1 778 116 CELL-FREE DNA METHYLATION: THE NEW FRONTIERS OF PANCREATIC CANCER BIOMARKERS' DISCOVERY. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS AMONG THE MOST LETHAL CANCER TYPES WORLD-WIDE. ITS HIGH MORTALITY IS RELATED TO THE DIFFICULTY IN THE DIAGNOSIS, WHICH OFTEN OCCURS WHEN THE DISEASE IS ALREADY ADVANCED. AS OF TODAY, NO EARLY DIAGNOSTIC TESTS ARE AVAILABLE, WHILE ONLY A LIMITED NUMBER OF PROGNOSTIC TESTS HAVE REACHED CLINICAL PRACTICE. THE MAIN REASON IS THE LACK OF RELIABLE BIOMARKERS THAT ARE ABLE TO CAPTURE THE EARLY DEVELOPMENT OR THE PROGRESSION OF THE DISEASE. HENCE, THE DISCOVERY OF BIOMARKERS FOR EARLY DIAGNOSIS OR PROGNOSIS OF PDAC REMAINS, DE FACTO, AN UNMET NEED. AN INCREASING NUMBER OF STUDIES HAS SHOWN THAT CELL-FREE DNA (CFDNA) METHYLATION ANALYSIS REPRESENTS A PROMISING NON-INVASIVE APPROACH FOR THE DISCOVERY OF BIOMARKERS WITH DIAGNOSTIC OR PROGNOSTIC POTENTIAL. IN PARTICULAR, CFDNA METHYLATION COULD BE UTILIZED FOR THE IDENTIFICATION OF DISEASE-SPECIFIC SIGNATURES IN PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS (CP), REPRESENTING A SENSITIVE AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PDAC. IN THIS REVIEW, WE WILL DISCUSS THE ADVANTAGES AND PITFALLS OF CFDNA METHYLATION STUDIES. FURTHER, WE WILL PRESENT THE CURRENT ADVANCES IN THE DISCOVERY OF PANCREATIC CANCER BIOMARKERS WITH EARLY DIAGNOSTIC OR PROGNOSTIC POTENTIAL, FOCUSING ON PANCREAS-SPECIFIC (E.G., CUX2 OR REG1A) OR ABNORMAL (E.G., ADAMTS1 OR BNC1) CFDNA METHYLATION SIGNATURES IN HIGH RISK PRE-NEOPLASTIC CONDITIONS AND PDAC. 2019 2 1280 61 DECIPHERING DNA METHYLATION SIGNATURES OF PANCREATIC CANCER AND PANCREATITIS. BACKGROUND: CHRONIC PANCREATITIS PRESENTS A HIGH RISK OF INFLAMMATION-RELATED PROGRESSION TO PANCREATIC CANCER. PANCREATIC CANCER IS THE FOURTH LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE HIGH MORTALITY RATE IS DIRECTLY RELATED TO THE DIFFICULTY IN PROMPTLY DIAGNOSING THE DISEASE, WHICH OFTEN PRESENTS AS OVERT AND ADVANCED. HENCE, EARLY DIAGNOSIS FOR PANCREATIC CANCER BECOMES CRUCIAL, PROPELLING RESEARCH INTO THE MOLECULAR AND EPIGENETIC LANDSCAPE OF THE DISEASE. MAIN BODY: RECENT STUDIES HAVE SHOWN THAT CELL-FREE DNA METHYLATION PROFILES FROM INFLAMMATORY DISEASES OR CANCER CAN VARY, THUS OPENING A NEW VENUE FOR THE DEVELOPMENT OF BIOMARKERS FOR EARLY DIAGNOSIS. IN PARTICULAR, CELL-FREE DNA METHYLATION COULD BE EMPLOYED IN THE IDENTIFICATION OF PRE-NEOPLASTIC SIGNATURES IN INDIVIDUALS WITH SUSPECTED PANCREATIC CONDITIONS, REPRESENTING A SPECIFIC AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PANCREATIC CANCER. IN THIS REVIEW, WE DESCRIBE THE MOLECULAR DETERMINANTS OF PANCREATIC CANCER AND HOW THESE ARE RELATED TO CHRONIC PANCREATITIS. WE WILL THEN PRESENT AN OVERVIEW OF DIFFERENTIAL METHYLATED GENES IN THE TWO CONDITIONS, HIGHLIGHTING THEIR DIAGNOSTIC OR PROGNOSTIC POTENTIAL. CONCLUSION: EXPLOITING THE RELATION BETWEEN ABNORMALLY METHYLATED CELL-FREE DNA AND PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS MAY BECOME A GAME-CHANGING APPROACH FOR THE DEVELOPMENT OF TOOLS FOR THE EARLY DIAGNOSIS OF PANCREATIC CANCER. 