1  6381 144 THE ROLE OF ONCOGENIC DNA VIRUSES IN PENILE CANCER DEVELOPMENT. PENILE CANCER IS A RELATIVELY RARE NEOPLASIA IN DEVELOPED COUNTRIES, WITH SIGNIFICANT MORBIDITY AND MORTALITY IN DEVELOPING COUNTRIES. PENILE CANCER CAN BE SUBDIVIDED INTO HUMAN PAPILLOMAVIRUS (HPV)-POSITIVE AND HPV-NEGATIVE CASES. WORLDWIDE, THE HPV PREVALENCE IN PENILE CANCER SAMPLES IS AROUND 50%, AND HPV16 IS THE MOST PREVALENT GENOTYPE. ALTHOUGH HPV IS AN IMPORTANT FACTOR FOR CANCER DEVELOPMENT, OTHER ONCOGENIC FACTORS MAY BE ASSOCIATED WITH CARCINOGENESIS. SOME OF THESE FACTORS CAN BE INFECTIOUS, SUCH AS THE EPSTEIN-BARR VIRUS (EBV), AS WELL AS THE MERKEL CELL POLYOMAVIRUS (MCPYV). THE PREVALENCE RATES OF NEARLY 50% FOR BOTH HPV AND EBV INFECTIONS INDICATE AN IMPORTANT ROLE OF THESE VIRUSES IN PENILE TISSUE MALIGNANCY, REINFORCING THE IDEA OF A MULTIFACTORIAL ETIOLOGY OF THE DISEASE. ALTHOUGH THE HPV ROLE IS BETTER UNDERSTOOD, EBV IS THOUGHT TO FACILITATE PERSISTENCE, INTEGRATION, AND MUTATIONS. RECENT STUDIES ON THE MERKEL CELL POLYOMAVIRUS HAVE NOT SHOWN A RELEVANT PREVALENCE IN PENILE CANCER SAMPLES, BUT ITS PRESENCE INDICATES THE OPPORTUNISTIC INFECTIOUS POTENTIAL OF THIS VIRUS. REGARDING HPV-NEGATIVE CASES, THE LITERATURE SUGGESTS A LINK WITH YOUNGER AGE AND EPIGENETIC ALTERATIONS, MAINLY THROUGH THE P16INK4A PATHWAY. RECENTLY, SEVERAL BIOMARKERS THAT MIGHT ACT AS PROGNOSTIC TOOLS (E.G., KI-67, SQUAMOUS CELL CARCINOMA ANTIGEN, AMONG OTHERS) HAVE BEEN PROPOSED, BUT THE RESULTS REMAIN CONTROVERSIAL. IN ADDITION, OTHER RISK FACTORS HAVE ALSO BEEN ASSOCIATED WITH PENILE CARCINOGENESIS, SUCH AS THE PRESENCE OF PHIMOSIS, NONCIRCUMCISION, CHRONIC INFLAMMATION, AND NUMBER OF SEXUAL PARTNERS. FURTHER STUDIES ARE NEEDED TO DEVELOP TOOLS FOR EARLY DETECTION AND EPIDEMIOLOGICAL SURVEILLANCE OF PENILE CANCER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  5582  36 ROLE OF NITRATIVE AND OXIDATIVE DNA DAMAGE IN INFLAMMATION-RELATED CARCINOGENESIS. CHRONIC INFLAMMATION INDUCED BY BIOLOGICAL, CHEMICAL, AND PHYSICAL FACTORS HAS BEEN FOUND TO BE ASSOCIATED WITH THE INCREASED RISK OF CANCER IN VARIOUS ORGANS. WE REVEALED THAT INFECTIOUS AGENTS INCLUDING LIVER FLUKE, HELICOBACTER PYLORI, AND HUMAN PAPILLOMA VIRUS AND NONINFECTIOUS AGENTS SUCH AS ASBESTOS FIBER INDUCED INOS-DEPENDENT FORMATION OF 8-NITROGUANINE AND 8-OXO-7, 8-DIHYDRO-2'-DEOXYGUANOSINE (8-OXODG) IN CANCER TISSUES AND PRECANCEROUS REGIONS. OUR RESULTS WITH THE COLOCALIZATION OF PHOSPHORYLATED ATM AND GAMMA-H2AX WITH 8-OXODG AND 8-NITROGUANINE IN INFLAMMATION-RELATED CANCER TISSUES SUGGEST THAT DNA BASE DAMAGE LEADS TO DOUBLE-STRANDED BREAKS. IT IS INTERESTING FROM THE ASPECT OF GENETIC INSTABILITY. WE ALSO DEMONSTRATED IL-6-MODULATED INOS EXPRESSION VIA STAT3 AND EGFR IN EPSTEIN-BARR-VIRUS-ASSOCIATED NASOPHARYNGEAL CARCINOMA AND FOUND PROMOTER