1 3897 145 LARGE-SCALE ANALYSIS OF THE GENETIC AND EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA FROM SOUTHEAST CHINA. OUR KNOWLEDGE ABOUT MOLECULAR ALTERATIONS DURING HEPATOCARCINOGENESIS IS STILL FRAGMENTARY, DUE TO LACK OF COMPREHENSIVE GENETIC AND EPIGENETIC ANALYSES IN THE SAME SET OF HEPATOCELLULAR CARCINOMAS (HCCS). IN THIS STUDY, WE CONDUCTED A LARGE-SCALE ANALYSIS, INCLUDING MUTATION SCREENING IN 50 GENES AND METHYLATION ASSAYS IN THREE GENES IN 54 PAIRS OF HCCS AND THEIR NEIGHBORING NON-CANCEROUS TISSUES. ALL SAMPLES WERE COLLECTED FROM THE RESIDENTS IN SOUTHEAST CHINA. WE FOUND HBV INFECTION AND CHRONIC HEPATITIS/CIRRHOSIS IN 83.3% AND 98.1% OF THE CASES, RESPECTIVELY. MUTATIONS WERE IDENTIFIED IN 18 OUT OF 54 (33.3%) SAMPLES, WITH P53 ALTERATIONS IN 14 CASES AND BETA-CATENIN MUTATIONS IN FOUR TUMORS. NO MUTATIONS WERE IDENTIFIED IN THE NEIGHBORING TISSUES. INTERESTINGLY, 9 OUT OF 14 (64.3%) TUMORS CARRYING P53 MUTATIONS DISPLAYED SUBSTITUTION OF SERINE BY ARGININE AT CODON 249, A CHARACTERISTIC CHANGE BELIEVED TO BE INDUCED BY AFLATOXIN-B1. FURTHERMORE, P53 MUTATION WAS SIGNIFICANTLY ASSOCIATED WITH SHORTER RECURRENCE-FREE SURVIVAL (P=0.004). THE RESULTS ALSO REVEALED ABERRANT METHYLATION IN TWO OR MORE GENES IN AS HIGH AS 90% OF TUMORS AND 40% OF ADJACENT TISSUES. THE FREQUENCY OF RASSF1A HYPERMETHYLATION WAS MUCH HIGHER THAN THAT OF P16INK4A AND HAI2 IN BOTH HCC AND NEIGHBORING TISSUES, INDICATING THAT DEREGULATION OF RASSF1A MAY PRECEDE THE OTHER TWO GENES. THESE DATA SUGGEST THAT ABERRANT METHYLATION OCCURS BEFORE MUTATION AND IS AN EARLY EVENT IN THE DEVELOPMENT OF THIS SET OF HCC. OUR FINDINGS HIGHLIGHT P53 AS A PROGNOSTIC FACTOR OF HCC AND RASSF1A AS A POTENTIAL TARGET IN PREVENTING MALIGNANT TRANSFORMATION OF HEPATOCYTES. 2008 2 1582 34 DNA METHYLATION PROFILES IN PRECANCEROUS TISSUE AND CANCERS: CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION BASED ON DNA METHYLATION STATUS. ALTERATIONS IN DNA METHYLATION, WHICH ARE ASSOCIATED WITH DNA METHYLTRANSFERASE ABNORMALITIES AND RESULT IN SILENCING OF TUMOR-RELATED GENES AND CHROMOSOMAL INSTABILITY, ARE INVOLVED EVEN IN PRECANCEROUS CHANGES IN VARIOUS ORGANS. DNA METHYLATION ALTERATIONS ALSO ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. THEREFORE, WE HAVE ANALYZED DNA METHYLATION ON A GENOME-WIDE SCALE IN CLINICAL TISSUE SAMPLES. OUR APPROACH USING THE BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION METHOD HAS REVEALED THAT DNA METHYLATION ALTERATIONS CORRELATED WITH THE FUTURE DEVELOPMENT OF MORE MALIGNANT CANCERS ARE ALREADY ACCUMULATED AT THE PRECANCEROUS STAGE IN THE KIDNEY, LIVER AND URINARY TRACT. DNA METHYLATION PROFILES AT PRECANCEROUS STAGES ARE BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. SUCH DNA METHYLATION ALTERATIONS MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. ON THE BASIS OF BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION DATA, INDICATORS FOR CARCINOGENETIC RISK ESTIMATION HAVE BEEN ESTABLISHED USING LIVER TISSUE SPECIMENS FROM PATIENTS WITH HEPATITIS VIRUS INFECTION, CHRONIC HEPATITIS AND LIVER CIRRHOSIS OR HISTOLOGICALLY NORMAL UROTHELIA, AND FOR PROGNOSTICATION USING BIOPSY OR SURGICALLY RESECTED SPECIMENS FROM PATIENTS WITH RENAL CELL CARCINOMA, HEPATOCELLULAR CARCINOMA AND UROTHELIAL CARCINOMA. SUCH GENOME-WIDE DNA METHYLATION PROFILING HAS NOW FIRMLY ESTABLISHED THE CLINICAL RELEVANCE OF TRANSLATIONAL EPIGENETICS. 