2019 3 4334 31 MICRORNAS: NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS FOR PANCREATIC DUCTAL ADENOCARCINOMA? PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS KNOWN FOR ITS VERY POOR OVERALL PROGNOSIS, MAKING TOOLS FOR EARLY DIAGNOSIS AND NEW THERAPEUTIC MODALITIES URGENTLY NEEDED. MICRORNAS (MIRNAS), ENDOGENOUS NONCODING RNA MOLECULES OF APPROXIMATELY 22 NT, HAVE GAINED ATTENTION AS AN EPIGENETIC COMPONENT INVOLVED IN THE DEVELOPMENT OF MANY CANCERS, INCLUDING PDAC. MIRNA EXPRESSION PROFILES OF VARYING PANCREATIC TISSUES HAVE IDENTIFIED A NUMBER OF DIFFERENTIALLY EXPRESSED MIRNAS AND SEEM TO BE ABLE TO DIFFERENTIATE BETWEEN THREE TISSUES OF CLINICAL IMPORTANCE: NORMAL PANCREAS, CHRONIC PANCREATITIS, AND PDAC. THIS ARTICLE GATHERS OUR CURRENT KNOWLEDGE OF DIFFERENTIALLY EXPRESSED MIRNAS IN PANCREATIC TISSUES WITH RELEVANCE TO PDAC AND PRESENTS POTENTIAL DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES. 2009 4 1435 44 DIFFERENTIAL METHYLATION LANDSCAPE OF PANCREATIC DUCTAL ADENOCARCINOMA AND ITS PRECANCEROUS LESIONS. BACKGROUND: PANCREATIC CANCER IS ONE OF THE MOST LETHAL DISEASES WITH AN INCIDENCE ALMOST EQUAL TO THE MORTALITY. IN ADDITION TO HAVING GENETIC CAUSES, CANCER CAN ALSO BE CONSIDERED AN EPIGENETIC DISEASE. DNA METHYLATION IS THE PREMIER EPIGENETIC MODIFICATION AND PATTERNS OF ABERRANT DNA METHYLATION ARE RECOGNIZED TO BE A COMMON HALLMARK OF HUMAN TUMOR. IN THE MULTISTAGE CARCINOGENESIS OF PANCREAS STARTING FROM PRECANCEROUS LESIONS TO PANCREATIC DUCTAL ADENOCARCINOMA (PDAC), THE EPIGENETIC CHANGES PLAY A SIGNIFICANT ROLE. DATA SOURCES: RELEVANT STUDIES FOR THIS REVIEW WERE DERIVED VIA AN EXTENSIVE LITERATURE SEARCH IN PUBMED VIA USING VARIOUS KEYWORDS SUCH AS PANCREATIC DUCTAL ADENOCARCINOMA, PRECANCEROUS LESIONS, METHYLATION PROFILE, EPIGENETIC BIOMARKERS THAT ARE RELEVANT DIRECTLY OR CLOSELY ASSOCIATED WITH THE CONCERNED AREA OF OUR INTEREST. THE LITERATURE SEARCH WAS INTENSIVELY DONE CONSIDERING A TIME FRAME OF 20 YEARS (1998-2018). RESULT: IN THIS REVIEW WE HAVE HIGHLIGHTED THE HYPERMETHYLATION AND HYPOMETHYLATION OF THE PRECANCEROUS PDAC LESIONS (PANCREATIC INTRA-EPITHELIAL NEOPLASIA, INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM, MUCINOUS CYSTIC NEOPLASM AND CHRONIC PANCREATITIS) AND PDAC ALONG WITH THE POTENTIAL BIOMARKERS. WE