1  4232 149 METHYLATION OF RUNX3 IN VARIOUS TYPES OF HUMAN CANCERS AND PREMALIGNANT STAGES OF GASTRIC CARCINOMA. ACCUMULATING EVIDENCE HAS IDENTIFIED A MECHANISM POTENTIALLY RESPONSIBLE FOR THE INACTIVATION OF TUMOR SUPPRESSOR GENES, NAMELY TRANSCRIPTIONAL SILENCING BY ABERRANT METHYLATION OF CPG ISLANDS. A PREVIOUS STUDY HAS SHOWN THE LOSS OF RUNX3 EXPRESSION, DUE TO ABERRANT METHYLATION OF ITS CPG ISLAND, IN GASTRIC CANCER CELL LINES, SUGGESTING THAT RUNX3 IS A TARGET FOR EPIGENETIC GENE SILENCING IN GASTRIC CARCINOGENESIS. HOWEVER, THERE ARE LIMITED DATA ON THE METHYLATION STATUS OF RUNX3 IN THE NEOPLASTIC AND NON-NEOPLASTIC TISSUES IN VARIOUS TYPES OF HUMAN CANCERS, INCLUDING GASTRIC CANCER. HERE, WE REPORT THAT 60% OF GASTRIC CANCER CELL LINES AND 64% OF PRIMARY GASTRIC CARCINOMAS (N=75) WERE METHYLATED AT THE RUNX3 CPG ISLAND. RUNX3 METHYLATION WAS ALSO DETECTED IN HEPATOCELLULAR CARCINOMAS (73%, N=48), LARYNX CANCERS (62%, N=37), LUNG CANCERS (46%, N=24), BREAST CANCERS (25%, N=25), PROSTATE CANCERS (23%, N=44), ENDOMETRIAL CANCERS (12.5%, N=24), COLON CANCERS (4.9%, N=61) AND UTERINE CERVICAL CANCERS (2.5%, N=40), SHOWING THAT RUNX3 METHYLATION IS NOT RESTRICTED TO GASTRIC CANCER. INTERESTINGLY, THE RUNX3 METHYLATION WAS ESPECIALLY FREQUENT IN TUMORS FROM TISSUES OF A FOREGUT DERIVATIVE, THAT IS, THE STOMACH, LIVER, LARYNX AND LUNG. NEXT, THE METHYLATION STATUS OF RUNX3 IN VARIOUS NON-NEOPLASTIC TISSUES WAS EXAMINED, INCLUDING THE PREMALIGNANT LESIONS OF GASTRIC CARCINOMAS. THE RUNX3 METHYLATION WAS FOUND IN 8.1% OF CHRONIC GASTRITIS (N=99), 28.1% OF INTESTINAL METAPLASIA (N=32), 27.3% OF GASTRIC ADENOMAS (N=77) AND 64% OF GASTRIC CARCINOMAS (N=75), BUT NOT IN CHRONIC HEPATITIS B, NORMAL PROSTATE AND COLON MUCOSA, EVEN THOUGH IN CASES OF CHRONIC HEPATITIS, THE METHYLATION FREQUENCY OF ITS NEOPLASTIC TISSUES WAS VERY HIGH. IN CONCLUSION, RUNX3 METHYLATION IS FREQUENTLY FOUND IN HUMAN CANCERS, INCLUDING GASTRIC CANCER, AND IS MOSTLY CANCER SPECIFIC, WITH THE EXCEPTION OF THE STOMACH, AND THUS, MIGHT BE USEFUL AS A POTENTIAL DIAGNOSTIC BIOMARKER OF CANCER.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2   610  32 BEYOND THE GENOME: EPIGENETIC MECHANISMS IN LUNG REMODELING. THE LUNG DEVELOPS FROM A VERY SIMPLE OUTPOUCHING OF THE FOREGUT INTO A HIGHLY COMPLEX, FINELY STRUCTURED ORGAN WITH MULTIPLE SPECIALIZED CELL TYPES THAT ARE REQUIRED FOR ITS NORMAL PHYSIOLOGICAL FUNCTION. DURING BOTH THE DEVELOPMENT OF THE LUNG AND ITS REMODELING IN THE CONTEXT OF DISEASE OR RESPONSE TO INJURY, GENE EXPRESSION MUST BE ACTIVATED AND SILENCED IN A COORDINATED MANNER TO ACHIEVE THE TREMENDOUS PHENOTYPIC HETEROGENEITY OF CELL TYPES REQUIRED FOR HOMEOSTASIS AND PATHOGENESIS. EPIGENETIC MECHANISMS, CONSISTING OF DNA BASE MODIFICATIONS SUCH AS METHYLATION, ALTERATION OF HISTONES RESULTING IN CHROMATIN