2010 3 5960 44 TELOMERE LENGTH IN HEPATOCELLULAR CARCINOMA AND PAIRED ADJACENT NON-TUMOR TISSUES BY QUANTITATIVE PCR. TELOMERE SHORTENING LIMITS THE PROLIFERATIVE CAPACITY OF HUMAN CELLS, RESTRAINS THE REGENERATIVE CAPACITY OF ORGAN SYSTEMS DURING CHRONIC DISEASES AND AGING AND ALSO INDUCES CHROMOSOMAL INSTABILITY AS WELL AS INITIATION OF CANCER. PREVIOUS STUDIES DEMONSTRATED THAT TELOMERES ARE OFTEN SIGNIFICANTLY SHORTER IN TUMOR TISSUE, INCLUDING HEPATOCELLULAR CARCINOMA (HCC), COMPARED TO THE SURROUNDING TISSUE, BUT TELOMERE LENGTH IN HCC TISSUES WAS NOT CORRELATED WITH SEVERAL CLINICAL PARAMETERS, SUCH AS AGE, SEX, HBV OR HCV INFECTIONS AND TUMOR SIZE. IN THE PRESENT STUDY, THE TELOMERE LENGTH RATIO OF 36 PAIRED HCC, AND THEIR ADJACENT NON-TUMOR TISSUES WAS MEASURED BY QUANTITATIVE PCR (Q-PCR). THE MEAN TELOMERE LENGTHS (SD) FOR HCC AND ADJACENT NON-TUMOR TISSUES WERE 0.26 (0.10) AND 0.47 (0.20) RESPECTIVELY (T = 6.22, P < 0.0001). THERE WAS A LARGE DIFFERENCE IN THE DISTRIBUTION OF SUBJECTS BASED ON TELOMERE LENGTH IN TUMOR AND ADJACENT NON-TUMOR TISSUES. THE NUMBER OF TUMORS WITH TELOMERE LENGTH SHORTER THAN 0.50 WAS MUCH HIGHER THAN THAT OF ADJACENT NON-TUMOR TISSUES; MORE THAN 90% OF THE TISSUES WITH TELOMERE LENGTH > OR = 0.50 WERE ADJACENT NON-TUMOR TISSUES. THE CORRELATIONS BETWEEN TELOMERE LENGTH AND AFLATOXIN B1- AND POLYCYCLIC AROMATIC HYDROCARBON-DNA ADDUCTS LEVEL, P53 MUTATIONS AND P16 HYPERMETHYLATION STATUS WERE ALSO TESTED, BUT NO SIGNIFICANT ASSOCIATIONS WERE FOUND. THE RELATIONSHIP BETWEEN TELOMERE LENGTH SHORTENING, CHEMICAL CARCINOGEN EXPOSURE, AND GENETIC AND EPIGENETIC CHANGES IN HEPATOCARCINOGENESIS NEEDS FURTHER INVESTIGATION. 2007 4 1544 25 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 5 4903 31 P16 PROMOTER HYPERMETHYLATION IN HUMAN HEPATOCELLULAR CARCINOMA WITH OR WITHOUT HEPATITIS VIRUS INFECTION. BACKGROUND: EPIGENETIC ALTERATION THROUGH METHYLATION IS ONE OF THE MOST IMPORTANT STEPS IN CARCINOGENESIS. HOWEVER, THE RELATION BETWEEN HEPATITIS VIRUS INFECTION AND EPIGENETIC ALTERATIONS IS POORLY UNDERSTOOD. METHODS: SIXTEEN PATIENTS WITHOUT HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) AND 35 PATIENTS WITH HBV OR HCV WHO UNDERWENT LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA (HCC) WERE STUDIED. MUTATION OF P53 WAS DETECTED BY DIRECT SEQUENCING. METHYLATION STATUS OF P16 WAS EVALUATED IN TUMOR AND NONCANCEROUS LIVER TISSUES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: IN HCC WITHOUT HBV AND HCV, P53 MUTATIONS WERE DETECTED IN 5 (31%) OF 16 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (25%) OF 8 MODERATELY DIFFERENTIATED HCCS, 6 (75%) OF 8 POORLY DIFFERENTIATED HCCS, AND NONE OF 16 NONCANCEROUS TISSUE SPECIMENS. IN HCC WITH HBV OR HCV, P53 MUTATIONS WERE DETECTED IN 8 (23%) OF 35 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (100%) OF 2 WELL-DIFFERENTIATED HCCS, 13 (76%) OF 17 MODERATELY DIFFERENTIATED HCCS, 12 (75%) OF 16 POORLY DIFFERENTIATED HCCS, AND 9 (26%) OF 35 NONCANCEROUS LIVER TISSUE SPECIMENS. CONCLUSIONS: OUR RESULTS SUGGEST THAT HEPATITIS VIRUSES MIGHT INDUCE METHYLATION OF P16 PROMOTER IN LIVER WITH CHRONIC INFLAMMATION, BEFORE APPEARANCE OF HCC. 2004 6 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 7 3067 36 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 8 5969 40 TERT PROMOTER MUTATIONS IN PRIMARY LIVER TUMORS. NEXT-GENERATION SEQUENCING HAS DRAWN THE GENETIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA AND SEVERAL SIGNALING PATHWAYS ARE ALTERED AT THE DNA LEVEL IN TUMORS: WNT/BETA-CATENIN, CELL CYCLE REGULATOR, EPIGENETIC MODIFIER, HISTONE METHYLTRANSFERASE, OXIDATIVE STRESS, RAS/RAF/MAP KINASE AND AKT/MTOR PATHWAYS. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS STARTING WITH THE EXPOSURE TO DIFFERENT RISK FACTORS, FOLLOWED BY THE DEVELOPMENT OF A CHRONIC LIVER DISEASE AND CIRRHOSIS PRECEDE IN THE VAST MAJORITY OF THE CASES THE DEVELOPMENT OF HCC. SEVERAL LINES OF EVIDENCE HAVE UNDERLINED THE PIVOTAL ROLE OF TELOMERE MAINTENANCE IN BOTH CIRRHOSIS AND HCC PATHOGENESIS. TERT PROMOTER MUTATIONS WERE IDENTIFIED AS THE MOST FREQUENT GENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH AN OVERALL FREQUENCY AROUND 60%. MOREOVER, IN CIRRHOSIS, TERT PROMOTER MUTATIONS ARE OBSERVED AT THE EARLY STEPS OF HEPATOCARCINOGENESIS SINCE THEY ARE RECURRENTLY IDENTIFIED IN LOW-GRADE AND HIGH-GRADE DYSPLASTIC NODULES. IN CONTRAST, ACQUISITION OF GENOMIC DIVERSITY THROUGH MUTATIONS OF CLASSICAL ONCOGENES AND TUMOR SUPPRESSOR GENES (TP53, CTNNB1, ARID1A...) OCCURRED ONLY IN PROGRESSED HCC. IN NORMAL LIVER, A SUBSET OF HCC CAN DERIVED FROM THE MALIGNANT TRANSFORMATION OF HEPATOCELLULAR ADENOMA (HCA). IN HCA, CTNNB1 MUTATIONS PREDISPOSE TO TRANSFORMATION OF HCA IN HCC AND TERT PROMOTER MUTATIONS ARE REQUIRED IN MOST OF THE CASES AS A SECOND HIT FOR A FULL MALIGNANT TRANSFORMATION. ALL THESE FINDINGS HAVE REFINED OUR KNOWLEDGE OF HCC PATHOGENESIS AND HAVE POINTED TELOMERASE AS A TARGET FOR TAILORED THERAPY IN THE FUTURE. 2016 9 2656 27 EPIMUTATION AND CANCER: A NEW CARCINOGENIC MECHANISM OF LYNCH SYNDROME (REVIEW). EPIMUTATION IS DEFINED AS ABNORMAL TRANSCRIPTIONAL REPRESSION OF ACTIVE GENES AND/OR ABNORMAL ACTIVATION OF USUALLY REPRESSED GENES CAUSED BY ERRORS IN EPIGENETIC GENE REPRESSION. EPIMUTATION ARISES IN SOMATIC CELLS AND THE GERMLINE, AND CONSTITUTIONAL EPIMUTATION MAY ALSO OCCUR. EPIMUTATION IS THE FIRST STEP OF TUMORIGENESIS AND CAN BE A DIRECT CAUSE OF CARCINOGENESIS. CANCERS ASSOCIATED WITH EPIMUTATION INCLUDE LYNCH SYNDROME (HEREDITARY NON-POLYPOSIS COLORECTAL CANCER, HNPCC), CHRONIC LYMPHOCYTIC LEUKEMIA, BREAST CANCER AND OVARIAN CANCER. EPIMUTATION HAS BEEN SHOWN FOR MANY TUMOR SUPPRESSOR GENES, INCLUDING RB, VHL, HMLH1, APC AND BRCA1, IN SPORADIC CANCERS. METHYLATION HAS RECENTLY BEEN SHOWN IN DNA FROM NORMAL TISSUES AND PERIPHERAL BLOOD IN CASES OF SPORADIC COLORECTAL CANCER AND MANY STUDIES SHOW CONSTITUTIVE EPIMUTATION IN CANCERS. EPIMUTATION OF DNA MISMATCH REPAIR (MMR) GENES (BRCA1, HMLH1 AND HMSH2) INVOLVED IN DEVELOPMENT FAMILIAL CANCERS HAS ALSO BEEN FOUND. THESE RESULTS HAVE LED TO A FOCUS ON EPIMUTATION AS A NOVEL ONCOGENIC MECHANISM. 