1  3825 133 INVESTIGATION OF CTNNB1 GENE MUTATIONS AND EXPRESSION IN HEPATOCELLULAR CARCINOMA AND CIRRHOSIS IN ASSOCIATION WITH HEPATITIS B VIRUS INFECTION. HEPATITIS B VIRUS (HBV), ALONG WITH HEPATITIS C VIRUS CHRONIC INFECTION, REPRESENTS A MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT. HOWEVER, MOLECULAR MECHANISMS INVOLVED IN THE DEVELOPMENT OF HCC ARE NOT YET COMPLETELY UNDERSTOOD. RECENT STUDIES HAVE INDICATED THAT MUTATIONS IN CTNNB1 GENE ENCODING FOR BETA-CATENIN PROTEIN LEAD TO ABERRANT ACTIVATION OF THE WNT/ BETA-CATENIN PATHWAY. THE MUTATIONS IN TURN ACTIVATE SEVERAL DOWNSTREAM GENES, INCLUDING C-MYC, PROMOTING THE NEOPLASTIC PROCESS. THE PRESENT STUDY EVALUATED THE MUTATIONAL PROFILE OF THE CTNNB1 GENE AND EXPRESSION LEVELS OF CTNNB1 AND C-MYC GENES IN HBV-RELATED HCC, AS WELL AS IN CIRRHOTIC AND CONTROL TISSUES. MUTATIONAL ANALYSIS OF THE BETA-CATENIN GENE AND HBV GENOTYPING WERE CONDUCTED BY DIRECT SEQUENCING. EXPRESSION OF BETA-CATENIN AND C-MYC GENES WAS ASSESSED USING REAL-TIME PCR. AMONG THE HCC CASES, 18.1% SHOWED MISSENSE POINT MUTATION IN EXON 3 OF CTNNB1, MORE FREQUENTLY IN CODONS 32, 33, 38 AND 45. THE FREQUENCY OF MUTATION IN THE HOTSPOTS OF EXON 3 WAS SIGNIFICANTLY HIGHER IN NON-VIRAL HCCS (29.4%) RATHER THAN HBV-RELATED CASES (12.7%, P = 0.021). THE EXPRESSION OF BETA-CATENIN AND C-MYC GENES WAS FOUND UPREGULATED IN CIRRHOTIC TISSUES IN ASSOCIATION WITH HBV INFECTION. MUTATIONS AT BOTH PHOSPHORYLATION AND NEIGHBORING SITES WERE ASSOCIATED WITH INCREASED ACTIVITY OF THE WNT PATHWAY. THE RESULTS DEMONSTRATED THAT MUTATED BETA-CATENIN CAUSED ACTIVATION OF THE WNT PATHWAY, BUT THE RATE OF CTNNB1 GENE MUTATIONS WAS NOT RELATED TO HBV INFECTION. HBV FACTORS MAY DEREGULATE THE WNT PATHWAY BY CAUSING EPIGENETIC ALTERATIONS IN THE HBV-RELATED HCC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  4546  36 MUTANT P53 REGULATES ENHANCER-ASSOCIATED H3K4 MONOMETHYLATION THROUGH INTERACTIONS WITH THE METHYLTRANSFERASE MLL4. MONOMETHYLATION OF HISTONE H3 LYSINE 4 (H3K4ME1) IS ENRICHED AT ENHANCERS THAT ARE PRIMED FOR ACTIVATION AND THE LEVELS OF THIS HISTONE MARK ARE FREQUENTLY ALTERED IN VARIOUS HUMAN CANCERS. YET, HOW ALTERATIONS IN H3K4ME1 ARE ESTABLISHED AND THE CONSEQUENCES OF THESE EPIGENETIC CHANGES IN TUMORIGENESIS ARE NOT WELL UNDERSTOOD. USING CHIP-SEQ IN HUMAN COLON CANCER CELLS, WE DEMONSTRATE THAT MUTANT P53 DEPLETION RESULTS IN DECREASED H3K4ME1 LEVELS AT ACTIVE ENHANCERS THAT REVEAL A STRIKING COLOCALIZATION OF MUTANT P53 AND THE H3K4 MONOMETHYLTRANSFERASE MLL4 FOLLOWING CHRONIC TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) SIGNALING. WE FURTHER REVEAL THAT MUTANT P53 FORMS PHYSIOLOGICAL ASSOCIATIONS AND DIRECT INTERACTIONS WITH MLL4 AND PROMOTES THE ENHANCER BINDING OF MLL4, WHICH IS REQUIRED FOR TNFALPHA-INDUCIBLE H3K4ME1 AND HISTONE H3 LYSINE 27 ACETYLATION (H3K27AC) LEVELS, ENHANCER-DERIVED TRANSCRIPT (ERNA) SYNTHESIS, AND MUTANT P53-DEPENDENT TARGET GENE ACTIVATION. COMPLEMENTARY IN VITRO STUDIES WITH RECOMBINANT CHROMATIN AND PURIFIED PROTEINS DEMONSTRATE THAT BINDING OF THE MLL3/4 COMPLEX AND H3K4ME1 DEPOSITION IS ENHANCED BY MUTANT P53 AND P300-MEDIATED ACETYLATION, WHICH IN TURN REFLECTS A MLL3/4-DEPENDENT ENHANCEMENT OF MUTANT P53 AND P300-DEPENDENT TRANSCRIPTIONAL ACTIVATION. COLLECTIVELY, OUR FINDINGS ESTABLISH A MECHANISM IN WHICH MUTANT P53 COOPERATES WITH MLL4 TO REGULATE ABERRANT ENHANCER ACTIVITY AND TUMOR-PROMOTING GENE EXPRESSION IN RESPONSE TO CHRONIC IMMUNE SIGNALING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  1062  28 CLINICAL SIGNIFICANCE OF DNA METHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS: RESULTS FROM 3 UK CLINICAL TRIALS. CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS WITH MUTATED IMMUNOGLOBULIN HEAVY-CHAIN GENES (IGHV-M), PARTICULARLY THOSE LACKING POOR-RISK GENOMIC LESIONS, OFTEN RESPOND WELL TO CHEMOIMMUNOTHERAPY (CIT). DNA METHYLATION PROFILING CAN SUBDIVIDE EARLY-STAGE PATIENTS INTO