MODIFICATION, AND THE ACTION OF NONCODING RNA, CONTROL THE REGULATION OF INFORMATION "BEYOND THE GENOME" REQUIRED FOR BOTH LUNG MODELING AND REMODELING. EPIGENETIC REGULATION IS SUBJECT TO MODIFICATION BY ENVIRONMENTAL STIMULI, SUCH AS OXIDATIVE STRESS, INFECTION, AND AGING, AND IS THUS CRITICALLY IMPORTANT IN CHRONIC REMODELING DISORDERS SUCH AS IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BRONCHOPULMONARY DYSPLASIA (BPD), AND PULMONARY HYPERTENSION (PH). TECHNOLOGICAL ADVANCES HAVE MADE IT POSSIBLE TO EVALUATE GENOME-WIDE EPIGENETIC CHANGES (EPIGENOMICS) IN DISEASES OF LUNG REMODELING, CLARIFYING EXISTING PATHOPHYSIOLOGICAL PARADIGMS AND UNCOVERING NOVEL MECHANISMS OF DISEASE. MANY OF THESE REPRESENT NEW THERAPEUTIC TARGETS. ADVANCES IN EPIGENOMIC TECHNOLOGY WILL ACCELERATE OUR UNDERSTANDING OF LUNG DEVELOPMENT AND REMODELING, AND LEAD TO NOVEL TREATMENTS FOR CHRONIC LUNG DISEASES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3  5180  28 PREMALIGNANT CONDITIONS OF GASTRIC CANCER. PREMALIGNANT LESIONS OF GASTRIC CANCER ENCOMPASS A VARIETY OF CONDITIONS SUCH AS CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA, IN WHICH ELEVATED RISK OF DEVELOPING GASTRIC CANCER HAVE BEEN DOCUMENTED. AMONG THEM, INTESTINAL METAPLASIA IS FREQUENTLY ENCOUNTERED IN OUR DAILY ENDOSCOPIC EXAMINATION, YET ITS CLINICAL SIGNIFICANCE IS OFTEN UNDERESTIMATED DESPITE OF A NUMBER OF REPORTS DEMONSTRATING GENETIC AND EPIGENETIC ALTERATIONS IN THE INTESTINAL METAPLASTIC MUCOSA. IN THIS REVIEW, I WILL DESCRIBE THE MOLECULAR MECHANISMS OF PHENOTYPIC CHANGES FROM GASTRIC MUCOSA TO INTESTINAL METAPLASIA BASED ON OUR ANALYSIS OF MOUSE MODEL OF INTESTINAL METAPLASIA GENERATED BY ECTOPIC EXPRESSION OF CDX2 IN CONJUNCTION WITH THE STUDIES WITH HUMAN INTESTINAL METAPLASIA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  6770  45 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  5181  29 PREMALIGNANT LESIONS IN GASTRIC CANCER. DESPITE A PLATEAU IN INCIDENCE, GASTRIC CANCER IS ONE OF THE MOST COMMON CANCERS WORLDWIDE AND CAUSES CONSIDERABLE MORBIDITY AND MORTALITY. PREMALIGNANT GASTRIC LESIONS ARE WELL KNOWN RISK FACTORS FOR THE DEVELOPMENT OF INTESTINAL-TYPE GASTRIC ADENOCARCINOMAS. IN THIS MULTISTEP MODEL OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI CAUSES CHRONIC ACTIVE INFLAMMATION OF THE GASTRIC MUCOSA, WHICH SLOWLY PROGRESSES THROUGH THE PREMALIGNANT STAGES OF ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND ADENOMA/DYSPLASIA TO GASTRIC CARCINOMA. THIS PROGRESSION IS PARALLELED BY A STEPWISE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. DETECTION, TREATMENT, AND MOLECULAR ANALYSES OF PREMALIGNANT LESIONS MAY THUS PROVIDE A BASIS FOR GASTRIC CANCER PREVENTION. THIS REVIEW DESCRIBES AN OVERVIEW OF CURRENT KNOWLEDGE ON PREMALIGNANT GASTRIC LESIONS. IT ALSO REVIEWS THE ISSUE OF SURVEILLANCE OF PATIENTS WITH PREMALIGNANT LESIONS IN ORDER TO IMPROVE THE SURVIVAL OF PATIENTS WITH GASTRIC CANCER.