HAVE ALSO ACHIEVED THE EARLY EPIGENETIC DRIVER THAT LEADS TO PROGRESSION FROM PRECANCEROUS LESIONS TO PDAC. A BUNCH OF EPIGENETIC DRIVER GENES LEADS TO PROGRESSION OF PRECANCEROUS LESIONS TO PDAC (PPENK, APC, P14/5/16/17, HMLH1 AND MGMT) ARE ALSO DOCUMENTED. WE SUMMARIZED THE IMPORTANCE OF THESE OBSERVATIONS IN THERAPEUTICS AND DIAGNOSIS OF PDAC HENCE IDENTIFYING THE POTENTIAL USE OF EPIGENETIC BIOMARKERS IN EPIGENETIC TARGETED THERAPY. EPIGENETIC INACTIVATION OCCURS BY HYPERMETHYLATION OF CPG ISLANDS IN THE PROMOTER REGIONS OF TUMOR SUPPRESSOR GENES. WE LISTED ALL HYPER- AND HYPOMETHYLATION OF CPG ISLANDS OF SEVERAL GENES IN PDAC INCLUDING ITS PRECANCEROUS LESIONS. CONCLUSIONS: THE CONCEPT OF THE REVIEW WOULD HELP TO UNDERSTAND THEIR BIOLOGICAL EFFECTS, AND TO DETERMINE WHETHER THEY MAY BE SUCCESSFULLY COMBINED WITH OTHER EPIGENETIC DRUGS. HOWEVER, WE NEED TO CONTINUE OUR RESEARCH TO DEVELOP MORE SPECIFIC DNA-DEMETHYLATING AGENTS, WHICH ARE THE TARGETS FOR HYPERMETHYLATED CPG METHYLATION SITES. 2020 5 3925 35 LIQUID BIOPSIES BASED ON DNA METHYLATION AS BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG CANCER. LUNG CANCER (LC) IS THE MAIN CAUSE OF CANCER-RELATED MORTALITY. MOST LC PATIENTS ARE DIAGNOSED IN AN ADVANCED STAGE WHEN THE SYMPTOMS ARE OBVIOUS, AND THE PROGNOSIS IS QUITE POOR. ALTHOUGH LOW-DOSE COMPUTED TOMOGRAPHY (LDCT) IS A ROUTINE CLINICAL EXAMINATION FOR EARLY DETECTION OF LC, THE FALSE-POSITIVE RATE IS OVER 90%. AS ONE OF THE INTENSELY STUDIED EPIGENETIC MODIFICATIONS, DNA METHYLATION PLAYS A KEY ROLE IN VARIOUS DISEASES, INCLUDING CANCER AND OTHER DISEASES. HYPERMETHYLATION IN TUMOR SUPPRESSOR GENES OR HYPOMETHYLATION IN ONCOGENES IS AN IMPORTANT EVENT IN TUMORIGENESIS. REMARKABLY, DNA METHYLATION USUALLY OCCURS IN THE VERY EARLY STAGE OF MALIGNANT TUMORS. THUS, DNA METHYLATION ANALYSIS MAY PROVIDE SOME USEFUL INFORMATION ABOUT THE EARLY DETECTION OF LC. IN RECENT YEARS, LIQUID BIOPSY HAS DEVELOPED RAPIDLY. LIQUID BIOPSY CAN DETECT AND MONITOR BOTH PRIMARY AND METASTATIC MALIGNANT TUMORS AND CAN REFLECT TUMOR HETEROGENEITY. MOREOVER, IT IS A MINIMALLY INVASIVE PROCEDURE, AND IT CAUSES LESS PAIN FOR PATIENTS. THIS REVIEW SUMMARIZED VARIOUS LIQUID BIOPSIES BASED ON DNA METHYLATION FOR LC. AT FIRST, WE BRIEFLY DISCUSSED SOME EMERGING TECHNOLOGIES FOR DNA METHYLATION ANALYSIS. SUBSEQUENTLY, WE OUTLINED CELL-FREE DNA (CFDNA), SPUTUM, BRONCHOALVEOLAR LAVAGE FLUID, BRONCHIAL ASPIRATES, AND BRONCHIAL WASHINGS DNA METHYLATION-BASED LIQUID BIOPSY FOR THE EARLY DETECTION OF LC. FINALLY, THE PROGNOSTIC VALUE OF DNA METHYLATION IN CFDNA AND SPUTUM AND THE DIAGNOSTIC VALUE OF OTHER DNA METHYLATION-BASED LIQUID BIOPSIES FOR LC WERE ALSO ANALYZED. 