NAIVE B-CELL-LIKE CLL (N-CLL), MEMORY B-CELL-LIKE CLL (M-CLL), AND INTERMEDIATE CLL (I-CLL), WITH DIFFERING TIMES TO FIRST TREATMENT AND OVERALL SURVIVAL. HOWEVER, WHETHER DNA METHYLATION CAN IDENTIFY PATIENTS DESTINED TO RESPOND FAVORABLY TO CIT HAS NOT BEEN ASCERTAINED. WE CLASSIFIED TREATMENT-NAIVE PATIENTS (N = 605) FROM 3 UK CHEMO AND CIT CLINICAL TRIALS INTO THE 3 EPIGENETIC SUBGROUPS, USING PYROSEQUENCING AND MICROARRAY ANALYSIS, AND PERFORMED EXPANSIVE SURVIVAL ANALYSIS. THE N-CLL, I-CLL, AND M-CLL SIGNATURES WERE FOUND IN 80% (N = 245/305), 17% (53/305), AND 2% (7/305) OF IGHV-UNMUTATED (IGHV-U) CASES, RESPECTIVELY, AND IN 9%, (19/216), 50% (108/216), AND 41% (89/216) OF IGHV-M CASES, RESPECTIVELY. MULTIVARIATE COX PROPORTIONAL ANALYSIS IDENTIFIED M-CLL AS AN INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL (HAZARD RATIO [HR], 0.46; 95% CONFIDENCE INTERVAL [CI], 0.24-0.87; P = .018) IN CLL4, AND FOR PROGRESSION-FREE SURVIVAL (HR, 0.25; 95% CI, 0.10-0.57; P = .002) IN ARCTIC AND ADMIRE PATIENTS. THE ANALYSIS OF EPIGENETIC SUBGROUPS IN PATIENTS ENTERED INTO 3 FIRST-LINE UK CLL TRIALS IDENTIFIES M-CLL AS AN INDEPENDENT MARKER OF PROLONGED SURVIVAL AND MAY AID IN THE IDENTIFICATION OF PATIENTS DESTINED TO DEMONSTRATE PROLONGED SURVIVAL AFTER CIT.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  3392  39 HOST AND VIRAL GENETIC VARIATION IN HBV-RELATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER IN MEN AND THE SECOND LEADING CAUSE OF CANCER DEATHS GLOBALLY. THE HIGH PREVALENCE OF HCC IS DUE IN PART TO THE HIGH PREVALENCE OF CHRONIC HBV INFECTION AND THE HIGH MORTALITY RATE IS DUE TO THE LACK OF BIOMARKERS FOR EARLY DETECTION AND LIMITED TREATMENT OPTIONS FOR LATE STAGE HCC. THE OBSERVED INDIVIDUAL VARIANCE IN DEVELOPMENT OF HCC IS ATTRIBUTABLE TO DIFFERENCES IN HBV GENOTYPE AND MUTATIONS, HOST PREDISPOSING GERMLINE GENETIC VARIATIONS, THE ACQUISITION OF TUMOR-SPECIFIC SOMATIC MUTATIONS, AS WELL AS ENVIRONMENTAL FACTORS. HBV GENOTYPE C AND MUTATIONS IN THE PRES, BASIC CORE PROMOTER (BCP) OR HBX REGIONS ARE ASSOCIATED WITH AN INCREASED RISK OF HCC. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED COMMON POLYMORPHISMS IN KIF1B, HLA-DQ, STAT4, AND GRIK1 WITH ALTERED RISK OF HBV-RELATED HCC. HBV INTEGRATION INTO GROWTH CONTROL GENES (SUCH AS TERT), PRO-ONCOGENIC GENES, OR TUMOR SUPPRESSOR GENES AND THE ONCOGENIC ACTIVITY OF TRUNCATED HBX PROMOTE HEPATOCARCINOGENESIS. SOMATIC MUTATIONS IN THE TERT PROMOTER AND CLASSIC CANCER SIGNALING PATHWAYS, INCLUDING WNT (CTNNB1), CELL CYCLE REGULATION (TP53), AND EPIGENETIC MODIFICATION (ARID2 AND MLL4) ARE FREQUENTLY DETECTED IN HEPATIC TUMOR TISSUES. THE IDENTIFICATION OF HBV AND HOST VARIATION ASSOCIATED WITH TUMOR INITIATION AND PROGRESSION HAS CLINICAL UTILITY FOR IMPROVING EARLY DIAGNOSIS AND PROGNOSIS; WHEREAS THE IDENTIFICATION OF SOMATIC MUTATIONS DRIVING TUMORIGENESIS HOLD PROMISE TO INFORM PRECISION TREATMENT FOR HCC PATIENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  1133  37 COMPREHENSIVE EPIGENOMIC PROFILING OF HUMAN ALVEOLAR EPITHELIAL DIFFERENTIATION IDENTIFIES KEY EPIGENETIC STATES AND TRANSCRIPTION FACTOR CO-REGULATORY NETWORKS FOR MAINTENANCE OF DISTAL LUNG IDENTITY. BACKGROUND: DISRUPTION OF ALVEOLAR EPITHELIAL CELL (AEC) DIFFERENTIATION IS IMPLICATED IN DISTAL LUNG DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE, IDIOPATHIC PULMONARY FIBROSIS, AND LUNG ADENOCARCINOMA THAT IMPACT MORBIDITY AND MORTALITY WORLDWIDE. ELUCIDATING UNDERLYING DISEASE PATHOGENESIS REQUIRES A MECHANISTIC MOLECULAR UNDERSTANDING OF AEC DIFFERENTIATION. PREVIOUS STUDIES HAVE FOCUSED ON CHANGES OF INDIVIDUAL TRANSCRIPTION FACTORS, AND TO DATE NO STUDY HAS COMPREHENSIVELY CHARACTERIZED THE DYNAMIC, GLOBAL EPIGENOMIC ALTERATIONS THAT FACILITATE THIS CRITICAL DIFFERENTIATION PROCESS IN HUMANS. RESULTS: WE COMPREHENSIVELY PROFILED THE EPIGENOMIC STATES OF HUMAN AECS DURING TYPE 2 TO TYPE 1-LIKE CELL DIFFERENTIATION, INCLUDING THE