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  3174  33 H19 LNCRNA IDENTIFIED AS A MASTER REGULATOR OF GENES THAT DRIVE UTERINE LEIOMYOMAS. UTERINE LEIOMYOMAS OR FIBROIDS (UFS) ARE BENIGN TUMORS CHARACTERIZED BY HYPERPLASTIC SMOOTH MUSCLE CELLS AND EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM). AFFLICTING ~80% OF WOMEN, AND SYMPTOMATIC IN 25%, UFS BRING TREMENDOUS SUFFERING AND ARE AN ECONOMIC BURDEN WORLDWIDE; THEY CAUSE SEVERE PAIN AND BLEEDING, AND ARE THE LEADING CAUSE OF HYSTERECTOMY. YET, UFS ARE SEVERELY UNDERSTUDIED WITH FEW EFFECTIVE TREATMENT OPTIONS AVAILABLE; THOSE THAT ARE AVAILABLE FREQUENTLY HAVE SIGNIFICANT SIDE EFFECTS SUCH AS MENOPAUSAL SYMPTOMS. RECENTLY, INTEGRATED GENOME-SCALE STUDIES HAVE REVEALED MUTATIONS AND FIBROID SUBTYPE-SPECIFIC EXPRESSION CHANGES IN KEY DRIVER GENES, WITH MED12 AND HMGA2 TOGETHER CONTRIBUTING TO NEARLY 90% OF ALL UFS, BUT THEIR REGULATION OF EXPRESSION IS POORLY CHARACTERIZED. HERE WE REPORT THAT THE EXPRESSION OF H19 LONG NONCODING RNA (LNCRNA) IS ABERRANTLY INCREASED IN UFS. USING CELL CULTURE AND GENOME-WIDE TRANSCRIPTOME AND METHYLATION PROFILING ANALYSES, WE DEMONSTRATE THAT H19 PROMOTES EXPRESSION OF MED12, HMGA2, AND KEY ECM-REMODELING GENES VIA MULTIPLE MECHANISMS INCLUDING A NEW CLASS OF EPIGENETIC MODIFICATION BY TET3. OUR RESULTS MARK THE FIRST EXAMPLE OF AN EVOLUTIONARILY CONSERVED LNCRNA IN PATHOGENESIS OF UFS AND REGULATION OF TET EXPRESSION. GIVEN THE LINK BETWEEN A H19 SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AND INCREASED RISK AND TUMOR SIZE OF UFS, AND THE EXISTENCE OF MULTIPLE FIBROID SUBTYPES DRIVEN BY KEY PATHWAY GENES REGULATED BY H19, WE PROPOSE A UNIFYING MECHANISM FOR PATHOGENESIS OF UTERINE FIBROIDS MEDIATED BY H19 AND IDENTIFY A PATHWAY FOR FUTURE EXPLORATION OF NOVEL TARGET THERAPIES FOR UTERINE LEIOMYOMAS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7   414  32 ANALYSIS OF PROMOTER METHYLATION IN STOOL: A NOVEL METHOD FOR THE DETECTION OF COLORECTAL CANCER. BACKGROUND & AIMS: DETECTION OF TUMOR-DERIVED DNA ALTERATIONS IN STOOL IS AN INTRIGUING NEW APPROACH WITH HIGH POTENTIAL FOR THE NONINVASIVE DETECTION OF COLORECTAL CANCER (CRC). BECAUSE OF HETEROGENEITY OF TUMORS, USUALLY MULTIPLE MARKERS DISTRIBUTED THROUGHOUT THE HUMAN GENOME NEED TO BE ANALYZED. THIS IS LABOR INTENSIVE AND DOES NOT ALLOW FOR HIGH THROUGH-PUT SCREENING. THEREFORE, MARKERS WITH HIGH SENSITIVITY AND GOOD SPECIFICITY ARE NEEDED. WE EXPLORED THE POTENTIAL OF A SINGLE EPIGENETIC MARKER IN COMPARISON WITH FECAL OCCULT BLOOD TESTING (FOBT) FOR THE DISCRIMINATION OF PATIENTS WITH CRCS AND ADENOMAS FROM THOSE WITHOUT. METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) WAS