2022 6 777 28 CELL-FREE CIRCULATING EPIGENOMIC SIGNATURES: NON-INVASIVE BIOMARKER FOR CARDIOVASCULAR AND OTHER AGE-RELATED CHRONIC DISEASES. THE BURDEN OF CARDIO-VASCULAR AND OTHER AGE-RELATED NON-COMMUNICABLE DISEASES ARE RAPIDLY INCREASING WORLDWIDE. MAJORITY OF THESE CHRONIC AILMENTS ARE CURABLE, IF DIAGNOSED AT EARLY STAGES. CANDIDATE BIOMARKERS OF EARLY DETECTION ARE THEREFORE ESSENTIAL FOR IDENTIFICATION OF HIGH-RISK INDIVIDUALS, PROMPT AND ACCURATE DISEASE DIAGNOSIS, AND TO MONITOR THERAPEUTIC RESPONSE. THE FUNCTIONAL SIGNIFICANCE OF CIRCULATING NUCLEIC ACIDS THAT RECAPITULATE SPECIFIC DISEASE PROFILES IS NOW WELL ESTABLISHED. BUT SUBTLE CHANGES IN DNA SEQUENCE MAY NOT SOLELY REFLECT THE DIFFERENTIATION OF GENE EXPRESSION PATTERNS OBSERVED IN DIVERSE SET OF DISEASES AS EPIGENETIC PHENOMENA PLAY A LARGER ROLE IN AETIOLOGY AND PATHO-PHYSIOLOGY. UNLIKE GENETIC MARKERS, KNOWLEDGE ABOUT THE DIAGNOSTIC UTILITY OF CIRCULATING EPIGENETIC SIGNATURES: METHYLATED DNA; MICRO RNA AND MODIFIED HISTONES ARE DEFICIENT. CHARACTERIZATION OF THESE NOVEL ENTITIES THROUGH OMICS-BASED MOLECULAR TECHNOLOGIES MIGHT PROMPT DEVELOPMENT OF A RANGE OF LABORATORY-BASED STRATEGIES, THEREBY ACCELERATING THEIR BROADER TRANSLATIONAL PURPOSE FOR EARLY DISEASE DIAGNOSIS, MONITORING THERAPEUTIC RESPONSE AND DRUG RESISTANCE. HOWEVER, LARGEST OPPORTUNITY FOR INNOVATION LIES IN DEVELOPING POINT-OF-CARE TESTS WITH ACCURATE DIAGNOSTIC AND HIGHER PROGNOSTIC SCORE THAT IS APPLICABLE FOR SCREENING OF HIGH-RISK POPULATIONS. 2017 7 4733 29 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 8 4316 37 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 9 4429 37 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 10 4531 34 MULTILAYER-OMICS ANALYSES OF HUMAN CANCERS: EXPLORATION OF BIOMARKERS AND DRUG TARGETS BASED ON THE ACTIVITIES OF THE INTERNATIONAL HUMAN EPIGENOME CONSORTIUM. EPIGENETIC ALTERATIONS CONSISTING MAINLY OF DNA METHYLATION ALTERATIONS AND HISTONE MODIFICATION ALTERATIONS ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, 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 FREQUENTLY ASSOCIATED WITH TUMOR AGGRESSIVENESS AND POOR PATIENT OUTCOME. RECENTLY, EPIGENOME ALTERATIONS HAVE BEEN ATTRACTING A GREAT DEAL OF ATTENTION FROM RESEARCHERS WHO ARE FOCUSING ON NOT ONLY CANCERS BUT ALSO NEURONAL, IMMUNE AND METABOLIC DISORDERS. IN ORDER TO ACCURATELY IDENTIFY DISEASE-SPECIFIC EPIGENOME PROFILES THAT COULD BE POTENTIALLY APPLICABLE FOR DISEASE PREVENTION, DIAGNOSIS AND THERAPY, STRICT COMPARISON WITH STANDARD EPIGENOME PROFILES OF NORMAL TISSUES IS INDISPENSABLE. HOWEVER, EPIGENOME MECHANISMS SHOW HETEROGENEITY AMONG TISSUES AND CELL LINEAGES. THEREFORE, IT IS NOT EASY TO OBTAIN A COMPREHENSIVE