HYPERMETHYLATION IN SEVERAL TUMOR SUPPRESSOR GENES. SUCH EPIGENETIC ALTERATION MAY OCCUR BY CONTROLLING THE DNA METHYLATION THROUGH IL-6-MEDIATED JAK/STAT3 PATHWAYS. COLLECTIVELY, 8-NITROGUANINE WOULD BE A USEFUL BIOMARKER FOR PREDICTING THE RISK OF INFLAMMATION-RELATED CANCERS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  3671  45 INFLAMMATION AND CANCER. INFECTION AND INFLAMMATION ACCOUNT FOR APPROXIMATELY 25% OF CANCER-CAUSING FACTORS. INFLAMMATION-RELATED CANCERS ARE CHARACTERIZED BY MUTAGENIC DNA LESIONS, SUCH AS 8-OXO-7,8-DIHYDRO-2'-DEOXYGUANOSINE (8-OXODG) AND 8-NITROGUANINE. OUR PREVIOUS STUDIES DEMONSTRATED THE FORMATION OF 8-OXODG AND 8-NITROGUANINE IN THE TISSUES OF CANCER AND PRECANCEROUS LESIONS DUE TO INFECTION (E.G., OPISTHORCHIS VIVERRINI-RELATED CHOLANGIOCARCINOMA, SCHISTOSOMA HAEMATOBIUM-ASSOCIATED BLADDER CANCER, HELICOBACTER PYLORI-INFECTED GASTRIC CANCER, HUMAN PAPILLOMAVIRUS-RELATED CERVICAL CANCER, EPSTEIN-BARR VIRUS-INFECTED NASOPHARYNGEAL CARCINOMA) AND PRO-INFLAMMATORY FACTORS (E.G., ASBESTOS, NANOMATERIALS, AND INFLAMMATORY DISEASES SUCH AS BARRETT'S ESOPHAGUS AND ORAL LEUKOPLAKIA). INTERESTINGLY, SEVERAL OF OUR STUDIES SUGGESTED THAT INFLAMMATION-ASSOCIATED DNA DAMAGE IN CANCER STEM-LIKE CELLS LEADS TO CANCER DEVELOPMENT WITH AGGRESSIVE CLINICAL FEATURES. REACTIVE OXYGEN/NITROGEN SPECIES FROM INFLAMMATION DAMAGE NOT ONLY DNA BUT ALSO OTHER BIOMACROMOLECULES, SUCH AS PROTEINS AND LIPIDS, RESULTING IN THEIR DYSFUNCTION. WE IDENTIFIED OXIDATIVELY DAMAGED PROTEINS IN CANCER TISSUES BY 2D OXYBLOT FOLLOWED BY MALDI-TOF/TOF. AS AN EXAMPLE, OXIDATIVELY DAMAGED TRANSFERRIN RELEASED IRON ION, WHICH MAY MEDIATE FENTON REACTIONS AND GENERATE ADDITIONAL REACTIVE OXYGEN SPECIES. DYSFUNCTION OF ANTI-OXIDATIVE PROTEINS DUE TO THIS DAMAGE MIGHT INCREASE OXIDATIVE STRESS. SUCH DAMAGE IN BIOMACROMOLECULES MAY FORM A VICIOUS CYCLE OF OXIDATIVE STRESS, LEADING TO CANCER DEVELOPMENT. EPIGENETIC ALTERATIONS SUCH AS DNA METHYLATION AND MICRORNA DYSREGULATION PLAY VITAL ROLES IN CARCINOGENESIS, ESPECIALLY IN INFLAMMATION-RELATED CANCERS. WE EXAMINED EPIGENETIC ALTERATIONS, DNA METHYLATION AND MICRORNA DYSREGULATION, IN EPSTEIN-BARR VIRUS-RELATED NASOPHARYNGEAL CARCINOMA IN THE ENDEMIC AREA OF SOUTHERN CHINA AND FOUND SEVERAL DIFFERENTIALLY METHYLATED TUMOR SUPPRESSOR GENE CANDIDATES BY USING A NEXT-GENERATION SEQUENCER. AMONG THESE CANDIDATES, WE REVEALED HIGHER METHYLATION RATES OF RAS-LIKE ESTROGEN-REGULATED GROWTH INHIBITOR (RERG) IN BIOPSY SPECIMENS OF NASOPHARYNGEAL CARCINOMA MORE CONVENIENTLY BY USING RESTRICTION ENZYME-BASED REAL-TIME PCR. THIS RESULT MAY HELP TO IMPROVE CANCER SCREENING STRATEGIES. WE PROFILED MICRORNAS OF NASOPHARYNGEAL CARCINOMA TISSUES USING MICROARRAYS. QUANTITATIVE RT-PCR ANALYSIS CONFIRMED THE CONCORDANT DOWNREGULATION OF MIR-497 IN CANCER TISSUES AND PLASMA, SUGGESTING THAT PLASMA MIR-497 COULD BE USED AS A DIAGNOSTIC BIOMARKER FOR NASOPHARYNGEAL CARCINOMA. CHRONIC INFLAMMATION PROMOTES GENETIC AND EPIGENETIC ABERRATIONS, WITH VARIOUS PATHOGENESES. THESE CHANGES MAY BE USEFUL BIOMARKERS IN LIQUID BIOPSY FOR EARLY DETECTION AND PREVENTION OF CANCER.	