METHYLOME AND CHROMATIN FUNCTIONAL DOMAINS, AND INTEGRATED THIS WITH TRANSCRIPTOME-WIDE RNA EXPRESSION DATA. ENHANCER REGIONS WERE DRASTICALLY ALTERED DURING AEC DIFFERENTIATION. TRANSCRIPTION FACTOR BINDING ANALYSIS WITHIN ENHANCER REGIONS REVEALED DIVERSE INTERACTIVE NETWORKS WITH ENRICHMENT FOR MANY TRANSCRIPTION FACTORS, INCLUDING NKX2-1 AND FOXA FAMILY MEMBERS, AS WELL AS TRANSCRIPTION FACTORS WITH LESS WELL CHARACTERIZED ROLES IN AEC DIFFERENTIATION, SUCH AS MEMBERS OF THE MEF2, TEAD, AND AP1 FAMILIES. ADDITIONALLY, ASSOCIATIONS AMONG TRANSCRIPTION FACTORS CHANGED DURING DIFFERENTIATION, IMPLICATING A COMPLEX NETWORK OF HETEROTRIMERIC COMPLEX SWITCHING IN DRIVING DIFFERENTIATION. INTEGRATION OF AEC ENHANCER STATES WITH THE CATALOG OF ENHANCER ELEMENTS IN THE ROADMAP EPIGENOMICS MAPPING CONSORTIUM AND ENCYCLOPEDIA OF DNA ELEMENTS (ENCODE) REVEALED THAT AECS HAVE SIMILAR EPIGENOMIC STRUCTURES TO OTHER PROFILED EPITHELIAL CELL TYPES, INCLUDING HUMAN MAMMARY EPITHELIAL CELLS (HMECS), WITH NKX2-1 SERVING AS A DISTINGUISHING FEATURE OF DISTAL LUNG DIFFERENTIATION. CONCLUSIONS: ENHANCER REGIONS ARE HOTSPOTS OF EPIGENOMIC ALTERATION THAT REGULATE AEC DIFFERENTIATION. FURTHERMORE, THE DIFFERENTIATION PROCESS IS REGULATED BY DYNAMIC NETWORKS OF TRANSCRIPTION FACTORS ACTING IN CONCERT, RATHER THAN INDIVIDUALLY. THESE FINDINGS PROVIDE A ROADMAP FOR UNDERSTANDING THE RELATIONSHIP BETWEEN DISRUPTION OF THE EPIGENETIC STATE DURING AEC DIFFERENTIATION AND DEVELOPMENT OF LUNG DISEASES THAT MAY BE THERAPEUTICALLY AMENABLE.	2021	
                                  
7  6770  41 [ABERRANT METHYLATION OF MULTIPLE GENES AND ITS CLINICAL IMPLICATION IN HEPATOCELLULAR CARCINOMA]. OBJECTIVE: TO INVESTIGATE THE METHYLATION FREQUENCIES OF MULTIPLE TUMOR SUPPRESSOR GENES (TSGS) IN HEPATOCELLULAR CARCINOMA (HCC) AND THE CLINICAL IMPLICATION OF ABERRANT DNA METHYLATION IN MOLECULAR CARCINOGENESIS OF HCC. METHODS: SIXTY SAMPLES OF HCC AND THE PAIRED ADJACENT LIVER TISSUE, 16 SAMPLES FROM POST-HEPATITIS CIRRHOTIC LIVERS, 5 FROM LIVERS WITH CHRONIC HEPATITIS AND 5 FROM NORMAL LIVERS WERE COLLECTED. EIGHT TSGS FREQUENTLY SILENCED BY HYPERMETHYLATION OF THEIR PROMOTERS IN VARIOUS TYPES OF DIGESTIVE TUMORS WERE SELECTED, INCLUDING APC, RASSF1A, P16, GSTP1, MGMT, DAPK, SOCS-1 AND RIZ1. THE STATUS OF PROMOTER METHYLATION IN THESE 8 GENES WAS INVESTIGATED USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THE CLINICOPATHOLOGICAL DATA OF HCC WERE ALSO ANALYZED IN ORDER TO EVALUATE THE CLINICAL IMPLICATION OF ABERRANT METHYLATION IN HCC. RESULTS: METHYLATION OF THE 8 TSGS WAS QUITE FREQUENT IN HCC, WITH A METHYLATION RATE OF 95.0% IN RASSF1A, 90.0% IN APC, 73.3% IN GSTP1, 65.0% IN P16, 61.6% IN RIZ1 AND 60.0% IN MGMT. METHYLATION OF THE 6 GENES WAS MORE FREQUENT IN HCC THAN THAT IN ADJACENT TISSUES (P < 0.05). THE METHYLATION RATE OF MGMT, GSTP1 AND RIZ1 IN THE ADJACENT TISSUES WAS 41.6%, 40.0% AND 25.0%, RESPECTIVELY, SIGNIFICANTLY HIGHER THAN THAT IN CIRRHOTIC LIVER (P < 0.05). P16 METHYLATION WAS MORE FREQUENTLY OBSERVED IN HCC IN ELDERLY PATIENTS. THE FREQUENCY OF MGMT METHYLATION WAS TENDED TO BE HIGHER IN GIANT HCC THAN THAT IN THE OTHER TYPES OF HCC. PATIENTS WITH MGMT METHYLATION IN THE TUMOR WERE FOUND TO HAVE A SHORTER DISEASE FREE SURVIVAL. CONCLUSION: DIFFERENT FREQUENCY OF METHYLATION IN HEPATOCELLULAR CARCINOMAS, ADJACENT LIVER TISSUES AND CIRRHOTIC LIVERS IMPLIES THAT EPIGENETIC ALTERATION IN THE HEPATOCELLULAR CARCINOGENESIS MAY BE A GRADUALLY PROGRESSIVE PROCESS. METHYLATION STATUS OF MGMT, GSTP1 AND RIZ1 MAY BE PROMISING IN RISK ASSESSMENT OF HEPATOCELLULAR CARCINOMA AND IN EARLY DIAGNOSIS. FURTHERMORE, MGMT METHYLATION MIGHT BE ALSO USED AS A POTENTIAL PROGNOSTIC BIOMARKER FOR HEPATOCELLULAR CARCINOMA PATIENTS.	2008	
                                                                                                                                                                                                                                                                                                                                                               