2012 10 5360 41 RECENT ADVANCEMENTS IN COMPREHENSIVE GENETIC ANALYSES FOR HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) TYPICALLY DEVELOPS IN THE LIVER WITH CHRONIC HEPATITIS AND CIRRHOSIS, AND ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS DURING CARCINOGENESIS VIA GENETIC AND EPIGENETIC MECHANISMS. RECENT ADVANCEMENTS IN THE DEVELOPMENT OF ANALYSES FOR EXAMINING THE CANCER GENOME HAVE REVEALED INFORMATION REGARDING GENETIC ALTERATIONS IN HCC TISSUES. ACCORDING TO PREVIOUS STUDIES, THE INCIDENCE OF RECURRENT GENETIC ALTERATIONS IN INDIVIDUAL GENES WAS THOUGHT TO BE RELATIVELY RARE AND LIMITED TO A SUBSET OF A FEW CANCER-SPECIFIC GENES SUCH AS TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS CTNNB1. HOWEVER, RECENT WHOLE-GENOME ANALYSES AND EXOME SEQUENCING OF TUMOR DNA HAVE REVEALED NUMEROUS NOVEL ALTERATIONS OF CANCER-RELATED GENES AND PATHWAYS CRITICAL FOR HCC DEVELOPMENT. IN ADDITION, VARIOUS RISK FACTORS FOR HCC, SUCH AS THE PRESENCE OR ABSENCE OF HEPATITIS B AND C VIRUS, MAY AFFECT THE MUTATION PROFILE OF THE CORRESPONDING CANCER GENOME. ON THE OTHER HAND, GENOME-WIDE ASSOCIATION STUDIES HAVE ALSO IDENTIFIED IMPORTANT SINGLE-NUCLEOTIDE POLYMORPHISMS INVOLVED IN HCC DEVELOPMENT, WHICH MAY ALLOW DETECTION OF A GROUP AT HIGH RISK OF HCC EMERGENCE. SUCH ANALYSES WILL CLARIFY HOW THIS MALIGNANCY CAN BE TREATED, DIAGNOSED AND PREVENTED MORE EFFECTIVELY. 2013 11 342 35 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 12 1502 35 DNA METHYLATION AND EPIGENETIC EVENTS UNDERLYING RENAL CELL CARCINOMAS. RENAL CELL CARCINOMA (RCC) REFERS TO A GROUP OF TUMORS THAT DEVELOP FROM THE EPITHELIUM OF THE KIDNEY TUBES, INCLUDING CLEAR CELL RCC, PAPILLARY RCC, AND CHROMOPHOBE RCC. MOST CLEAR CELL RENAL CARCINOMAS HAVE A LARGE HISTOLOGIC SUBTYPE, GENETIC OR EPIGENETIC VON HIPPEL-LINDAU (VHL). A COMPREHENSIVE ANALYSIS OF THE GENETIC MODIFICATION GENOME SUGGESTED THAT CHROMOSOME 3P LOSS AND CHROMOSOME GAINS 5Q AND 7 MAY BE SIGNIFICANT COPY DEFECTS IN THE DEVELOPMENT OF CLEAR RCC. A MORE POTENT RCC MAY DEVELOP IF CHROMOSOME 1P, 4, 9, 13Q, OR 14Q IS ALSO LOST. RENAL CARCINOGENESIS IS NOT ASSOCIATED WITH CHRONIC INFLAMMATION OR HISTOLOGICAL CHANGES. HOWEVER, IF REGIONAL HYPERMETHYLATION OF DNA IN CPG C-TYPE ISLANDS HAS ALREADY ACCUMULATED IN CANCER-FREE KIDNEY TISSUE, IT IMPLIES THAT THE PRESENCE OF MALIGNANT KIDNEY LESIONS MAY ALSO BE DETECTED BY MODIFIED DNA METHYLATION. MODIFICATION OF DNA METHYLATION IN CANCEROUS KIDNEY TISSUE MAY ADVANCE KIDNEY TISSUE TO EPIGENETIC MUTATIONS AND GENES, LEADING TO MORE SERIOUS CANCERS AND EVEN DETERMINING A PATIENT'S OUTCOME. THE GENETIC AND EPIGENETIC PROFILE PROVIDES ACCURATE PREDICTORS FOR PATIENTS WITH KIDNEY CANCER. NEW GENETIC AND EPIGENETIC ANALYSIS TECHNOLOGIES WILL HELP TO SPEED UP THE IDENTIFICATION OF VITAL CELLS FOR KIDNEY CANCER PREVENTION, DIAGNOSIS, AND TREATMENT. 