2018	
                                                                                                                                                                                                                                                                               
4  3597  53 IMPLICATIONS OF VIRAL INFECTIONS AND ONCOGENESIS IN UTERINE CERVICAL CARCINOMA ETIOLOGY AND PATHOGENESIS. BACKGROUND: UTERINE CERVICAL CARCINOMA (UCC) IS THE MOST PREVALENT GYNECOLOGICAL MALIGNANCY GLOBALLY, WITH A RISING INCIDENCE IN RECENT YEARS. ACCUMULATING EVIDENCE INDICATES THAT SPECIFIC VIRAL INFECTIONS, INCLUDING HUMAN PAPILLOMAVIRUS (HPV), EPSTEIN-BARR VIRUS (EBV), HEPATITIS B AND C VIRUSES (HBV AND HCV), AND HUMAN HERPESVIRUS (HHV), MAY CONTRIBUTE TO UCC DEVELOPMENT AND PROGRESSION. UNDERSTANDING THE COMPLEX INTERPLAY BETWEEN VIRAL INFECTIONS AND UCC RISK IS CRUCIAL FOR DEVELOPING NOVEL PREVENTATIVE AND THERAPEUTIC INTERVENTIONS. METHODS: THIS COMPREHENSIVE REVIEW INVESTIGATES THE ASSOCIATION BETWEEN VIRAL INFECTIONS AND UCC RISK BY EXAMINING THE ROLES OF VARIOUS VIRAL PATHOGENS IN UCC ETIOLOGY AND PATHOGENESIS, AND POSSIBLE MOLECULAR MECHANISMS. ADDITIONALLY, WE EVALUATE CURRENT DIAGNOSTIC METHODS AND POTENTIAL THERAPEUTIC STRATEGIES TARGETING VIRAL INFECTIONS FOR UCC PREVENTION OR TREATMENT. RESULTS: THE PREVENTION OF UCC HAS BEEN SIGNIFICANTLY ADVANCED BY THE EMERGENCE OF SELF-SAMPLING FOR HPV TESTING AS A CRUCIAL TOOL, ALLOWING FOR EARLY DETECTION AND INTERVENTION. HOWEVER, AN ESSENTIAL CHALLENGE IN UCC PREVENTION LIES IN UNDERSTANDING HOW HPV AND OTHER VIRAL COINFECTIONS, INCLUDING EBV, HBV, HCV, HHV, HIV, OR THEIR CONCURRENT PRESENCE, MAY POTENTIALLY CONTRIBUTE TO UCC DEVELOPMENT. THE MOLECULAR MECHANISMS IMPLICATED IN THE ASSOCIATION BETWEEN VIRAL INFECTIONS AND CERVICAL CANCER DEVELOPMENT INCLUDE: (1) INTERFERENCE OF VIRAL ONCOGENES WITH CELLULAR REGULATORY PROTEINS, RESULTING IN UNCONTROLLED CELL PROLIFERATION AND MALIGNANT TRANSFORMATION; (2) INACTIVATION OF TUMOR SUPPRESSOR GENES BY VIRAL PROTEINS; (3) EVASION OF HOST IMMUNE RESPONSES BY VIRUSES; (4) INDUCTION OF A PERSISTENT INFLAMMATORY RESPONSE, CONTRIBUTING TO A TUMOR-PROMOTING MICROENVIRONMENT; (5) EPIGENETIC MODIFICATIONS THAT LEAD TO ABERRANT GENE EXPRESSION; (6) STIMULATION OF ANGIOGENESIS BY VIRUSES; AND (7) ACTIVATION OF TELOMERASE BY VIRAL PROTEINS, LEADING TO CELLULAR IMMORTALIZATION. ADDITIONALLY, VIRAL COINFECTIONS CAN ALSO ENHANCE ONCOGENIC POTENTIAL THROUGH SYNERGISTIC INTERACTIONS BETWEEN VIRAL