PERFORMED TO ANALYZE HYPERMETHYLATED IN CANCER 1 (HIC1) PROMOTER METHYLATION STATUS IN A BLINDED FASHION IN STOOL SAMPLES FROM 26 PATIENTS WITH CRC, 13 WITH ADENOMA > OR =1 CM, 9 WITH HYPERPLASTIC POLYPS, 9 WITH CHRONIC INFLAMMATORY BOWEL DISEASE, AND 32 WITH ENDOSCOPICALLY NORMAL COLON. RESULTS: NINETY-SEVEN PERCENT OF THE STOOL SAMPLES CONTAINED AMPLIFIABLE DNA. FORTY-TWO PERCENT OF THE SAMPLES FROM PATIENTS WITH CRC AND 31% OF THE SAMPLES FROM PATIENTS WITH COLORECTAL ADENOMA > OR =1 CM WERE POSITIVE FOR HIC1 PROMOTER METHYLATION. NO METHYLATED HIC1 PROMOTER DNA WAS DETECTED IN THE FECAL DNA FROM PATIENTS WITH ENDOSCOPICALLY NORMAL COLON OR HYPERPLASTIC POLYPS. CONCLUSIONS: THE EPIGENETIC MARKER HIC1 PROMOTER METHYLATION CARRIES HIGH POTENTIAL FOR THE REMOTE DETECTION OF CRCS. WE POSTULATE THAT A PANEL OF MERELY A FEW GENETIC AND EPIGENETIC MARKERS WILL BE REQUIRED FOR THE HIGHLY SENSITIVE AND SPECIFIC DETECTION OF CRCS AND ADENOMAS IN FECAL SAMPLES FROM AFFECTED PATIENTS.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  5338  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  3413  36 HSA-MIR-29C AND HSA-MIR-135B DIFFERENTIAL EXPRESSION AS POTENTIAL BIOMARKER OF GASTRIC CARCINOGENESIS. AIM: TO INVESTIGATE THE EXPRESSION PROFILES OF HSA-MIR-29C AND HSA-MIR-135B IN GASTRIC MUCOSAL SAMPLES AND THEIR VALUES AS GASTRIC CARCINOGENESIS BIOMARKERS. METHODS: THE EXPRESSION LEVELS OF HSA-MIR-29C AND HSA-MIR-135B IN NORMAL GASTRIC MUCOSA, NON-ATROPHIC CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA WERE ANALYSED USING QUANTITATIVE REAL-TIME PCR. THE DIFFERENCE BETWEEN HSA-MIR-29C AND HSA-MIR-135B EXPRESSION PROFILES IN THE GROUPED SAMPLES WAS EVALUATED BY ANOVA AND STUDENT'S T-TEST TESTS. THE RESULTS WERE ADJUSTED FOR MULTIPLE TESTING BY USING BONFERRONI'S CORRECTION. P VALUES </= 0.05 WERE CONSIDERED STATISTICALLY SIGNIFICANT. TO EVALUATE HSA-MIR-29C AND HSA-MIR-135B EXPRESSIONS AS POTENTIAL BIOMARKERS OF GASTRIC CARCINOGENESIS, WE PERFORMED A RECEIVER OPERATING CHARACTERISTIC CURVE ANALYSIS AND THE DERIVED AREA UNDER THE CURVE, AND A CATEGORICAL PRINCIPAL COMPONENTS ANALYSIS. IN SILICO IDENTIFICATION OF THE GENETIC TARGETS OF HSA-MIR-29C AND HSA-MIR-135B WAS PERFORMED USING DIFFERENT PREDICTION TOOLS, IN ORDER TO IDENTIFY POSSIBLE GENES INVOLVED IN GASTRIC CARCINOGENESIS. RESULTS: THE EXPRESSION LEVELS OF HSA-MIR-29C WERE HIGHER IN NORMAL GASTRIC MUCOSAL SAMPLES, AND DECREASED PROGRESSIVELY IN NON-ATROPHIC CHRONIC GASTRITIS SAMPLES, INTESTINAL METAPLASIA SAMPLES AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA SAMPLES. THE EXPRESSION OF HSA-MIR-29C IN THE GASTRIC LESIONS SHOWED THAT NON-ATROPHIC GASTRITIS HAVE AN INTERMEDIATE PROFILE TO GASTRIC NORMAL MUCOSA AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA, AND THAT INTESTINAL METAPLASIA SAMPLES PRESENTED AN EXPRESSION