METHYLATION STATUS HAS REVEALED THAT THE DNA METHYLATION PROFILE AT THE PRECANCEROUS STAGE IS BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. DNA METHYLATION STATUS IS NOT SIMPLY ALTERED AT THE PRECANCEROUS STAGE; RATHER, DNA METHYLATION ALTERATIONS AT THE PRECANCEROUS STAGE MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. THEREFORE, GENOME-WIDE DNA METHYLATION PROFILING MAY PROVIDE OPTIMAL INDICATORS FOR CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION, AND THUS PROVIDE AN AVENUE FOR CANCER PREVENTION AND THERAPY ON AN INDIVIDUAL BASIS. 2010 11 3220 38 HELICOBACTER PYLORI AND MICRORNAS: RELATION WITH INNATE IMMUNITY AND PROGRESSION OF PRENEOPLASTIC CONDITIONS. THE ACCEPTED PARADIGM FOR INTESTINAL-TYPE GASTRIC CANCER PATHOGENESIS IS A MULTISTEP PROGRESSION FROM CHRONIC GASTRITIS INDUCED BY HELICOBACTER PYLORI (H. PYLORI) TO GASTRIC ATROPHY, INTESTINAL METAPLASIA, DYSPLASIA AND ULTIMATELY GASTRIC CANCER. THE GENETIC AND MOLECULAR MECHANISMS UNDERLYING DISEASE PROGRESSION ARE STILL NOT COMPLETELY UNDERSTOOD AS ONLY A FRACTION OF COLONIZED INDIVIDUALS EVER DEVELOP NEOPLASIA SUGGESTING THAT BACTERIAL, HOST AND ENVIRONMENTAL FACTORS ARE INVOLVED. MICRORNAS ARE NONCODING RNAS THAT MAY INFLUENCE H. PYLORI-RELATED PATHOLOGY THROUGH THE REGULATION OF THE TRANSCRIPTION AND EXPRESSION OF VARIOUS GENES, PLAYING AN IMPORTANT ROLE IN INFLAMMATION, CELL PROLIFERATION, APOPTOSIS AND DIFFERENTIATION. INDEED, H. PYLORI HAVE BEEN SHOWN TO MODIFY MICRORNA EXPRESSION IN THE GASTRIC MUCOSA AND MICRORNAS ARE INVOLVED IN THE IMMUNE HOST RESPONSE TO THE BACTERIA AND IN THE REGULATION OF THE INFLAMMATORY RESPONSE. MICRORNAS HAVE A KEY ROLE IN THE REGULATION OF INFLAMMATORY PATHWAYS AND H. PYLORI MAY INFLUENCE INFLAMMATION-MEDIATED GASTRIC CARCINOGENESIS POSSIBLY THROUGH DNA METHYLATION AND EPIGENETIC SILENCING OF TUMOR SUPPRESSOR MICRORNAS. FURTHERMORE, MICRORNAS INFLUENCED BY H. PYLORI ALSO HAVE BEEN FOUND TO BE INVOLVED IN CELL CYCLE REGULATION, APOPTOSIS AND EPITHELIAL-MESENCHYMAL TRANSITION. ALTOGETHER, MICRORNAS SEEM TO HAVE AN IMPORTANT ROLE IN THE PROGRESSION FROM GASTRITIS TO PRENEOPLASTIC CONDITIONS AND NEOPLASTIC LESIONS AND SINCE EACH MICRORNA CAN CONTROL THE EXPRESSION OF HUNDREDS TO THOUSANDS OF GENES, KNOWLEDGE OF MICRORNAS TARGET GENES AND THEIR FUNCTIONS ARE OF PARAMOUNT IMPORTANCE. IN THIS ARTICLE WE PRESENT A COMPREHENSIVE REVIEW ABOUT THE ROLE OF MICRORNAS IN H. PYLORI GASTRIC CARCINOGENESIS, IDENTIFYING THE MICRORNAS DOWNREGULATED AND UPREGULATED IN THE INFECTION AND CLARIFYING THEIR BIOLOGICAL ROLE IN THE LINK BETWEEN IMMUNE HOST RESPONSE, INFLAMMATION, DNA METHYLATION AND GASTRIC CARCINOGENESIS. 