PICTURE OF STANDARD EPIGENOME PROFILES OF NORMAL TISSUES. IN 2010, THE INTERNATIONAL HUMAN EPIGENOME CONSORTIUM (IHEC) WAS ESTABLISHED TO COORDINATE THE PRODUCTION OF REFERENCE MAPS OF HUMAN EPIGENOMES FOR KEY CELLULAR STATES. IN ORDER TO GAIN SUBSTANTIAL COVERAGE OF THE HUMAN EPIGENOME, THE IHEC HAS SET AN AMBITIOUS GOAL TO DECIPHER AT LEAST 1000 EPIGENOMES WITHIN THE NEXT 7-10 YEARS. WE CONSIDER THAT PATHWAY ANALYSIS USING GENES SHOWING MULTILAYER-OMICS ABNORMALITIES, INCLUDING GENOME, EPIGENOME, TRANSCRIPTOME, PROTEOME AND METABOLOME ABNORMALITIES, MAY BE USEFUL FOR ELUCIDATING THE MOLECULAR BACKGROUND OF PATHOGENESIS AND FOR EXPLORING POSSIBLE THERAPEUTIC TARGETS FOR EACH DISEASE. 2014 11 4918 35 PANCREATIC CANCER: FROM BENCH TO 5-YEAR SURVIVAL. PANCREATIC DUCTAL ADENOCARCINOMA IS ONE OF THE MOST AGGRESSIVE HUMAN MALIGNANCIES, WITH AN OVERALL 5-YEAR SURVIVAL RATE OF LESS THAN 4%. ON THE MOLECULAR LEVEL, AN INCREASING NUMBER OF GENETIC AND EPIGENETIC ALTERATIONS HAVE BEEN DISCOVERED, WITH A PARTICULAR FOCUS ON GROWTH FACTORS AND RELATED PATHWAYS. SMALL-MOLECULE TYROSINE KINASE INHIBITORS, ANTIBODIES, AND OTHER APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS TO TARGET THESE SIGNAL TRANSDUCTION PATHWAYS, AND FIRST CLINICAL TRIALS SHOW ENCOURAGING RESULTS. IN ADDITION, MOLECULAR ALTERATIONS HAVE BEEN IDENTIFIED THAT ENABLE THE CANCER CELLS TO INVADE THE PERINEURIUM AND THE RETROPERITONEAL SPACE, THUS EXPLAINING AT LEAST IN PART THE HIGH RATE OF LOCAL RECURRENCE AND THE SEVERE PAIN SYNDROME. TECHNICALLY, PANCREATIC SURGERY HAS ADVANCED, WITH ACCEPTABLE MORBIDITY AND MORTALITY RATES IN HIGH-VOLUME CENTERS. RANDOMIZED CONTROLLED TRIALS ARE INCREASINGLY CARRIED OUT TO DEFINE THE BEST PALLIATIVE AND ADJUVANT THERAPY FOR THIS DISEASE. TRANSLATIONAL RESEARCH COMBINED WITH CLINICAL TRIALS WILL HOPEFULLY LEAD TO IMPROVED SURVIVAL AND BETTER QUALITY OF LIFE FOR PANCREATIC CANCER PATIENTS IN THE FUTURE. 2006 12 5770 34 SPECIFIC MOLECULAR SIGNATURES OF NON-TUMOR LIVER TISSUE MAY PREDICT A RISK OF HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON HUMAN CANCERS AND A MAJOR CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE BLEAK OUTCOMES OF HCC PATIENTS EVEN AFTER CURATIVE TREATMENT HAVE BEEN, AT LEAST PARTIALLY, ATTRIBUTED TO ITS MULTICENTRIC ORIGIN. THEREFORE, IT IS NECESSARY TO EXAMINE NOT ONLY TUMOR TISSUE BUT ALSO NON-TUMOR LIVER TISSUE TO INVESTIGATE THE MOLECULAR MECHANISMS OPERATING DURING HEPATOCARCINOGENESIS BASED ON THE CONCEPT OF "FIELD CANCERIZATION". SEVERAL STUDIES PREVIOUSLY INVESTIGATED THE ASSOCIATION OF MOLECULAR ALTERATIONS IN NON-TUMOR LIVER TISSUE WITH CLINICAL FEATURES AND PROGNOSIS IN HCC PATIENTS ON A GENOME-WIDE SCALE. IN PARTICULAR, SPECIFIC