2022 13 1617 48 DNA METHYLTRANSFERASE EXPRESSION AND DNA METHYLATION IN HUMAN HEPATOCELLULAR CARCINOMA AND THEIR CLINICOPATHOLOGICAL CORRELATION. ABERRANT DNA METHYLATION ON CPG ISLANDS IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS, AND THE METHYLATION PROCESS IS CATALYZED BY DNA METHYLTRANSFERASE (DNMT). WE EVALUATED I) THE MRNA LEVELS OF THREE DNMTS; DNMT1, DNMT3A AND DNMT3B, IN 25 HEPATOCELLULAR CARCINOMAS (HCCS), IN THEIR CORRESPONDING NON-CANCEROUS LIVER TISSUES AND IN 7 NORMAL LIVERS BY USING REAL-TIME REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION; II) NUCLEAR EXPRESSION OF DNMT1 AND DNMT3A PROTEINS IN THE HCCS BY IMMUNOHISTOCHEMISTRY, III) THE METHYLATION STATUS OF 5 GENES; P16, P15, E-CADHERIN, HIC-1 AND RASSF1A IN THE SAME TISSUES, AND IV) THE RELATIONSHIPS BETWEEN THE ABOVE RESULTS AND THE CLINICOPATHOLOGICAL CHARACTERISTICS, INCLUDING PROGNOSIS. THE DIFFERENCES IN MRNA EXPRESSION LEVELS FOR DNMT1, DNMT3A AND DNMT3B WERE STATISTICALLY SIGNIFICANT BETWEEN HCC AND NORMAL LIVERS (P<0.001), HCC AND CHRONIC HEPATITIS (P<0.001) AND HCC AND CIRRHOSIS (P<0.001). AN INCREASE IN MRNA EXPRESSION LEVELS OF >4-FOLD FOR DNMT3B IN HCCS WAS SIGNIFICANTLY ASSOCIATED WITH A POORER OVERALL SURVIVAL (P=0.027) AND SHORTER METASTASIS-FREE SURVIVAL (P=0.0299). A POORER RECURRENCE-FREE SURVIVAL WAS NOTED IN HCCS WITH A >4-FOLD INCREASE IN DNMT3A MRNA (P=0.0120). THE AVERAGE NUMBERS OF METHYLATED GENES WERE 0, 1.27, 1.38 AND 2.72 FOR NORMAL LIVERS, CHRONIC HEPATITIS, CIRRHOSIS AND HCCS, RESPECTIVELY, AND THIS PROGRESSIVE INCREASE FROM NORMAL LIVERS TO CHRONIC HEPATITIS/CIRRHOSIS THROUGH HCC MAY SUGGEST THAT TUMOR SUPPRESSOR GENE METHYLATION IS AN EARLY EVENT IN HEPATOCARCINOGENESIS. THESE RESULTS FIRST SUGGEST THAT HEPATOCARCINOGENESIS INVOLVES AN INCREASED EXPRESSION OF DNMT1, DNMT3A AND DNMT3B MRNA AND A PROGRESSIVE INCREASE IN THE NUMBER OF METHYLATED GENES FROM NORMAL LIVER, CHRONIC HEPATITIS/CIRRHOSIS TO HCC AND SECONDLY THAT AN INCREASE IN THE DNMT3A AND DNMT3B MRNA LEVELS IN HCCS RELATIVE TO THEIR NON-CANCEROUS TISSUES MAY BE A PREDICTOR OF POOR SURVIVAL. 2007 14 3163 32 GREEN TEA CATECHIN EXTRACT IN INTERVENTION OF CHRONIC BREAST CELL CARCINOGENESIS INDUCED BY ENVIRONMENTAL CARCINOGENS. SPORADIC BREAST CANCERS ARE MAINLY ATTRIBUTABLE TO LONG-TERM EXPOSURE TO ENVIRONMENTAL FACTORS, VIA A MULTI-YEAR, MULTI-STEP, AND MULTI-PATH PROCESS OF TUMORIGENESIS INVOLVING CUMULATIVE GENETIC AND EPIGENETIC ALTERATIONS IN THE CHRONIC CARCINOGENESIS OF BREAST CELLS FROM A NON-CANCEROUS STAGE TO PRECANCEROUS AND CANCEROUS STAGES. EPIDEMIOLOGIC AND EXPERIMENTAL STUDIES HAVE SUGGESTED THAT GREEN TEA COMPONENTS MAY BE USED AS PREVENTIVE AGENTS FOR BREAST CANCER CONTROL. IN OUR RESEARCH, WE HAVE DEVELOPED A CELLULAR MODEL THAT MIMICS BREAST CELL CARCINOGENESIS CHRONICALLY INDUCED BY CUMULATIVE EXPOSURES TO LOW DOSES OF ENVIRONMENTAL CARCINOGENS. IN THIS STUDY, WE USED OUR CHRONIC CARCINOGENESIS MODEL AS A TARGET SYSTEM TO INVESTIGATE THE ACTIVITY OF GREEN TEA CATECHIN EXTRACT (GTC) AT NON-CYTOTOXIC LEVELS IN INTERVENTION OF CELLULAR CARCINOGENESIS INDUCED BY CUMULATIVE EXPOSURES TO PICO-MOLAR 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE (NNK) AND BENZO[A]PYRENE (B[A]P). WE IDENTIFIED THAT GTC, AT A NON-CYTOTOXIC, PHYSIOLOGICALLY ACHIEVABLE CONCENTRATION OF 2.5 MICROG/ML, WAS EFFECTIVE IN SUPPRESSING NNK- AND B[A]P-INDUCED CELLULAR CARCINOGENESIS, AS MEASURED BY REDUCTION OF THE ACQUIRED CANCER-ASSOCIATED PROPERTIES OF REDUCED DEPENDENCE ON GROWTH FACTORS, ANCHORAGE-INDEPENDENT GROWTH, INCREASED