2015 12 606 32 BEYOND GENETICS--THE EMERGING ROLE OF EPIGENETIC CHANGES IN HEMATOPOIETIC MALIGNANCIES. THE TERM EPIGENETIC REFERS TO A HERITABLE CHANGE IN GENE EXPRESSION THAT IS MEDIATED BY MECHANISMS OTHER THAN ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. DNA METHYLATION AT CYTOSINE BASES THAT ARE LOCATED 5' TO GUANOSINE WITHIN A CPG DINUCLEOTIDE IS THE MAIN EPIGENETIC MODIFICATION IN HUMANS. PATTERNS OF DNA METHYLATION ARE PROFOUNDLY DERANGED IN HUMAN CANCER AND COMPRISE GENOME-WIDE LOSSES AS WELL AS REGIONAL GAINS IN DNA METHYLATION. HYPERMETHYLATION OF CPG ISLANDS WITHIN GENE PROMOTER REGIONS IS ASSOCIATED WITH TRANSCRIPTIONAL INACTIVATION AND REPRESENTS, IN ADDITION TO GENETIC ABERRATIONS, AN IMPORTANT MECHANISM OF GENE SILENCING IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THIS EPIGENETIC PHENOMENON ACTS AS AN ALTERNATIVE TO MUTATIONS AND DELETIONS TO DISRUPT TUMOR SUPPRESSOR GENE FUNCTION. A LARGE NUMBER OF GENES INVOLVING FUNDAMENTAL CELLULAR PATHWAYS MAY BE AFFECTED IN VIRTUALLY ALL TYPES OF HUMAN CANCER BY ABERRANT CPG ISLAND METHYLATION IN ASSOCIATION WITH TRANSCRIPTIONAL SILENCING. ALTERED METHYLATION PATTERNS CAN BE USED AS BIOMARKERS FOR CANCER DETECTION, ASSESSMENT OF PROGNOSIS, AND PREDICTION OF RESPONSE TO ANTITUMOR TREATMENT. FURTHERMORE, CLINICAL TRIALS USING EPIGENETICALLY TARGETED THERAPIES HAVE YIELDED PROMISING RESULTS FOR ACUTE AND CHRONIC LEUKEMIAS AS WELL AS FOR MYELODYSPLASTIC SYNDROMES. THE EXPLORATION OF OUR GROWING KNOWLEDGE ABOUT EPIGENETIC ABERRATIONS MAY HELP DEVELOP NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES IN THE FUTURE. 2004 13 1562 29 DNA METHYLATION OF ENHANCER ELEMENTS IN MYELOID NEOPLASMS: THINK OUTSIDE THE PROMOTERS? GENE REGULATION THROUGH DNA METHYLATION IS A WELL DESCRIBED PHENOMENON THAT HAS A PROMINENT ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL CELL-STATES. THIS EPIGENETIC MODIFICATION IS USUALLY GROUPED IN REGIONS DENOMINATED CPG ISLANDS, WHICH FREQUENTLY CO-LOCALIZE WITH GENE PROMOTERS, SILENCING THE TRANSCRIPTION OF THOSE GENES. RECENT GENOME-WIDE DNA METHYLATION STUDIES HAVE CHALLENGED THIS PARADIGM, DEMONSTRATING THAT DNA METHYLATION OF REGULATORY REGIONS OUTSIDE PROMOTERS IS ABLE TO INFLUENCE CELL-TYPE SPECIFIC GENE EXPRESSION PROGRAMS UNDER PHYSIOLOGIC OR PATHOLOGIC CONDITIONS. COUPLING GENOME-WIDE DNA METHYLATION ASSAYS WITH HISTONE MARK ANNOTATION HAS ALLOWED FOR THE IDENTIFICATION OF SPECIFIC EPIGENOMIC CHANGES THAT AFFECT ENHANCER REGULATORY REGIONS, REVEALING AN ADDITIONAL LAYER OF COMPLEXITY TO THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN THIS REVIEW, WE SUMMARIZE THE NOVEL EVIDENCE FOR THE