8  3897  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  5969  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10  5243  28 PROGNOSTIC IMPACT OF EPIGENETIC CLASSIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: THE CASE OF SUBSET #2. BASED ON THE METHYLATION STATUS OF 5 SINGLE CPG SITES, A NOVEL EPIGENETIC CLASSIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WAS RECENTLY PROPOSED, CLASSIFYING CLL PATIENTS INTO 3 CLINICO-BIOLOGICAL SUBGROUPS WITH DIFFERENT OUTCOME, TERMED MEMORY LIKE CLL (M-CLL), NAIVE LIKE CLL (N-CLL), AND A THIRD INTERMEDIATE CLL SUBGROUP (I-CLL). WHILE M-CLL AND N-CLL PATIENTS AT LARGE CORRESPONDED TO PATIENTS CARRYING MUTATED AND UNMUTATED IGHV GENES, RESPECTIVELY, LIMITED INFORMATION EXISTS REGARDING THE LESS DEFINED I-CLL GROUP. USING PYROSEQUENCING, WE INVESTIGATED THE PROGNOSTIC IMPACT OF THE PROPOSED 5 CPG SIGNATURE IN A WELL-CHARACTERIZED CLL COHORT (135 CASES), INCLUDING IGHV-MUTATED AND UNMUTATED PATIENTS AS WELL AS CLINICALLY AGGRESSIVE STEREOTYPED SUBSET #2 PATIENTS. OVERALL, WE CONFIRMED THE SIGNATURE'S ASSOCIATION WITH ESTABLISHED PROGNOSTIC MARKERS. MOREOVER, IN THE PRESENCE OF THE IGHV MUTATIONAL STATUS, THE EPIGENETIC SIGNATURE REMAINED INDEPENDENTLY ASSOCIATED WITH BOTH TIME-TO-FIRST-TREATMENT AND OVERALL SURVIVAL IN MULTIVARIATE ANALYSES. AS A PRIME FINDING, WE OBSERVED THAT SUBSET #2 PATIENTS WERE PREDOMINANTLY CLASSIFIED AS I-CLL, PROBABLY REFLECTING THEIR BORDERLINE IGHV MUTATIONAL STATUS (97-99% GERMLINE IDENTITY), THOUGH HAVING A SIMILARLY POOR PROGNOSIS AS N-CLL PATIENTS. IN SUMMARY, WE VALIDATED THE EPIGENETIC CLASSIFIER AS AN INDEPENDENT FACTOR IN CLL PROGNOSTICATION AND PROVIDE FURTHER EVIDENCE THAT SUBSET #2 IS A MEMBER OF THE I-CLL GROUP, HENCE SUPPORTING THE EXISTENCE OF A THIRD, INTERMEDIATE EPIGENETIC SUBGROUP.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11  2182  36 EPIGENETIC MECHANISMS REGULATING THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA AND THEIR PROMISE FOR THERAPEUTICS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS AROUND THE GLOBE AND THIRD MOST FATAL MALIGNANCY. CHRONIC LIVER DISORDERS SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS OFTEN LEAD TO THE DEVELOPMENT OF HCC. ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS ARE INVOLVED IN THE DEVELOPMENT OF HCC. GENETIC RESEARCH SPARKED BY RECENT DEVELOPMENTS IN NEXT GENERATION SEQUENCING HAS IDENTIFIED THE FREQUENCY OF GENETIC ALTERATIONS THAT OCCUR IN HCC AND HAS LED TO THE IDENTIFICATION OF GENETIC HOTSPOTS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC ABERRATIONS ARE STRONGLY ASSOCIATED WITH THE INITIATION AND DEVELOPMENT OF HCC. VARIOUS IMPORTANT GENES ENCODING TUMOR SUPPRESSORS INCLUDING P16, RASSF1A, DLC-1, RUNX3 AND SOCS-1 ARE TARGETS OF EPIGENETIC DYSREGULATION DURING THE DEVELOPMENT OF HCC. THE PRESENT REVIEW DISCUSSES THE IMPORTANCE OF EPIGENETIC REGULATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA MEDIATED REGULATION OF GENE EXPRESSION DURING TUMORIGENESIS AND THEIR USE AS DISEASE BIOMARKERS. FURTHERMORE, THESE EPIGENETIC ALTERATIONS HAVE BEEN DISCUSSED IN RELATIONSHIP WITH PROMISING THERAPEUTIC PERSPECTIVES FOR HCC AND RELATED CANCERS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12   817  39 CHARACTERISTIC PATTERNS OF ALTERED DNA METHYLATION PREDICT EMERGENCE OF HUMAN HEPATOCELLULAR CARCINOMA. WE AIMED TO IDENTIFY THE SPECIFIC SUBSET OF TUMOR SUPPRESSOR GENES (TSGS) THAT ARE METHYLATION-SILENCED DURING THE EARLIEST STEPS OF HEPATOCARCINOGENESIS, AND TO FURTHER EVALUATE WHETHER THESE GENES CAN SERVE AS PREDICTIVE BIOMARKERS OF HEPATOCELLULAR CARCINOMA (HCC) EMERGENCE. A TOTAL OF 482 LIVER TISSUES INCLUDING 177 PAIRS OF HCCS AND MATCHED NONTUMOR LIVERS AND 128 LIVER BIOPSIES FROM CHRONIC HEPATITIS C (CHC) PATIENTS WERE ANALYZED FOR