CELL MOBILITY, AND ACINAR-CONFORMATIONAL DISRUPTION. WE ALSO DETECTED THAT INTERVENTION OF CARCINOGEN-INDUCED ELEVATION OF REACTIVE OXYGEN SPECIES (ROS), INCREASE OF CELL PROLIFERATION, ACTIVATION OF THE ERK PATHWAY, DNA DAMAGE, AND CHANGES IN GENE EXPRESSION MAY ACCOUNT FOR THE MECHANISMS OF GTC'S PREVENTIVE ACTIVITY. THUS, GTC MAY BE USED IN DIETARY AND CHEMOPREVENTION OF BREAST CELL CARCINOGENESIS ASSOCIATED WITH LONG-TERM EXPOSURE TO LOW DOSES OF ENVIRONMENTAL CARCINOGENS. 2012 15 6848 42 [MOLECULAR GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR TYPE OF PRIMARY LIVER CANCER AND ONE OF THE MOST FREQUENT HUMAN MALIGNANT NEOPLASMS. COMMON RISK FACTORS OF HUMAN HCC INCLUDE CHRONIC HEPATITIS VIRUS (HBV AND HCV) INFECTION, DIETARY AFLATOXIN B1 (AFB1) INGESTION, CHRONIC ALCOHOL ABUSE, AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES. HEPATOCARCINOGENESIS IS THE RESULT OF INTERACTION BETWEEN HEREDITARY AND ENVIRONMENTAL FACTORS. INHERITANCE DETERMINES INDIVIDUAL SUSCEPTIBILITY TO CANCER; ENVIRONMENT DETERMINES WHICH SUSCEPTIBLE INDIVIDUALS EXPRESS CANCER. STUDIES OF GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS SHOWED THAT HCC DEVELOPMENT IS A COMPLEX POLYGENE AND MULTIPATHWAY PROCESS; THE ACTIVATION OF PROTO-ONCOGENES AND THE INACTIVATION OF TUMOR SUPPRESSOR GENES INDUCED BY GENETIC AND EPIGENETIC ALTERATIONS ARE CORE BIOLOGICAL PROCESSES OF HEPATOCARCINOGENESIS; RB1, P53, AND WNT PATHWAYS ARE COMMONLY AFFECTED IN HCCS OF DIFFERENT ETIOLOGIES, WHICH MAY REFLECT COMMON PATHOLOGIC SEQUENCE OF HCC: CHRONIC LIVER INJURY, CIRRHOSIS, ATYPICAL HYPERPLASTIC NODULES, AND HCC OF EARLY STAGES. HEPATITIS VIRUS INFECTION-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN RB1 PATHWAY, INCLUDING METHYLATION OF P16INK4A AND RB1 GENES AND AMPLIFICATION OF CYCLIN D1. AFB1 EXPOSURE-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN P53 PATHWAY; THE G-->T MUTATION OF P53 GENE AT CODON 249 HAS BEEN IDENTIFIED AS A GENETIC HALLMARK OF HCC CAUSED BY AFB1. ALCOHOLISM-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN BOTH RB1 AND P53 PATHWAYS. THE ROLES OF SOME IMPORTANT GENES RELATED TO CELL APOPTOSIS, DNA REPAIR, DRUG METABOLISM, AND TUMOR METASTASIS IN HEPATOCARCINOGENESIS HAD BEEN DISCUSSED. 2005 16 824 38 CHARACTERIZATION OF COPY NUMBER ALTERATIONS IN A MOUSE MODEL OF FIBROSIS-ASSOCIATED HEPATOCELLULAR CARCINOMA REVEALS CONCORDANCE WITH HUMAN DISEASE. HEPATOCELLULAR CARCINOMA (HCC) IS A PREVALENT HUMAN CANCER WITH RISING INCIDENCE WORLDWIDE. HUMAN HCC IS FREQUENTLY ASSOCIATED WITH CHRONIC LIVER INFLAMMATION AND CIRRHOSIS, PATHOPHYSIOLOGICAL PROCESSES THAT ARE A CONSEQUENCE OF CHRONIC VIRAL INFECTION, DISTURBANCES IN METABOLISM, OR EXPOSURE TO CHEMICAL TOXICANTS. TO BETTER CHARACTERIZE THE PATHOGENESIS OF HCC, WE USED A HUMAN DISEASE-RELEVANT MOUSE MODEL OF FIBROSIS-ASSOCIATED HEPATOCARCINOGENESIS. IN THIS MODEL, MARKED LIVER TUMOR RESPONSE CAUSED BY THE PROMUTAGENIC CHEMICAL N-NITROSODIETHYLAMINE IN THE PRESENCE OF LIVER FIBROSIS WAS ASSOCIATED WITH EPIGENETIC EVENTS INDICATIVE OF GENOMIC INSTABILITY. THEREFORE, WE HYPOTHESIZED THAT DNA COPY NUMBER ALTERATIONS (CNAS), A FEATURE OF GENOMIC INSTABILITY AND A COMMON CHARACTERISTIC OF