ONCOPROTEINS, EMPLOY IMMUNE EVASION STRATEGIES, CONTRIBUTE TO CHRONIC INFLAMMATION, MODULATE HOST CELLULAR SIGNALING PATHWAYS, AND INDUCE EPIGENETIC ALTERATIONS, ULTIMATELY LEADING TO CERVICAL CARCINOGENESIS. CONCLUSION: RECOGNIZING THE IMPLICATIONS OF VIRAL ONCOGENES IN UCC ETIOLOGY AND PATHOGENESIS IS VITAL FOR ADDRESSING THE ESCALATING BURDEN OF UCC. DEVELOPING INNOVATIVE PREVENTATIVE AND THERAPEUTIC INTERVENTIONS REQUIRES A THOROUGH UNDERSTANDING OF THE INTRICATE RELATIONSHIP BETWEEN VIRAL INFECTIONS AND UCC RISK.	2023	
                                                                                                                                                                                                                                                                                                                                            
5  5115  38 PORTRAIT OF DNA METHYLATED GENES PREDICTIVE OF POOR PROGNOSIS IN HEAD AND NECK CANCER AND THE IMPLICATION FOR TARGETED THERAPY. IN ADDITION TO CHRONIC INFECTION WITH HUMAN PAPILLOMA VIRUS (HPV) AND EXPOSURE TO ENVIRONMENTAL CARCINOGENS, GENETIC AND EPIGENETIC FACTORS ACT AS MAJOR RISK FACTORS FOR HEAD AND NECK CANCER (HNC) DEVELOPMENT AND PROGRESSION. HERE, WE CONDUCTED A SYSTEMATIC REVIEW IN ORDER TO ASSESS WHETHER DNA HYPERMETHYLATED GENES ARE PREDICTIVE OF HIGH RISK OF DEVELOPING HNC AND/OR IMPACT ON SURVIVAL AND OUTCOMES IN NON-HPV/NON-TOBACCO/NON-ALCOHOL ASSOCIATED HNC. WE IDENTIFIED 85 STUDIES COVERING 32,187 SUBJECTS WHERE THE RELATIONSHIP BETWEEN DNA METHYLATION, RISK FACTORS AND SURVIVAL OUTCOMES WERE ADDRESSED. CHANGES IN DNA HYPERMETHYLATION WERE IDENTIFIED FOR 120 GENES. INTERACTOME ANALYSIS REVEALED ENRICHMENT IN COMPLEX REGULATORY PATHWAYS THAT COORDINATE CELL CYCLE PROGRESSION (CCNA1, SFN, ATM, GADD45A, CDK2NA, TP53, RB1 AND RASSF1). HOWEVER, NOT ALL THESE GENES SHOWED SIGNIFICANT STATISTICAL ASSOCIATION WITH ALCOHOL CONSUMPTION, TOBACCO AND/OR HPV INFECTION IN THE MULTIVARIATE ANALYSIS. GENES WITH THE MOST ROBUST HNC RISK ASSOCIATION INCLUDED TIMP3, DCC, DAPK, CDH1, CCNA1, MGMT, P16, MINT31, CD44, RARBETA. FROM THESE CANDIDATES, WE FURTHER VALIDATED CD44 AT TRANSLATIONAL LEVEL IN AN INDEPENDENT COHORT OF 100 PATIENTS WITH TONGUE CANCER FOLLOWED-UP BEYOND 10 YEARS. CD44 EXPRESSION WAS ASSOCIATED WITH HIGH-RISK OF TUMOR RECURRENCE AND METASTASIS (P = 0.01) IN HPV-CASES. IN SUMMARY, GENES REGULATED BY METHYLATION PLAY A MODULATORY FUNCTION IN HNC SUSCEPTIBILITY AND IT REPRESENT A CRITICAL THERAPEUTIC TARGET TO MANAGE PATIENTS WITH ADVANCED DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  2842  33 FREQUENT CONCOMITANT EPIGENETIC SILENCING OF SOX1 AND SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) IN HUMAN HEPATOCELLULAR CARCINOMA. BACKGROUND AND AIM: EXCEPT FOR GENETIC MUTATIONS, EPIGENETIC CHANGES