PATTERN SIMILAR TO THAT IN INTESTINAL-TYPE GASTRIC ADENOCARCINOMA. THIS MICRORNA (MIRNA) HAS A GOOD DISCRIMINATORY ACCURACY BETWEEN NORMAL GASTRIC SAMPLES AND (1) INTESTINAL-TYPE GASTRIC ADENOCARCINOMA; AND (2) INTESTINAL METAPLASIA, AND REGULATES THE DMNT3A ONCOGENE. HSA-MIR-135B IS UP-REGULATED IN NON-ATROPHIC CHRONIC GASTRITIS AND INTESTINAL METAPLASIA SAMPLES AND DOWN-REGULATED IN NORMAL GASTRIC MUCOSA AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA SAMPLES. NON-ATROPHIC CHRONIC GASTRITIS AND INTESTINAL METAPLASIA ARE SIGNIFICANTLY DIFFERENT FROM NORMAL GASTRIC MUCOSA SAMPLES. HSA-MIR-135B EXPRESSION PRESENTED A GREATER DISCRIMINATORY ACCURACY BETWEEN NORMAL SAMPLES AND GASTRIC LESIONS. THIS MIRNA WAS ASSOCIATED WITH HELICOBACTER PYLORI PRESENCE IN NON-ATROPHIC CHRONIC GASTRITIS SAMPLES AND REGULATES THE APC AND KLF4 TUMOUR SUPPRESSOR GENES. CONCLUSION: OUR RESULTS PROVIDE EVIDENCE OF EPIGENETIC ALTERATIONS IN NON-ATROPHIC CHRONIC GASTRITIS AND INTESTINAL METAPLASIA AND SUGGEST THAT HSA-MIR-29C AND HSA-MIR-135B ARE PROMISING BIOMARKERS OF GASTRIC CARCINOGENESIS.	2016	

10  1031  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  5277  44 PROMOTER METHYLATION PROFILE IN PRENEOPLASTIC AND NEOPLASTIC GALLBLADDER LESIONS. GALLBLADDER CARCINOMA (GBC) IS A HIGHLY MALIGNANT NEOPLASM AND REPRESENTS THE LEADING CAUSE OF CANCER DEATH IN CHILEAN WOMEN. IN ORDER TO DETERMINE THE POTENTIAL ROLE OF PROMOTER METHYLATION IN GALLBLADDER CARCINOGENESIS, WE INVESTIGATED THE FREQUENCY OF THIS EPIGENETIC MECHANISM BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) IN 35 CHRONIC CHOLECYSTITIS (CC, SEPARATED ACCORDING TO THE PRESENCE OR ABSENCE OF METAPLASIA), 19 EARLY CANCERS (MUCOSA OR MUSCULARIS PROPIA INVASION) AND 48 ADVANCED CARCINOMAS WITH INVASION OF THE GALLBLADDER SUBSEROSA (25 CASES) AND SEROSA (23 CASES). WE EXAMINED 14 GENES AND OBSERVED AN INCREASE OF MULTIGENIC METHYLATION DURING TUMORAL PROGRESSION WHICH WAS NOT SIGNIFICANTLY ASSOCIATED WITH THE PATIENT'S AGE. FOUR GENES (DAPK1, DLC1, TIMP3, AND RARBETA2) DISPLAYED A PROGRESSIVE INCREASE IN THEIR METHYLATION STATUS FROM CC WITHOUT METAPLASIA TO ADVANCED CARCINOMA INVADING THE SEROSA LAYER (P <OR= 0.05). THE SURVIVAL ANALYSIS INDICATED THAT A METHYLATED CONDITION OF DLC1 GENE IS SIGNIFICANTLY ASSOCIATED WITH POOR PROGNOSIS (P = 0.04), WHEREAS A METHYLATED STATE OF MGMT GENE CORRELATED WITH BETTER PATIENT SURVIVAL (P = 0.006). OUR FINDINGS INDICATE THAT ABERRANT HYPERMETHYLATION OF PROMOTER REGIONS IS AN EARLY, PROGRESSIVE AND CUMULATIVE EVENT IN GALLBLADDER CARCINOGENESIS. FURTHERMORE, THE METHYLATION LEVELS SEEMS TO ACCUMULATE IN THE PROGRESSION OF CC WITHOUT METAPLASIA TO CC WITH METAPLASIA, A FACT THAT COULD PROVIDE NEW EVIDENCE TO CONSIDER THIS MORPHOLOGICAL ADAPTATION OF GB MUCOSA AS A PREMALIGNANT LESION. FINALLY, THE