CANCER, ARE CONCORDANT BETWEEN HUMAN HCC AND MOUSE MODELS OF FIBROSIS-ASSOCIATED HEPATOCARCINOGENESIS. WE EVALUATED DNA CNAS AND CHANGES IN GENE EXPRESSION IN THE MOUSE LIVER (NORMAL, TUMOR, AND NONTUMOR FIBROTIC TISSUES). ADDITIONALLY, WE COMPARED OUR FINDINGS TO DNA CNAS IN HUMAN HCC CASES (TUMOR AND NONTUMOR CIRRHOTIC/FIBROTIC TISSUES) USING PUBLICLY AVAILABLE DATA FROM THE CANCER GENOME ATLAS (TCGA). WE OBSERVED THAT WHILE FIBROTIC LIVER TISSUE IS LARGELY DEVOID OF DNA CNAS, HIGHLY FREQUENTLY OCCURRING DNA CNAS ARE FOUND IN MOUSE TUMORS, WHICH IS INDICATIVE OF A PROFOUND INCREASE IN CHROMOSOMAL INSTABILITY IN HCC. THE CROSS-SPECIES GENE-LEVEL COMPARISON OF CNAS IDENTIFIED SHARED REGIONS OF CNAS BETWEEN HUMAN FIBROSIS- AND CIRRHOSIS-ASSOCIATED LIVER TUMORS AND MOUSE FIBROSIS-ASSOCIATED HCC. OUR RESULTS SUGGEST THAT CNAS MOST COMMONLY ARISE IN NEOPLASTIC TISSUE RATHER THAN IN FIBROTIC OR CIRRHOTIC LIVER, AND DEMONSTRATE THE UTILITY OF THIS MOUSE MODEL IN REPLICATING THE MOLECULAR FEATURES OF HUMAN HCC. 2016 17 2846 37 FREQUENT INVOLVEMENT OF CHROMATIN REMODELER ALTERATIONS IN GASTRIC FIELD CANCERIZATION. A FIELD FOR CANCERIZATION, OR A FIELD DEFECT, IS FORMED BY THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL-APPEARING TISSUES, AND IS INVOLVED IN VARIOUS CANCERS, ESPECIALLY MULTIPLE CANCERS. EPIGENETIC ALTERATIONS ARE FREQUENTLY PRESENT IN CHRONIC INFLAMMATION-EXPOSED TISSUES, BUT INFORMATION ON INDIVIDUAL GENES INVOLVED IN THE FORMATION OF A FIELD DEFECT IS STILL FRAGMENTAL. HERE, USING NON-CANCEROUS GASTRIC TISSUES OF CANCER PATIENTS, WE ISOLATED 16 ABERRANTLY METHYLATED GENES, AND IDENTIFIED CHROMATIN REMODELERS ACTL6B AND SMARCA1 AS NOVEL GENES FREQUENTLY METHYLATED IN NON-CANCEROUS TISSUES. SMARCA1 WAS EXPRESSED AT HIGH LEVELS IN NORMAL GASTRIC TISSUES, BUT WAS FREQUENTLY SILENCED BY ABERRANT METHYLATION IN GASTRIC CANCER CELLS. MOREOVER, SOMATIC MUTATIONS OF ADDITIONAL CHROMATIN REMODELERS, SUCH AS ARID1A, SMARCA2, AND SMARCA4, WERE FOUND IN 30% OF GASTRIC CANCERS. MUTANT ALLELE FREQUENCY SUGGESTED THAT THE MAJORITY OF CANCER CELLS HARBORED A MUTATION WHEN PRESENT. DEPLETION OF A CHROMATIN REMODELER, SMARCA1 OR SMARCA2, IN CANCER CELL LINES PROMOTED THEIR GROWTH. THESE RESULTS SHOWED THAT EPIGENETIC AND GENETIC ALTERATIONS OF CHROMATIN REMODELERS ARE INDUCED AT AN EARLY STAGE OF CARCINOGENESIS AND ARE FREQUENTLY INVOLVED IN THE FORMATION OF A FIELD DEFECT. 2015 18 1031 34 CIRCULATING TUMOR DNA DETECTION AND ITS APPLICATION STATUS IN GASTRIC CANCER: A NARRATIVE REVIEW. CIRCULATING TUMOR DNA (CTDNA) IS THE SMALL GENOMIC FRAGMENT RELEASED BY TUMOR CELLS INTO THE CIRCULATING SYSTEM, WHICH CARRIES THE GENE VARIATION FEATURES, SUCH AS MUTATION, INSERTION, DELETION, REARRANGEMENT, COPY NUMBER VARIATION (CNV) AND METHYLATION, RENDERING IT AN IMPORTANT BIOMARKER. IT CAN BE USED NOT ONLY TO DIAGNOSE CERTAIN TYPES OF SOLID TUMORS, BUT ALSO TO MONITOR THE THERAPEUTIC RESPONSE AND EXPLORE THE MINIMAL RESIDUAL DISEASE (MRD) AND RESISTANT MUTATION OF TARGETED THERAPY. THEREFORE, CTDNA DETECTION MAY BECOME THE PREFERRED NON-INVASIVE TUMOR SCREENING METHOD. FOR PATIENTS WHO CANNOT RECEIVE FURTHER GENE DETECTION DUE TO INSUFFICIENT OR RESTRICTED SAMPLE