ARE ALSO INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS. RECENTLY, WE HAVE IDENTIFIED SOX1, SRY (SEX DETERMINING REGION Y)-BOX 1, IS HYPERMETHYLATED IN CERVICAL CANCER AND OVARIAN CANCER. THEREFORE, WE INVESTIGATED WHETHER PROMOTER HYPERMETHYLATION OF SOX1 IS COMMON IN HEPATOCELLULAR CARCINOMA (HCC). METHODS: WE USED METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MS-PCR) AND BISULFITE SEQUENCING TO ANALYZE THE METHYALTION LEVEL OF THE SOX1 PROMOTER IN SEVEN HCC CELL LINES, 54 CLINICAL HCCS, 42 CIRRHOTIC LIVERS, 21 LIVERS WITH CHRONIC HEPATITIS, AND 15 CONTROL LIVERS. THEN, WE EMPLOYED QUANTITATIVE MS-PCR (QMSP) TO VALIDATE IN AN INDEPENDENT SET OF SAMPLES (60 PAIRED HCCS AND 30 CONTROL LIVERS). FINALLY, WE USED LUCIFERASE REPORTER AND COLONY FORMATION ASSAY TO CHECK THE EFFECT OF SOX1 IN HCC. RESULTS: PROMOTER METHYLATION OF SOX1 WAS SIGNIFICANTLY FREQUENT IN HCC CELL LINES AND CLINICAL HCCS, CIRRHOTIC LIVERS, BUT NOT IN CONTROL LIVERS (P < 0.0001). THERE IS A SIGNIFICANT CORRELATION BETWEEN DOWNREGULATION OF SOX1 EXPRESSION AND PROMOTER METHYLATION. QMSP RESULTS CONFIRMED THAT PROMOTER HYPERMETHYLATION OF SOX1 IS SIGNIFICANTLY MORE FREQUENT IN HCCS THAN CONTROL LIVERS (P < 0.0001). THE FREQUENCY OF SOX1 METHYLATION IN PATIENTS WITH SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) METHYLATION IS SIGNIFICANTLY HIGHER THAN IN PATIENTS WITHOUT SFRPS METHYLATION (P < 0.0001). FURTHERMORE, ECTOPIC EXPRESSION OF SOX1 COULD SUPPRESS T-CELL FACTOR-DEPENDENT TRANSCRIPTIONAL ACTIVITY AND COLONY FORMATION NUMBER IN HCCS. CONCLUSIONS: CONCOMITANT EPIGENETIC SILENCING OF SOX1 AND SFRPS THROUGH PROMOTER HYPERMETHYLATION IS FREQUENT IN HCCS, AND THIS MIGHT CONTRIBUTE TO ABNORMAL ACTIVATION OF CANONICAL WNT SIGNAL PATHWAY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7   864  37 CHROMOSOMAL INSTABILITY IN ORAL SQUAMOUS CELL CARCINOMA. ORAL SQUAMOUS CELL CARCINOMA (OSCC) DEMONSTRATES AN INCREASING RATE DUE TO HIGH RISK HUMAN PAPILLOMA VIRUS (HR-HPV) PERSISTENT INFECTION, AND ALSO TO CHRONIC CIGARETTE AND ALCOHOL CONSUMPTION. GROSS CHROMOSOMAL ALTERATIONS (POLYSOMY, ANEUPLOIDY, INTRA-CHROMOSOME REARRANGEMENTS) AND SPECIFIC GENE ABERRATIONS SUCH AS AMPLIFICATIONS, DELETIONS, POINT MUTATIONS COMBINED OR NOT WITH EPIGENETIC ONES (PROMOTER METHYLATIONS AND MIRNA DEREGULATIONS) ARE RESPONSIBLE FOR THE PROGRESSIVE TRANSFORMATION OF NORMAL SQUAMOUS CELL EPITHELIA TO THE CORRESPONDING MALIGNANT. CHROMOSOMAL INSTABILITY (CI) -BASED ON STRUCTURAL OR NUMERICAL ABNORMALITIES- LEADS TO SPECIFIC ABNORMAL KARYOTYPES COMBINED OR NOT WITH FUNCTIONAL SUPPRESSOR GENE INACTIVATION AND ONCOGENE OVERACTIVATION IN SOLID MALIGNANCIES, INCLUDING OSCC. EXTENSIVE CYTOGENETIC ANALYSES HAVE SHOWN THAT GROSS ALTERATIONS (GAINS/LOSSES) IN CHROMOSOMES 3, 4, 7, 8, 9, 11, 14, 17, 18, 19 AND ALSO 20 