ALTERATIONS OF DNA METHYLATION PROFILES HAVE BEEN CONFIRMED IN NON-TUMOR LIVER TISSUE. THIS REVIEW FOCUSES ON THE POSSIBLE CLINICAL VALUE OF ARRAY-BASED COMPREHENSIVE ANALYSES OF MOLECULAR ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IN NON-TUMOR LIVER TISSUE TO CLARIFY THE RISK OF HEPATOCARCINOGENESIS. CARCINOGENETIC RISK ESTIMATION BASED ON SPECIFIC METHYLATION SIGNATURES MAY BE ADVANTAGEOUS FOR CLOSE FOLLOW-UP OF PATIENTS WHO ARE AT HIGH RISK OF HCC DEVELOPMENT. FURTHERMORE, EPIGENETIC THERAPIES FOR PATIENTS WITH CHRONIC LIVER DISEASES MAY BE HELPFUL TO REDUCE THE RISK OF HCC DEVELOPMENT BECAUSE EPIGENETIC ALTERATIONS ARE POTENTIALLY REVERSIBLE, AND THUS PROVIDE PROMISING MOLECULAR TARGETS FOR THERAPEUTIC INTERVENTION. 2014 13 6013 30 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 14 4859 30 ORAL SQUAMOUS CELL CARCINOMA: DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS. OSCC IS THE MOST FREQUENT MALIGNANT TUMOUR OF THE ORAL CAVITY, ACCOUNTING FOR MORE THAN 90% OF MALIGNANT TUMOURS OF THIS ANATOMIC REGION AND IT OFTEN ARISES FROM PRECURSOR LESIONS. ASIDE FROM TOBACCO AND ALCOHOL CONSUMPTION, FURTHER DETERMINANTS HAVE BEEN CONSIDERED TO INCREASE THE RISK OF OSCC DEVELOPMENT, SUCH AS MICRONUTRIENT DEFICIENCIES, CHRONIC TRAUMATISM, POOR ORAL HYGIENE AND VIRUSES. RECURRENCE, SURVIVAL AND CONVERSELY, MORTALITY DEPENDS ON NUMEROUS AND DIFFERENT BIOLOGICAL, HISTOLOGICAL, MACROSCOPIC AND MICROSCOPIC FACTORS THAT HAVE BEEN INVESTIGATED IN ORDER TO DEFINE CAUSES, TO HELP DIAGNOSIS AND TO REFINE APPROPRIATE TREATMENTS THAT PERFECTLY FIT WITH THE DIFFERENT FEATURES OF OSCCS. FOR THIS PURPOSE, DURING THE LAST DECADES, THE IMPROVEMENT OF SCIENTIFIC TECHNOLOGIES AND MOLECULAR ANALYSES HAVE ALLOWED TO INVESTIGATE MARKERS AND GENETIC AND EPIGENETIC FACTORS, IN ORDER TO CLARIFY THEIR RESPONSIBILITIES RELATED TO EARLY DIAGNOSIS AND OSCC PROGRESSION AND PROGNOSIS IN ORDER TO ADDRESS THEM AS TARGETS IN FUTURE SELECTIVE AND INDIVIDUALLY-SHAPED THERAPIES. THIS REVIEW WILL FOCUS ON THE ETIOLOGY, ADVANCES IN DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS FOR ORAL CANCERS. 2016 15 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 16 5622 29 SEARCH FOR USEFUL BIOMARKERS IN HEPATOCELLULAR CARCINOMA, TUMOR FACTORS AND BACKGROUND LIVER FACTORS (REVIEW). HEPATOCARCINOGENESIS IS A COMPLEX AND MULTISTEP PROCESS THAT INVOLVES THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES. TO UNDERSTAND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CURRENT RESEARCH HAS UTILIZED IMPROVED ARRAY TECHNOLOGIES. THE IDENTIFICATION OF CANCER-RELATED MOLECULES COULD LEAD TO THE DEVELOPMENT OF NOVEL MOLECULAR TARGETS FOR TREATMENT AND BIOMARKERS FOR PREDICTING