COLLECTION WITH THE DEFINED PATHOLOGICAL DIAGNOSIS, CTDNA DETECTION CAN BE CARRIED OUT TO DETERMINE THE GENE MUTATION TYPE, WITH NO NEED FOR REPEATED SAMPLING. GASTRIC CANCER (GC) IS A MALIGNANCY WITH EXTREMELY HIGH MORBIDITY AND MORTALITY, AND ITS GENESIS AND DEVELOPMENT ARE THE CONSEQUENCE OF INTERACTIONS OF MULTIPLE FACTORS, INCLUDING ENVIRONMENT, DIET, HEREDITY, HELICOBACTER PYLORI INFECTION, CHRONIC INFLAMMATORY INFILTRATION, AND PRECANCEROUS LESION. AS THE RESEARCH ON GC MOVES FORWARD, THE EXISTING RESEARCH MAINLY FOCUSES ON GENETIC AND EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA CHANGES, GENE MUTATION, GENE HETEROZYGOSITY LOSS AND MICROSATELLITE INSTABILITY. THIS PAPER AIMED TO SUMMARIZE THE CONTENTS OF CTDNA DETECTION, ITS APPLICATION STATUS IN GC AND CLINICAL SIGNIFICANCE. 2021 19 5770 31 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 20 5338 39 QUANTITATIVE EVALUATION OF RASSF1A METHYLATION IN THE NON-LESIONAL, REGENERATIVE AND NEOPLASTIC LIVER. BACKGROUND: EPIGENETIC CHANGES DURING AGEING AND THEIR RELATIONSHIP WITH CANCER ARE UNDER THE FOCUS OF INTENSE RESEARCH. RASSF1A AND NORE1A ARE NOVEL GENES ACTING IN CONCERT IN THE PROAPOPTOTIC PATHWAY OF THE RAS SIGNALLING. WHILE NORE1A HAS NOT BEEN PREVIOUSLY INVESTIGATED IN THE HUMAN LIVER, RECENT REPORTS HAVE SUGGESTED THAT RASSF1A IS FREQUENTLY EPIGENETICALLY METHYLATED NOT ONLY IN HCC BUT ALSO IN THE CIRRHOTIC LIVER. METHODS: TO ADDRESS WHETHER EPIGENETIC CHANGES TAKE PLACE IN CONNECTION TO AGE AND/OR TO THE UNDERLYING DISEASE, WE INVESTIGATED RASSF1A AND NORE1A GENE PROMOTER METHYLATION BY CONVENTIONAL METHYLATION SPECIFIC PCR AND REAL-TIME MSP IN A SERIES OF HEPATITIC AND NON-HEPATITIC LIVERS HARBORING REGENERATIVE/HYPERPLASTIC (CIRRHOSIS/FOCAL NODULAR HYPERPLASIA), DYSPLASTIC (LARGE REGENERATIVE, LOW AND HIGH GRADE DYSPLASTIC NODULES) AND NEOPLASTIC (HEPATOCELLULAR ADENOMA AND CARCINOMA) GROWTHS. RESULTS: IN THE HEPATITIC LIVER (CHRONIC HEPATITIC/CIRRHOSIS, HEPATOCELLULAR NODULES AND HCC) WE FOUND WIDESPREAD RASSF1A GENE PROMOTER METHYLATION WITH A METHYLATION INDEX THAT INCREASED FROM REGENERATIVE CONDITIONS (CIRRHOSIS) TO HEPATOCELLULAR NODULES (P < 0.01) TO HCC (P < 0.001). IN THE NON-HEPATITIC LIVER A CONSISTENT PATTERN OF GENE METHYLATION WAS ALSO FOUND IN BOTH LESIONAL (FOCAL NODULAR HYPERPLASIA AND HEPATOCELLULAR ADENOMA) AND NON-LESIONAL TISSUE. SPECIFICALLY, HEPATOCELLULAR ADENOMAS (HA) SHOWED A METHYLATION INDEX SIGNIFICANTLY HIGHER THAN THAT DETECTED IN FOCAL NODULAR HYPERPLASIA (FNH) (P < 0.01) AND IN NON-LESIONAL TISSUE (P < 0.001). IN NON-LESIONAL LIVER ALSO THE METHYLATION INDEX GRADUALLY INCREASED BY AGEING (P = 0.002), SUGGESTING A PROGRESSIVE SPREADING OF METHYLATED CELLS OVER TIME. AS OPPOSED TO RASSF1A GENE PROMOTER METHYLATION, NORE1A GENE WAS NEVER FOUND EPIGENETICALLY ALTERATED IN BOTH HEPATITIC AND NON-HEPATITIC LIVER. CONCLUSION: WE HAVE SHOWN THAT IN NON-LESIONAL, REGENERATIVE AND NEOPLASTIC LIVER THE RASSF1A GENE IS INCREASINGLY METHYLATED, THAT THIS CONDITION TAKES PLACE AS AN AGE-RELATED PHENOMENON AND THAT THE EARLY SETTING AND SPREADING OVER TIME OF AN EPIGENETICALLY METHYLATED HEPATOCYTE SUBPOPULATION, MIGHT BE RELATED TO LIVER TUMORIGENESIS. 2006