FORM DIFFERENT CI PATTERNS IN OSCC, WHICH IN CONJUNCTION WITH AN AGGRESSIVE PHENOTYPE (PRESENCE OF LYMPH NODAL METASTASIS) NEGATIVELY AFFECT THE PROGNOSIS IN THE CORRESPONDING PATIENTS. IN THE MAJORITY OF OSCC CASES, LOSS OF CHROMOSOMAL BANDS ARE ALMOST EQUALLY DETECTED COMPARED WITH GAINS REGARDING THE CHROMOSOMES REFERRED ABOVE. IN THE CURRENT SPECIAL MOLECULAR PAPER WE EXPLORED THE ROLE OF CI IN THE PROGRESSION AND BIOLOGICAL BEHAVIOR OF OSCCS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8   342  43 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  4903  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  4905  39 P16INK4A HYPERMETHYLATION IS ASSOCIATED WITH HEPATITIS VIRUS INFECTION, AGE, AND GENDER IN HEPATOCELLULAR CARCINOMA. PURPOSE: THE TUMOR SUPPRESSOR GENE P16INK4A IS MAINLY INACTIVATED BY AN EPIGENETIC CHANGE INVOLVING PROMOTER HYPERMETHYLATION IN HEPATOCARCINOGENESIS. THE POSSIBLE CLINICAL IMPACT OF P16INK4A METHYLATION AND THE POTENTIAL RISK FACTORS FOR THIS EPIGENETIC ALTERATION HAVE NOT BEEN THOROUGHLY INVESTIGATED. EXPERIMENTAL DESIGN: WE STUDIED THE METHYLATION STATUS AND MRNA AND PROTEIN EXPRESSION OF P16INK4A IN 50 HEPATOCELLULAR CARCINOMAS AND CORRESPONDING NONNEOPLASTIC LIVER LESIONS USING METHYLATION-SPECIFIC PCR, REVERSE TRANSCRIPTION-PCR, AND IMMUNOHISTOCHEMICAL TECHNIQUES. RESULTS: P16INK4A HYPERMETHYLATION WAS OBSERVED IN 58% (29 OF 50) OF THE HEPATOCELLULAR CARCINOMAS AND 16% (6 OF 38) OF THE CORRESPONDING CHRONIC HEPATITIS AND CIRRHOSIS TISSUE SAMPLES. P16INK4A METHYLATION WAS SIGNIFICANTLY ASSOCIATED WITH MRNA AND PROTEIN EXPRESSION (P <0.001 AND P=0.003, RESPECTIVELY). ALL OF THE P16INK4A-METHYLATED TUMORS WERE POSITIVE FOR HEPATITIS B VIRUS OR HEPATITIS C VIRUS MARKERS, BUT NONE OF THE VIRUS-NEGATIVE TUMORS EXHIBITED P16INK4A METHYLATION (P=0.006). THE FREQUENCY OF P16INK4A HYPERMETHYLATION TENDED TO BE HIGHER IN HEPATITIS C VIRUS-RELATED TUMORS (23 OF 32, 72%) THAN IN HEPATITIS B VIRUS-RELATED TUMORS (6 OF 13, 46%; P=0.1). ABERRANT METHYLATION OF P16INK4A WAS ALSO RELATED SIGNIFICANTLY TO INCREASING AGE, FEMALE GENDER, AND NORMAL LEVELS OF SERUM PIVKA-II (P=0.02, 0.04, AND 0.04, RESPECTIVELY). NO STATISTICALLY SIGNIFICANT DIFFERENCE IN SURVIVAL WAS OBSERVED BETWEEN PATIENTS WITH P16INK4A HYPERMETHYLATION AND THOSE WITHOUT. CONCLUSIONS: OUR OBSERVATIONS SUGGEST THAT P16INK4A HYPERMETHYLATION MAY CONTRIBUTE TO HEPATOCARCINOGENESIS FROM AN EARLY STAGE AND THAT MULTIPLE RISK FACTORS, SUCH AS VIRAL INFECTIONS, AGE, AND GENDER, MAY BE ASSOCIATED WITH P16INK4A HYPERMETHYLATION IN HEPATOCARCINOGENESIS.