MOLECULAR AND BIOLOGICAL REGULATION OF DNA METHYLATION IN ENHANCER REGIONS AND THE DYNAMISM OF THESE CHANGES CONTRIBUTING TO THE FINE-TUNING OF GENE EXPRESSION. WE ALSO ANALYZE THE CONTRIBUTION OF ENHANCER DNA METHYLATION ON THE EXPRESSION OF RELEVANT GENES IN ACUTE MYELOID LEUKEMIA AND CHRONIC MYELOPROLIFERATIVE NEOPLASMS. THE CHARACTERIZATION OF THE ABERRANT ENHANCER DNA METHYLATION PROVIDES NOT ONLY A NOVEL PATHOGENIC MECHANISM FOR DIFFERENT TUMORS BUT ALSO HIGHLIGHTS NOVEL POTENTIAL THERAPEUTIC TARGETS FOR MYELOID DERIVED NEOPLASMS. 2019 14 2483 23 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 15 3659 32 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 16 4004 30 LOSS OF THE POLYCOMB MARK FROM BIVALENT PROMOTERS LEADS TO ACTIVATION OF CANCER-PROMOTING GENES IN COLORECTAL TUMORS. IN COLON TUMORS, THE TRANSCRIPTION OF MANY GENES BECOMES DEREGULATED BY POORLY DEFINED EPIGENETIC MECHANISMS THAT HAVE BEEN STUDIED MAINLY IN ESTABLISHED CELL LINES. IN THIS STUDY, WE USED FROZEN HUMAN COLON TISSUES TO ANALYZE PATTERNS OF HISTONE MODIFICATION AND DNA CYTOSINE METHYLATION IN CANCER AND MATCHED NORMAL MUCOSA SPECIMENS. DNA METHYLATION IS STRONGLY TARGETED TO BIVALENT H3K4ME3- AND H3K27ME3-ASSOCIATED PROMOTERS, WHICH LOSE BOTH HISTONE MARKS AND ACQUIRE DNA METHYLATION. HOWEVER, WE FOUND THAT LOSS OF THE POLYCOMB MARK H3K27ME3 FROM BIVALENT PROMOTERS WAS ACCOMPANIED OFTEN BY ACTIVATION OF GENES ASSOCIATED WITH CANCER PROGRESSION, INCLUDING NUMEROUS STEM CELL REGULATORS, ONCOGENES, AND PROLIFERATION-ASSOCIATED GENES. INDEED, WE FOUND MANY OF THESE SAME GENES WERE ALSO ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS WHERE CHRONIC INFLAMMATION PREDISPOSES THEM TO COLON CANCER. BASED ON OUR FINDINGS, WE PROPOSE THAT A LOSS OF POLYCOMB REPRESSION AT BIVALENT GENES COMBINED WITH AN ENSUING SELECTION FOR TUMOR-DRIVING EVENTS PLAYS A MAJOR ROLE IN CANCER PROGRESSION. 2014 17 3219 32 HELICOBACTER PYLORI AND GASTRIC CANCER. INFECTION WITH HELICOBACTER PYLORI IS ESTABLISHED AS THE MAJOR RISK FACTOR FOR GASTRIC CANCER DEVELOPMENT. DAMAGE OF THE MUCOSAL BARRIER DUE TO H. PYLORI-INDUCED INFLAMMATION ENHANCES THE CARCINOGENIC EFFECT OF OTHER RISK FACTORS SUCH AS SALT INTAKE OR TOBACCO SMOKING. THE GENETIC DISPOSITION OF BOTH THE BACTERIAL STRAIN AND THE HOST CAN INCREASE THE POTENTIAL TOWARDS GASTRIC CANCER FORMATION. GENETIC VARIANCE OF THE BACTERIAL PROTEINS CAGA AND VACA IS ASSOCIATED WITH A HIGHER GASTRIC CANCER RISK, AS ARE POLYMORPHISMS AND EPIGENETIC CHANGES IN HOST GENE CODING FOR INTERLEUKINS (IL1BETA, IL8), TRANSCRIPTION FACTORS (CDX2, RUNX3) AND DNA REPAIR ENZYMES. APPLICATION OF HIGH-THROUGHPUT ASSAYS FOR