QUANTITATIVE METHYLATION ANALYSIS IN 24 TSG PROMOTERS AND THREE MINT LOCI. THE TUMORS WERE CLASSIFIED AS EARLY, LESS-PROGRESSED, AND HIGHLY PROGRESSED HCCS USING HISTOLOGY AND RADIOLOGICAL APPROACHES. A SUBSET OF TSGS THAT HARBORED DISTINCTLY HIGH LEVELS OF METHYLATION IN EARLY HCCS WERE SELECTED. BASED ON THE METHYLATION PROFILES OF THESE GENES, KAPLAN-MEIER ANALYSES WERE PERFORMED TO DETERMINE TIME-TO-HCC OCCURRENCE IN CHC PATIENTS. SUBSEQUENTLY, MULTIVARIATE ANALYSIS WAS PERFORMED USING AGE, GENDER, FIBROSIS STAGE, AND NUMBER OF METHYLATED TSGS AS COVARIATES. AMONG TSGS ANALYZED, A SUBSET OF EIGHT TSGS (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3, AND PRDM2) DEMONSTRATED A DISTINCT CLUSTER BY HIERARCHICAL CLUSTERING AND RECEIVER OPERATING CHARACTERISTIC ANALYSES. THIS SUBSET OF TSGS SHOWED SIGNIFICANTLY HIGHER METHYLATION LEVELS IN THE EARLY HCCS (P < 0.0001). IN THE CHC PATIENTS, METHYLATION FREQUENCIES IN THESE TSGS WERE ASSOCIATED WITH SHORTER TIME-TO-HCC OCCURRENCE (P < 0.0001), AND NUMBER OF METHYLATED GENES WAS AN INDEPENDENT RISK FACTOR FOR HCC (HAZARD RATIO = 5.21, 95% CONFIDENCE INTERVAL = 2.25-11.76, P = 0.0002). CONCLUSION: EPIGENETIC INACTIVATION OF A SUBSET OF TSGS PLAYS A CRITICAL ROLE IN THE EARLIEST STEPS OF HEPATOCARCINOGENESIS. FURTHERMORE, EPIGENETIC INACTIVATION OF THESE GENES IN CHC PROVIDES A PROGNOSTIC VALUE FOR DETERMINING THE RISK FOR DEVELOPING HCC LATER IN LIFE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13    42  37 A COMPREHENSIVE GENOME-WIDE PROFILING COMPARISON BETWEEN HBV AND HCV INFECTED HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS WORLDWIDE, ESPECIALLY IN EAST ASIA. EVEN WITH THE PROGRESS IN THERAPY, 5-YEAR SURVIVAL RATES REMAIN UNSATISFIED. CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) HAS BEEN EPIDEMIOLOGICALLY ASSOCIATED WITH HCC AND IS THE MAJOR ETIOLOGY IN THE EAST ASIAN POPULATION. THE DETAILED MECHANISM, ESPECIALLY THE CHANGES OF DNA METHYLATION AND GENE EXPRESSION BETWEEN THE TWO TYPES OF VIRUS-RELATED HCC, AND THEIR CONTRIBUTIONS TO THE HCC DEVELOPMENT, METASTASIS, AND RECURRENCE REMAIN LARGELY UNKNOWN. METHODS: IN THIS INTEGRATED ANALYSIS, WE CHARACTERIZED GENOME-SCALE PROFILES OF HBV AND HCV INFECTED HCC BY COMPARING THEIR GENE EXPRESSION PATTERN, METHYLATION PROFILES, AND COPY NUMBER VARIATIONS FROM THE PUBLICLY ACCESSIBLE DATA OF THE CANCER GENOME ATLAS PROGRAM (TCGA). RESULTS: THE HLA-A, STAT1, AND OAS2 GENES WERE HIGHLY ENRICHED AND UP-REGULATED DISCOVERED IN THE HCV-INFECTED HCC. HYPOMETHYLATION BUT NOT COPY NUMBER VARIATIONS MIGHT BE THE MAJOR FACTOR FOR THE UP-REGULATION OF THESE IMMUNE-RELATED GENES IN HCV-INFECTED HCC. CONCLUSIONS: THE RESULTS INDICATED THE DIFFERENT EPIGENETIC CHANGES OF HBV/HCV RELATED HEPATOCARCINOGENESIS. THE TOP UP-REGULATED GENES IN HCV GROUP WERE SIGNIFICANTLY CLUSTERED IN THE IMMUNE-RELATED AND DEFENSE RESPONSE PATHWAYS. THESE FINDINGS WILL HELP US TO UNDERSTAND THE PATHOGENESIS OF HBV/HCV ASSOCIATED HEPATOCELLULAR CARCINOMA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  1342  41 DETECTING ABNORMAL METHYLATION OF TUMOR SUPPRESSOR GENES GSTP1, P16, RIZ1, AND RASSF1A IN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL SIGNIFICANCE. HEPATOCELLULAR CARCINOMA (HCC) HAS A HIGH RATE OF MORTALITY. FURTHER STUDIES INTO EPIGENETIC CHANGES IN HCC, PARTICULARLY THE ABNORMAL METHYLATION OF TUMOR SUPPRESSOR GENES (TSGS), ARE REQUIRED, SINCE THESE CHANGES MAY PROVIDE NOVEL BIOMARKERS FOR EARLY SCREENING AND DIAGNOSIS OF HCC. BY USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), THE PRESENT STUDY DETECTED THE METHYLATION STATUS IN THE PROMOTER REGION OF 4 CANDIDATE TSGS, GSTP1, P16, RIZ1, AND RASSF1A, RESPECTIVELY, IN 35 PAIRED HCC AND TUMOR-ADJACENT LIVER TISSUES IN ADDITION TO 20 NORMAL LIVER TISSUES. THEIR EFFECT ON THE INITIATION AND PROGRESSION OF HCC WAS ALSO INVESTIGATED BY ANALYZING THE CLINICOPATHOLOGICAL DATA. THE RESULTS OF THE PRESENT STUDY REVEALED THAT THE METHYLATION