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  3666  39 INFECTION, STEM CELLS AND CANCER SIGNALS. THE ASSOCIATION OF CANCER WITH PRECEDING PARASITIC INFECTIONS HAS BEEN OBSERVED FOR OVER 200 YEARS. SOME SUCH CANCERS ARISE FROM INFECTION OF TISSUE STEM CELLS BY VIRUSES WITH INSERTION OF VIRAL ONCOGENES INTO THE HOST DNA (MOUSE POLYOMA VIRUS, MOUSE MAMMARY TUMOR VIRUS). IN OTHER CASES THE VIRUS DOES NOT INSERT ITS DNA INTO THE HOST CELLS, BUT RATHER COMMANDEERS THE METABOLISM OF THE INFECTED CELLS, SO THAT THE CELLS CONTINUE TO PROLIFERATE AND DO NOT DIFFERENTIATE (HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER). CYTOPLASMIC EPSTEIN BARR VIRUS INFECTION IS ASSOCIATED WITH A SPECIFIC GENE TRANSLOCATION (IG/C-MYC) THAT ACTIVATES PROLIFERATION OF AFFECTED CELLS (BURKITT LYMPHOMA). IN CHRONIC OSTEOMYELITIS AN INFLAMMATORY REACTION TO THE INFECTION APPEARS TO ACT THROUGH PRODUCTION OF INFLAMMATORY CYTOKINES AND OXYGEN RADICAL FORMATION TO INDUCE EPITHELIAL CANCERS. INFECTION WITH HELICOBACTER PYLORI LEADS TO EPIGENETIC CHANGES IN METHYLATION AND INFECTION BY A PARASITE. CLONORCHIS SINENSIS ALSO ACTS AS A PROMOTER OF CANCER OF THE BILE DUCTS OF THE LIVER (CHOLANIOCARCINOMA). THE COMMON THREAD AMONG THESE DIVERSE PATHWAYS IS THAT THE INFECTIONS ACT TO ALTER TISSUE STEM CELL SIGNALING WITH CONTINUED PROLIFERATION OF TUMOR TRANSIT AMPLIFYING CELLS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  3232  24 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  6711  51 VIRTUES AND WEAKNESSES OF DNA METHYLATION AS A TEST FOR CERVICAL CANCER PREVENTION. EPIGENETICS IS THE STUDY OF HERITABLE AND NON-HERITABLE GENETIC CODING THAT IS ADDITIVE TO INFORMATION CONTAINED WITHIN CLASSICAL DNA BASE PAIR SEQUENCES. DIFFERENTIAL METHYLATION HAS A FUNDAMENTAL ROLE IN THE DEVELOPMENT AND OUTCOME OF MALIGNANCIES, CHRONIC AND DEGENERATIVE DISEASES AND AGING. DNA METHYLATION CAN BE MEASURED ACCURATELY AND EASILY VIA VARIOUS MOLECULAR METHODS AND HAS BECOME A KEY TECHNOLOGY FOR RESEARCH AND HEALTHCARE DELIVERY, WITH IMMEDIATE ROLES IN THE ELUCIDATION OF DISEASE NATURAL HISTORY, DIAGNOSTICS AND DRUG DISCOVERY. THIS REVIEW FOCUSES ON CANCERS OF THE LOWER GENITAL TRACT, FOR WHICH THE MOST EPIGENETIC INFORMATION EXISTS. DNA METHYLATION HAS BEEN PROPOSED AS A TRIAGE FOR WOMEN INFECTED WITH HUMAN PAPILLOMAVIRUS (HPV) AND MAY EVENTUALLY DIRECTLY COMPLEMENT OR REPLACE HPV SCREENING AS A ONE-STEP MOLECULAR DIAGNOSTIC AND PROGNOSTIC TEST. METHYLATION OF HUMAN GENES IS STRONGLY ASSOCIATED WITH CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) AND CANCER. OF THE MORE THAN 100 HUMAN METHYLATION BIOMARKER GENES TESTED SO FAR IN CERVICAL TISSUE, CLOSE TO 20 HAVE BEEN REPORTED IN DIFFERENT STUDIES, AND APPROXIMATELY 10 HAVE BEEN REPEATEDLY SHOWN TO HAVE ELEVATED METHYLATION IN CERVICAL CANCERS AND HIGH-GRADE CIN (CIN2 AND CIN3), MOST PROMINENTLY CADM1, EPB41L3, FAM19A4, MAL, MIR-124, PAX1 AND SOX1. OBTAINING CONSISTENT PERFORMANCE DATA FROM THE LITERATURE IS QUITE DIFFICULT BECAUSE MOST METHYLATION STUDIES USED A VARIETY OF DIFFERENT ASSAY