PROGNOSIS. HOWEVER, PROGNOSTIC PREDICTION IS INSUFFICIENT WHEN CONSIDERING ONLY TUMOR FACTORS, SINCE HEPATOCARCINOGENESIS IS ALSO GREATLY INFLUENCED BY THE STATUS OF THE BACKGROUND LIVER. CLINICAL BACKGROUND LIVER FACTORS, SUCH AS THE PRESENCE OF CHRONIC ACTIVE HEPATITIS OR CIRRHOSIS, ARE WELL KNOWN AS RISK FACTORS FOR DEVELOPING HCC. IN CONTRAST, GENETIC OR EPIGENETIC BACKGROUND LIVER FACTORS REMAIN UNKNOWN, ALBEIT THOSE ARE IMPORTANT TO UNDERSTAND THE DEVELOPING PROCESS OF HCC. INVESTIGATING BACKGROUND LIVER FACTORS COULD CONTRIBUTE TO THE DEVELOPMENT OF CARCINOGENIC MARKERS OF HCC AND TO THE PREVENTION OF THE DEVELOPMENT OF HCC. IN THE PRESENT STUDY, WE REVIEW THE CURRENTLY IDENTIFIED TUMOR FACTORS AND BACKGROUND LIVER FACTORS FROM A MOLECULAR BIOLOGICAL VIEWPOINT AND ALSO INTRODUCE OUR COMBINATION ARRAY ANALYSIS. 2017 17 1522 42 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 18 1958 33 EPIGENETIC AGING AND COLORECTAL CANCER: STATE OF THE ART AND PERSPECTIVES FOR FUTURE RESEARCH. ALTHOUGH TRANSLATIONAL RESEARCH HAS IDENTIFIED A LARGE NUMBER OF POTENTIAL BIOMARKERS INVOLVED IN COLORECTAL CANCER (CRC) CARCINOGENESIS, A BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS ASSOCIATED WITH BIOLOGICAL AGING IN COLORECTAL CELLS AND TISSUES IS NEEDED. HERE, WE AIM TO SUMMARIZE THE STATE OF THE ART ABOUT THE ROLE OF AGE ACCELERATION, DEFINED AS THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IN THE DEVELOPMENT AND PROGRESSION OF CRC. SOME STUDIES HAVE SHOWN THAT ACCELERATED BIOLOGICAL AGING IS POSITIVELY ASSOCIATED WITH THE RISK OF CANCER AND DEATH IN GENERAL. IN LINE WITH THESE FINDINGS, OTHER STUDIES HAVE SHOWN HOW THE ASSESSMENT OF EPIGENETIC AGE IN PEOPLE AT RISK FOR CRC COULD BE HELPFUL FOR MONITORING THE MOLECULAR RESPONSE TO PREVENTIVE INTERVENTIONS. MOREOVER, IT WOULD BE INTERESTING TO INVESTIGATE WHETHER ABERRANT EPIGENETIC AGING COULD HELP IDENTIFY CRC PATIENTS WITH A HIGH RISK OF RECURRENCE AND A WORST PROGNOSIS, AS WELL AS THOSE WHO RESPOND POORLY TO TREATMENT. YET, THE APPLICATION OF THIS NOVEL CONCEPT IS STILL IN ITS INFANCY, AND FURTHER RESEARCH SHOULD BE ENCOURAGED IN ANTICIPATION OF FUTURE APPLICATIONS IN CLINICAL PRACTICE. 2020 19 5787 37 SPUTUM ANALYSIS: NON-INVASIVE EARLY LUNG CANCER DETECTION. LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED DEATHS OVER THE WORLD, CHARACTERIZED BY A VERY HIGH MORTALITY RATE. MOLECULAR TECHNIQUE DEVELOPMENT TRIES TO FOCUS ON EARLY DETECTION OF CANCERS BY STUDYING MOLECULAR ALTERATIONS THAT CHARACTERIZE CANCER CELLS. WORLDWIDE LUNG CANCER RESEARCH HAS FOCUSED ON AN EVER-INCREASING NUMBER OF MOLECULAR ELEMENTS OF CARCINOGENESIS AT GENETIC, EPIGENETIC AND PROTEIN LEVELS. THE NON-INVASIVENESS IS THE CHARACTERISTIC