GENOME-WIDE ASSESSMENT OF EITHER GENETIC STRUCTURAL VARIANCE OR GENE EXPRESSION PATTERNS MAY LEAD TO A BETTER UNDERSTANDING OF THE PATHOBIOLOGICAL BACKGROUND OF THESE PROCESSES, INCLUDING THE UNDERLYING SIGNALING PATHWAYS. UNDERSTANDING OF THE STEPWISE ALTERATIONS THAT TAKE PLACE IN THE TRANSITION FROM CHRONIC ATROPHIC GASTRITIS, VIA METAPLASTIC CHANGES, TO INVASIVE NEOPLASIA IS VITAL TO DEFINE THE 'POINT OF NO RETURN' BEFORE WHICH ERADICATION OF H. PYLORI HAS THE POTENTIAL TO PREVENT GASTRIC CANCER. CURRENTLY, ERADICATION AS PREVENTIVE STRATEGY IS ONLY RECOMMENDED FOR HIGH-INCIDENCE REGIONS IN ASIA; LARGE POPULATION STUDIES WITH AN ADEQUATE FOLLOW-UP ARE REQUIRED TO DEMONSTRATE THE EFFECTIVENESS OF SUCH AN APPROACH IN WESTERN POPULATIONS. 2014 18 762 30 CAUSAL ROLE OF HELICOBACTER PYLORI INFECTION AND ERADICATION THERAPY IN GASTRIC CARCINOGENESIS. MANY EPIDEMIOLOGICAL REPORTS INDICATE THAT HELICOBACTER PYLORI (H PYLORI) INFECTION PLAYS AN IMPORTANT ROLE IN GASTRIC CARCINOGENESIS. SEVERAL GENETIC AND EPIGENETIC ALTERATIONS CONTRIBUTE TO THE INITIATION, PROMOTION, AND PROGRESSION OF THE CANCER CELLS IN A MULTI-STEP MANNER. H PYLORI IS KNOWN TO INDUCE CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA. ITS PRODUCTS, INCLUDING SUPEROXIDES, PARTICIPATE IN THE DNA DAMAGE FOLLOWED BY INITIATION, AND THE INFLAMMATION-DERIVED CYTOKINES AND GROWTH FACTORS CONTRIBUTE TO THE PROMOTION OF GASTRIC CARCINOGENESIS. BY ERADICATING H PYLORI, GASTRIC INFLAMMATION CAN BE CURED; THE THERAPY DIMINISHES THE LEVELS NOT ONLY OF INFLAMMATORY CELL INFILTRATION, BUT ALSO ATROPHY/INTESTINAL METAPLASIA IN PART. A RANDOMIZED CONTROLLED TRIAL REVEALED THAT THE ERADICATION THERAPY DIMINISHED THE GASTRIC CANCER PREVALENCE IN CASES WITHOUT PRE-CANCEROUS CONDITIONS. IN ADDITION, RECENT EPIDEMIOLOGICAL STUDIES FROM JAPANESE GROUPS DEMONSTRATED THAT THE DEVELOPMENT OF GASTRIC CANCER, ESPECIALLY OF THE INTESTINAL TYPE, WAS DECREASED BY SUCCESSFUL ERADICATION THERAPY, ALTHOUGH THESE WERE DESIGNED IN A NON-RANDOMIZED MANNER. HOWEVER, IT SHOULD BE MENTIONED THAT ENDOSCOPIC DETECTION IS THE ONLY WAY TO EVALUATE THE DEGREE OF GASTRIC CARCINOGENESIS. WE HAVE REPORTED THAT THE ENDOSCOPIC AND HISTOLOGICAL MORPHOLOGIES COULD BE MODIFIED BY ERADICATION THERAPY AND IT MIGHT CONTRIBUTE TO THE PREVALENCE OF GASTRIC CANCER DEVELOPMENT. CONSIDERING THE BIOLOGICAL NATURE OF CANCER CELL PROLIFERATION, IT IS CONSIDERED THAT A SUFFICIENTLY LONG-TERM FOLLOW-UP WOULD BE ESSENTIAL TO DISCUSS THE ANTICANCER EFFECT OF ERADICATION THERAPY. 2006 19 416 31 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION. 2019 20 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