LEVEL OF RIZ1 AND GSTP1 GENES IN HCC WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN THE ADJACENT TISSUES (P<0.01) AND THE NORMAL LIVER TISSUES (P<0.01). THE METHYLATION FREQUENCY OF P16 AND RASSF1A GENES WAS NOT SIGNIFICANTLY INCREASED COMPARED WITH THAT OBSERVED IN THE ADJACENT TISSUES (P>0.05) BUT WAS SIGNIFICANTLY INCREASED COMPARED WITH THE NORMAL TISSUES (P<0.01). IN HCC TISSUES, THE METHYLATION FREQUENCY OF THE GSTP1 GENE IN TUMORS WITH CAPSULAR INVASION WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN TUMORS WITHOUT CAPSULAR INVASION (P<0.05). THE METHYLATION FREQUENCY OF P16 GENE IN HEPATITIS B SURFACE ANTIGEN (HBSAG)-POSITIVE HCC PATIENTS WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN HBSAG-NEGATIVE PATIENTS (P<0.05). THE METHYLATION STATUS OF RIZ1 AND RASSF1A GENES WAS NOT SIGNIFICANTLY CORRELATED WITH THE CLINICOPATHOLOGICAL DATA (P>0.05). PREVIOUS STUDIES HAVE DEMONSTRATED THAT THE METHYLATION STATUS OF RIZ1 AND GSTP1 GENES IS HCC-SPECIFIC, AND THUS MAY BE USED AS A BIOMARKER TO ASSIST THE CLINICAL DIAGNOSIS OF HCC. WHILE THE METHYLATION OF GSTP1 GENE PROMOTER MAY ASSOCIATE WITH THE INVASIVENESS OF HCC, CHRONIC HEPATITIS B VIRUS INFECTION MAY BE THE CAUSE OF METHYLATION-INDUCED P16 INACTIVATION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                  
15   153  51 ABERRANT METHYLATION OF MULTIPLE TUMOR SUPPRESSOR GENES IN AGING LIVER, CHRONIC HEPATITIS, AND HEPATOCELLULAR CARCINOMA. ABERRANT DNA METHYLATION IS AN IMPORTANT EPIGENETIC ALTERATION IN HEPATOCELLULAR CARCINOMA (HCC). HOWEVER, THE MOLECULAR PROCESSES UNDERLYING THE METHYLATOR PHENOTYPE AND THE CONTRIBUTION OF HEPATITIS VIRUSES ARE POORLY UNDERSTOOD. THE CURRENT STUDY IS A COMPREHENSIVE METHYLATION ANALYSIS OF HUMAN LIVER TISSUE SPECIMENS. A TOTAL OF 176 LIVER TISSUES, INCLUDING 77 PAIRS OF HCCS AND MATCHING NONCANCEROUS LIVER AND 22 NORMAL LIVERS, WERE ANALYZED FOR METHYLATION. METHYLATION OF 19 EPIGENETIC MARKERS WAS QUANTIFIED, AND THE RESULTS WERE CORRELATED WITH DIFFERENT DISEASE STATES AND THE PRESENCE OR ABSENCE OF HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) INFECTIONS. BASED ON METHYLATION PROFILES, THE 19 LOCI WERE CATEGORIZED INTO 3 GROUPS. NORMAL LIVER TISSUES SHOWED METHYLATION PRIMARILY IN GROUP 1 LOCI (HIC-1, CASP8, GSTP1, SOCS1, RASSF1A, P16, APC), WHICH WAS SIGNIFICANTLY HIGHER THAN GROUP 2 (CDH1, RUNX3, RIZ1, SFRP2, MINT31) AND GROUP 3 MARKERS (COX2, MINT1, CACNA1G, RASSF2, MINT2, REPRIMO, DCC) (P < 0.0001). NONCANCEROUS LIVERS DEMONSTRATED INCREASED METHYLATION IN BOTH GROUP 1 AND GROUP 2 LOCI. METHYLATION WAS SIGNIFICANTLY MORE ABUNDANT IN HCV-POSITIVE LIVERS COMPARED WITH NORMAL LIVER TISSUES. CONVERSELY, HCC SHOWED FREQUENT METHYLATION AT EACH LOCUS INVESTIGATED IN ALL 3 GROUPS. HOWEVER, THE GROUP 3 LOCI SHOWED MORE DENSE AND FREQUENT METHYLATION IN HCV-POSITIVE CANCERS COMPARED WITH BOTH HBV-POSITIVE CANCERS AND VIRUS-NEGATIVE CANCERS (P < 0.0001). CONCLUSION: METHYLATION IN HCC IS FREQUENT BUT OCCURS IN A GENE-SPECIFIC AND DISEASE-SPECIFIC MANNER. METHYLATION PROFILING ALLOWED US TO DETERMINE THAT ABERRANT METHYLATION IS COMMONLY PRESENT IN NORMAL AGING LIVERS, AND SEQUENTIALLY PROGRESSES WITH ADVANCING STAGES OF CHRONIC VIRAL INFECTION. FINALLY, OUR DATA PROVIDE EVIDENCE THAT HCV INFECTION MAY ACCELERATE THE METHYLATION PROCESS AND SUGGESTS A CONTINUUM OF INCREASING METHYLATION WITH PERSISTENT VIRAL INFECTION AND CARCINOGENESIS IN THE LIVER.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                