THAT ALL CLINICAL TRIALS ON CANCER DETECTION SHOULD HAVE. ABNORMAL CHEST IMAGING AND/OR NON-SPECIFIC SYMPTOMS ARE INITIAL SIGNALS OF LUNG CANCER THAT APPEAR IN AN ADVANCED STAGE OF DISEASE. THIS FACT REPRESENTS THE CAUSE OF THE LOW 5-YEAR SURVIVAL RATE: OVER 90% OF PATIENTS DYING WITHIN 5 YEARS OF DIAGNOSIS. SINCE SMOKERS HAVE HIGHER QUANTITY OF SPUTUM CONTAINING EXFOLIATED CELLS FROM THE BRONCHIAL TREE, AND THE SPUTUM REPRESENTS THE MOST EASILY ACCESSIBLE BIOLOGICAL FLUID AND ITS COLLECTION IS NON-INVASIVE, ANALYSIS OF THIS SAMPLE REPRESENTS A GOOD AREA OF RESEARCH IN EARLY LUNG CANCER DIAGNOSIS. CONTINUED CIGARETTE SMOKING IS THE CAUSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), WITH AN ESTIMATED ATTRIBUTABLE RISK FACTOR EXCEEDING 80% IN SMOKING AFFECTED INDIVIDUALS. LUNG CANCER IS FOUND IN 40-70% OF PATIENTS WITH COPD, PARTICULARLY IN SEVERE DISEASE, AND IT IS A COMMON CAUSE OF DEATH IN THESE PATIENTS. A LARGE PROSPECTIVE TRIAL OF ALMOST HALF A MILLION NON-SMOKERS SHOWED AS LUNG CANCER IS ALSO COMMON IN PATIENTS WITH COPD WHO HAVE NEVER SMOKED. THIS REVIEW DESCRIBES ISSUES RELATED TO EARLY LUNG CANCER SCREENING USING NON-INVASIVE METHODS. 2013 20 6653 24 UPDATE ON PANCREATIC CANCER AND ALCOHOL-ASSOCIATED RISK. DUCTAL ADENOCARCINOMA OF THE PANCREAS IS CHARACTERIZED BY EXTREMELY AGGRESSIVE BEHAVIOR, WITH AN OVERALL 5-YEAR SURVIVAL OF <4%. BECAUSE CONVENTIONAL AND SPECIFICALLY TAILORED THERAPEUTIC REGIMENS HAVE LITTLE IMPACT ON PATIENT SURVIVAL, EPIDEMIOLOGICAL AND MOLECULAR RESEARCH AIMS AT IDENTIFYING AND REDUCING RISK FACTORS. CIGARETTE SMOKING, OBESITY, DIABETES MELLITUS, AND CHRONIC PANCREATITIS ARE AMENABLE TO MEDICAL PREVENTION OR THERAPY. HEAVY ALCOHOL CONSUMPTION IS AN INCONSISTENT SINGLE RISK FACTOR FOR PANCREATIC CANCER BUT MAY PROMOTE CARCINOGENESIS BY INCREASING THE RISK OF DIABETES MELLITUS OR CHRONIC PANCREATITIS. FOR VARIOUS AGENTS, THE KEY CARCINOGENIC EFFECT IS PROBABLY AN INFLAMMATORY RESPONSE IN THE PANCREATIC TISSUE. ON THE MOLECULAR LEVEL, MUTATIONS OF ONCOGENES AND TUMOR SUPPRESSOR GENES, AS WELL AS VARIOUS EPIGENETIC ALTERATIONS, SUCH AS OVEREXPRESSION OF GROWTH FACTORS AND THEIR RECEPTORS, ARE IMPORTANT IN TUMORIGENESIS. COMPLETE AND SAFE SURGICAL RESECTION, TOGETHER WITH ADJUVANT THERAPY, OFFERS PROLONGED SURVIVAL, WITH 5-YEAR SURVIVAL RATES OF APPROXIMATELY 25%. HOWEVER, FOR UNRESECTABLE OR DISSEMINATED DISEASE, WHICH CONSTITUTES THE VAST MAJORITY OF CASES, TREATMENT IS PALLIATIVE. DESPITE INCREASING KNOWLEDGE ABOUT THE MOLECULAR PATHOLOGY OF PANCREATIC CANCER AND DESPITE ADVANCES IN TREATMENT, THE OVERALL COURSE OF THE DISEASE IS DISMAL, AND REINFORCED EFFORTS TO REDUCE INCIDENCE AND IMPROVE OUTCOME ARE NEEDED DESPERATELY. 2006