METHYLATION STATUS OF SOME INDIVIDUAL GENES COULD BE USEFUL BIOMARKERS WITH POTENTIAL CLINICAL APPLICATION IN DIAGNOSIS OR PROGNOSIS OF GBC IF THEY ARE VALIDATED IN A GREATER NUMBER OF CLINICAL SAMPLES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  1582  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13   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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  4904  45 P16INK4A GENE ALTERATIONS ARE NOT A PROGNOSTIC INDICATOR FOR SURVIVAL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA UNDERGOING CURATIVE HEPATECTOMY. BACKGROUND AND AIM: HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON MALIGNANCY WORLDWIDE THAT IS HIGHLY ASSOCIATED WITH CHRONIC HEPATITIS B OR C INFECTION AND CIRRHOSIS. THE TUMOR SUPPRESSOR GENE P16INK4A IS AN IMPORTANT COMPONENT OF THE CELL CYCLE AND INACTIVATION OF THE GENE HAS BEEN FOUND IN A VARIETY OF HUMAN CANCERS. THE PRESENT STUDY WAS PERFORMED TO DETERMINE GENETIC AND EPIGENETIC ALTERATIONS IN THE P16INK4A TUMOR SUPPRESSOR GENE AND THE EFFECT OF THESE ON HCC PROGRESSION. METHODS: THE STATUS OF P16INK4A WAS EVALUATED IN 117 HCC TUMORAL NODULES AND 110 CORRESPONDING PERITUMORAL TISSUES BY LOSS OF HETEROZIGOSITY (LOH) AT THE 9P21-22 REGION, HOMOZYGOUS DELETIONS, SINGLE-STRAND CONFORMATION POLYMORPHISM-POLYMERASE CHAIN REACTION (PCR) MUTATIONAL ANALYSIS AND METHYLATION SPECIFIC PCR. RESULTS: THE MOST FREQUENT INACTIVATION MECHANISM WAS HYPERMETHYLATION OF THE PROMOTER REGION, WHICH WAS FOUND IN 63.2% OF THE TUMOR SAMPLES AND IN 28.2% OF THE PERITUMORAL SAMPLES. LOSS OF HETEROZYGOSITY AT THE 9P21 REGION WAS DETECTED IN 27.3% AND 10% OF TUMOR AND PERITUMORAL TISSUES, RESPECTIVELY. HOMOZYGOUS DELETIONS AND MUTATIONS WERE LESS COMMON EVENTS IN HEPATOCARCINOGENESIS. THE AUTHORS FOUND 5.9% OF THE TUMOR CASES WITH EXON 2 HOMOZYGOUS DELETIONS AND 8.6% WITH MUTATIONS. TWO POLYMORPHISMS WERE DETECTED, ONE AT CODON 148 (GCG --> ACG, ALA --> THR) IN THREE CASES AND THE OTHER IN EXON 3 AT 540 BP (34.2% OF THE SAMPLES). NO ASSOCIATION WAS FOUND BETWEEN INACTIVATION OF P16INK4A AND CLINICOPATHOLOGICAL CHARACTERISTICS OR PROGNOSIS. CONCLUSION: P16INK4A IS ALTERED FREQUENTLY AND EARLY IN HCC, BEING THE PREDOMINANT MECHANISM OF INACTIVATION PROMOTER HYPERMETHYLATION. THE PRESENT RESULTS SUGGEST THAT THE P16INK4A GENE PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF HCC.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15  1484  39 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  1544  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17   401  40 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18   824  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19   342  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  5960  33 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