16  3146  33 GLOBAL RESEARCH TRENDS ON EPIGENETICS AND NEUROPATHIC PAIN: A BIBLIOMETRIC ANALYSIS. OBJECTIVE: NEUROPATHIC PAIN (NP) IS A COMMON DISEASE THAT MANIFESTS WITH PATHOLOGICAL CHANGES IN THE SOMATOSENSORY SYSTEM. IN RECENT YEARS, THE INTERACTIONS OF NP WITH THE EPIGENETIC MECHANISM HAVE BEEN INCREASINGLY ELUCIDATED. HOWEVER, ONLY A FEW STUDIES HAVE USED BIBLIOMETRIC TOOLS TO SYSTEMATICALLY ANALYZE KNOWLEDGE IN THIS FIELD. THE OBJECTIVE OF THIS STUDY IS TO VISUALLY ANALYZE THE TRENDS, HOTSPOTS, AND FRONTIERS IN EPIGENETICS AND NP RESEARCH BY USING A BIBLIOMETRIC METHOD. METHODS: STUDIES RELATED TO EPIGENETICS AND NP WERE SEARCHED FROM THE SCIENCE CITATION INDEX-EXPANDED OF THE WEB OF SCIENCE CORE COLLECTION DATABASE. SEARCH TIME IS FROM INCEPTION TO NOVEMBER 30, 2022. NO RESTRICTIONS WERE PLACED ON LANGUAGE. ONLY ARTICLES AND REVIEWS WERE INCLUDED AS DOCUMENT TYPES. DATA ON INSTITUTIONS, COUNTRIES, AUTHORS, JOURNAL DISTRIBUTION, AND KEYWORDS WERE IMPORTED INTO CITESPACE SOFTWARE FOR VISUAL ANALYSIS. RESULTS: A TOTAL OF 867 PUBLICATIONS MET THE INCLUSION CRITERIA, WHICH SPANNED THE PERIOD FROM 2000 TO 2022. OVER THE YEARS, THE NUMBER OF PUBLICATIONS AND THE FREQUENCY OF CITATIONS EXHIBITED A CLEAR UPWARD TREND IN GENERAL, REACHING A PEAK IN 2021. THE MAJOR CONTRIBUTING COUNTRIES IN TERMS OF THE NUMBER OF PUBLICATIONS WERE CHINA, THE UNITED STATES, AND JAPAN. THE TOP THREE INSTITUTIONS WERE RUTGERS STATE UNIVERSITY, XUZHOU MEDICAL UNIVERSITY, AND NANJING MEDICAL UNIVERSITY. MOLECULAR PAIN, PAIN, AND JOURNAL OF NEUROINFLAMMATION CONTRIBUTED SIGNIFICANTLY TO THE VOLUME OF ISSUES. AMONG THE TOP 10 AUTHORS IN TERMS OF THE NUMBER OF PUBLICATIONS, TAO YUAN-XIANG CONTRIBUTED 30 ENTRIES, FOLLOWED BY ZHANG YI WITH 24 AND WU SHAO-GEN WITH 20. ON THE BASIS OF THE BURST AND CLUSTERS OF KEYWORDS, "DNA METHYLATION," "CIRCULAR RNA," "ACETYLATION," "LONG NON-CODING RNA," AND "MICROGLIA" ARE GLOBAL HOTSPOTS IN THE FIELD. CONCLUSION: THE BIBLIOMETRIC ANALYSIS INDICATES THAT THE NUMBER OF PUBLICATIONS RELATED TO EPIGENETICS AND NP IS EXHIBITING A RAPID INCREASE. KEYWORD ANALYSIS SHOWS THAT "DNA METHYLATION," "CIRCULAR RNA," "ACETYLATION," "LONG NON-CODING RNA" AND "MICROGLIA" ARE THE MOST INTERESTING TERMS FOR RESEARCHERS IN THE FIELD. MORE RIGOROUS CLINICAL TRIALS AND ADDITIONAL STUDIES THAT EXPLORE RELEVANT MECHANISMS ARE REQUIRED IN THE FUTURE.	2023	
                                                                                                                                                                   
17  6848  48 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  2234  38 EPIGENETIC MODIFICATIONS PRECEDE MOLECULAR ALTERATIONS AND DRIVE HUMAN HEPATOCARCINOGENESIS. DEVELOPMENT OF PRIMARY LIVER CANCER IS A MULTISTAGE PROCESS. DETAILED UNDERSTANDING OF SEQUENTIAL EPIGENETIC ALTERATIONS IS LARGELY MISSING. HERE, WE PERFORMED INFINIUM HUMAN METHYLATION 450K BEADCHIPS AND RNA-SEQ ANALYSES FOR GENOME-WIDE METHYLOME AND TRANSCRIPTOME PROFILING OF CIRRHOTIC LIVER (N = 7), LOW- (N = 4) AND HIGH-GRADE (N = 9) DYSPLASTIC LESIONS, AND EARLY (N = 5) AND PROGRESSED (N = 3) HEPATOCELLULAR CARCINOMAS (HCC) SYNCHRONOUSLY DETECTED IN 8 PATIENTS WITH HCC WITH CHRONIC HEPATITIS B INFECTION. INTEGRATIVE ANALYSES OF EPIGENETICALLY DRIVEN MOLECULAR CHANGES WERE IDENTIFIED AND VALIDATED IN 2 INDEPENDENT COHORTS COMPRISING 887 HCCS. MITOCHONDRIAL DNA SEQUENCING WAS FURTHER EMPLOYED FOR CLONALITY ANALYSES, INDICATING MULTICLONAL ORIGIN IN THE MAJORITY OF INVESTIGATED HCCS. ALTERATIONS IN DNA METHYLATION PROGRESSIVELY INCREASED FROM LIVER CIRRHOSIS (CL) TO DYSPLASTIC LESIONS AND REACHED A MAXIMUM IN EARLY HCCS. ASSOCIATED EARLY ALTERATIONS IDENTIFIED BY INGENUITY PATHWAY ANALYSIS (IPA) INVOLVED APOPTOSIS, IMMUNE REGULATION, AND STEMNESS PATHWAYS, WHILE LATE CHANGES CENTERED ON CELL SURVIVAL, PROLIFERATION, AND INVASION. WE FURTHER VALIDATED 23 PUTATIVE EPIDRIVERS WITH CONCOMITANT EXPRESSION CHANGES AND ASSOCIATED WITH OVERALL SURVIVAL. FUNCTIONALLY, STRIATIN 4 (STRN4) WAS DEMONSTRATED TO BE EPIGENETICALLY REGULATED, AND INHIBITION OF STRN4 SIGNIFICANTLY SUPPRESSED TUMORIGENICITY OF HCC CELL LINES. OVERALL, APPLICATION OF INTEGRATIVE GENOMIC ANALYSES DEFINES EPIGENETIC DRIVER ALTERATIONS AND PROVIDES PROMISING TARGETS FOR POTENTIALLY NOVEL THERAPEUTIC APPROACHES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  2848  31 FREQUENT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS IN NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA. ALTHOUGH TYROSINE KINASE INHIBITORS (TKIS) HAVE SIGNIFICANTLY IMPROVED THE PROGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), THE ABILITY OF TKIS TO ERADICATE CML REMAINS UNCERTAIN AND PATIENTS MUST CONTINUE TKI THERAPY FOR INDEFINITE PERIODS. IN THIS STUDY, WE PERFORMED WHOLE-EXOME SEQUENCING TO IDENTIFY SOMATIC MUTATIONS IN 24 PATIENTS WITH NEWLY DIAGNOSED CHRONIC PHASE CML WHO WERE REGISTERED IN THE JALSG CML212 STUDY. WE IDENTIFIED 191 SOMATIC MUTATIONS OTHER THAN THE BCR-ABL1 FUSION GENE (MEDIAN 8, RANGE 1-17). AGE, HEMOGLOBIN CONCENTRATION AND WHITE BLOOD CELL COUNTS WERE CORRELATED WITH THE NUMBER OF MUTATIONS. PATIENTS WITH MUTATIONS ?6 SHOWED HIGHER RATE OF ACHIEVING MAJOR MOLECULAR RESPONSE THAN THOSE<6 (P=0.0381). MUTATIONS IN EPIGENETIC REGULATOR, ASXL1, TET2, TET3, KDM1A AND MSH6 WERE FOUND IN 25% OF PATIENTS. TET2 OR TET3, AKT1 AND RUNX1 WERE MUTATED IN ONE PATIENT EACH. ASXL1 WAS MUTATED WITHIN EXON 12 IN THREE CASES. MUTATED GENES WERE SIGNIFICANTLY ENRICHED WITH CELL SIGNALING AND CELL DIVISION PATHWAYS. FURTHERMORE, DNA COPY NUMBER ANALYSIS SHOWED THAT 2 OF 24 PATIENTS HAD UNIPARENTAL DISOMY OF CHROMOSOME 1P OR 3Q, WHICH DISAPPEARED MAJOR MOLECULAR RESPONSE WAS ACHIEVED. THESE MUTATIONS MAY PLAY SIGNIFICANT ROLES IN CML PATHOGENESIS IN ADDITION TO THE STRONG DRIVER MUTATION BCR-ABL1.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  3190  39 HCV-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH LIVER CANCER RISK PERSIST AFTER SUSTAINED VIROLOGIC RESPONSE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE EFFECTIVE ANTIVIRAL THERAPIES, THE RISK FOR HCC IS DECREASED BUT NOT ELIMINATED AFTER A SUSTAINED VIROLOGIC RESPONSE (SVR) TO DIRECT-ACTING ANTIVIRAL (DAA) AGENTS, AND THE RISK IS HIGHER IN PATIENTS WITH ADVANCED FIBROSIS. WE INVESTIGATED HCV-INDUCED EPIGENETIC ALTERATIONS THAT MIGHT AFFECT RISK FOR HCC AFTER DAA TREATMENT IN PATIENTS AND MICE WITH HUMANIZED LIVERS. METHODS: WE PERFORMED GENOME-WIDE CHIPMENTATION-BASED CHIP-SEQ AND RNA-SEQ ANALYSES OF LIVER TISSUES FROM 6 PATIENTS WITHOUT HCV INFECTION (CONTROLS), 18 PATIENTS WITH CHRONIC HCV INFECTION, 8 PATIENTS WITH CHRONIC HCV INFECTION CURED BY DAA TREATMENT, 13 PATIENTS WITH CHRONIC HCV INFECTION CURED BY INTERFERON THERAPY, 4 PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION, AND 7 PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS IN EUROPE AND JAPAN. HCV-INDUCED EPIGENETIC MODIFICATIONS WERE MAPPED BY COMPARATIVE ANALYSES WITH MODIFICATIONS ASSOCIATED WITH OTHER LIVER DISEASE ETIOLOGIES. UPA/SCID MICE WERE ENGRAFTED WITH HUMAN HEPATOCYTES TO CREATE MICE WITH HUMANIZED LIVERS AND GIVEN INJECTIONS OF HCV-INFECTED SERUM SAMPLES FROM PATIENTS; MICE WERE GIVEN DAAS TO ERADICATE THE VIRUS. PATHWAYS ASSOCIATED WITH HCC RISK WERE IDENTIFIED BY INTEGRATIVE PATHWAY ANALYSES AND VALIDATED IN ANALYSES OF PAIRED HCC TISSUES FROM 8 PATIENTS WITH AN SVR TO DAA TREATMENT OF HCV INFECTION. RESULTS: WE FOUND CHRONIC HCV INFECTION TO INDUCE SPECIFIC GENOME-WIDE CHANGES IN H3K27AC, WHICH CORRELATED WITH CHANGES IN EXPRESSION OF MRNAS AND PROTEINS. THESE CHANGES PERSISTED AFTER AN SVR TO DAAS OR INTERFERON-BASED THERAPIES. INTEGRATIVE PATHWAY ANALYSES OF LIVER TISSUES FROM PATIENTS AND MICE WITH HUMANIZED LIVERS DEMONSTRATED THAT HCV-INDUCED EPIGENETIC ALTERATIONS WERE ASSOCIATED WITH LIVER CANCER RISK. COMPUTATIONAL ANALYSES ASSOCIATED INCREASED EXPRESSION OF SPHK1 WITH HCC RISK. WE VALIDATED THESE FINDINGS IN AN INDEPENDENT COHORT OF PATIENTS WITH HCV-RELATED CIRRHOSIS (N = 216), A SUBSET OF WHICH (N = 21) ACHIEVED VIRAL CLEARANCE. CONCLUSIONS: IN AN ANALYSIS OF LIVER TISSUES FROM PATIENTS WITH AND WITHOUT AN SVR TO DAA THERAPY, WE IDENTIFIED EPIGENETIC AND GENE EXPRESSION ALTERATIONS ASSOCIATED WITH RISK FOR HCC. THESE ALTERATIONS MIGHT BE TARGETED TO PREVENT LIVER CANCER IN PATIENTS TREATED FOR HCV INFECTION.	2019