METHODOLOGIES AND HAD INCOMPLETE AND/OR BIASED CLINICAL SPECIMEN SETS, VARYING ASSAY THRESHOLDS AND DISPARATE TARGET GENE REGIONS. THERE HAVE BEEN RELATIVELY FEW VALIDATION STUDIES OF DNA METHYLATION BIOMARKERS IN LARGE POPULATION-BASED SCREENING STUDIES, BUT AN ENCOURAGING DEVELOPMENT MORE RECENTLY IS THE EXECUTION OF WELL-DESIGNED STUDIES TO TEST THE TRUE PERFORMANCE OF THE MARKERS IN REAL-WORLD SETTINGS. METHYLATION OF HPV GENES, ESPECIALLY HPV16, HPV18, HPV31, HPV33 AND HPV45, IN DISEASE PROGRESSION HAS BEEN A MAJOR FOCUS OF RESEARCH. ELEVATED METHYLATION OF THE HPV16 L1 AND L2 OPEN READING FRAMES, IN PARTICULAR, IS ASSOCIATED WITH CIN2, CIN3 AND INVASIVE CANCER. ESSENTIALLY ALL CANCERS HAVE HIGH LEVELS OF METHYLATION FOR HUMAN GENES AND FOR DRIVER HPV TYPES, WHICH SUGGESTS THAT QUANTITATIVE METHYLATION TESTS MAY HAVE UTILITY IN PREDICTING CIN2 AND CIN3 THAT ARE LIKELY TO PROGRESS. IT IS STILL EARLY IN THE PROCESS OF DEVELOPMENT OF METHYLATION BIOMARKERS, BUT ALREADY THEY ARE SHOWING STRONG PROMISE AS A UNIVERSAL AND SYSTEMATIC APPROACH TO MOLECULAR TRIAGE, APPLICABLE TO ALL CANCERS, NOT JUST CANCER OF THE CERVIX. DNA METHYLATION TESTING IS BETTER THAN HPV GENOTYPING TRIAGE AND IS COMPETITIVE WITH OR COMPLEMENTARY TO OTHER APPROACHES SUCH AS CYTOLOGY AND P16 STAINING. GENOME-WIDE STUDIES ARE UNDERWAY TO SYSTEMATICALLY EXPAND METHYLATION CLASSIFIER PANELS AND FIND THE BEST COMBINATIONS OF BIOMARKERS. METHYLATION TESTING IS LIKELY TO SHOW BIG IMPROVEMENTS IN PERFORMANCE IN THE NEXT 5 YEARS.	2016	

14  4430  43 MOLECULAR BIOLOGY OF ONCOGENIC INFLAMMATORY PROCESSES. I. NON-ONCOGENIC AND ONCOGENIC PATHOGENS, INTRINSIC INFLAMMATORY REACTIONS WITHOUT PATHOGENS, AND MICRORNA/DNA INTERACTIONS (REVIEW). IN SOME INFLAMMASOMES TUMOR CELLS ARE GENERATED. THE INTERNAL ENVIRONMENT OF THE INFLAMMASOME IS CONDUCIVE TO THE INDUCTION OF MALIGNANT TRANSFORMATION. EPIGENETIC CHANGES INITIATE THIS PROCESS. THE SUBVERTED STROMAL CONNECTIVE TISSUE CELLS ACT TO PROMOTE AND SUSTAIN THE PROCESS OF MALIGNANT TRANS-FORMATION. IN ITS EARLY STAGES, THE PREMALIGNANT CELLS DEPEND ON PARACRINE CIRCUITRIES FOR THE RECEPTION OF GROWTH FACTORS. THE LIGANDS ARE DERIVED FROM THE CONNECTIVE TISSUE, AND THE RECEPTORS ARE EXPRESSED ON THE RECIPIENT PREMALIGNANT CELLS. THE INITIAL EVENTS ARE NOT A DIRECT ATTACK ON THE PROTO-ONCOGENES, AND THUS IT MAY BE ENTIRELY REVERSIBLE. EPIGENETIC PROCESSES OF HYPERMETHYLATION OF THE GENES AT THE PROMOTERS OF TUMOR SUPPRESSOR GENES (TO SILENCE THEM), AND DEACETYLATION OF THE HISTONES AIMED AT THE PROMOTERS OF PROTO-ONCOGENES (TO ACTIVATE THEM) ARE ON-GOING. A LARGE NUMBER OF SHORT RNA SEQUENCES (INTERFERING, MICRO-, SHORT HAIRPIN, NON-CODING RNAS) SILENCE TUMOR SUPPRESSOR GENES, BY NEUTRALIZING THEIR MRNAS. IN A SERIAL SEQUENCE ONCOGENES UNDERGO AMPLIFICATIONS, POINT-MUTATIONS, TRANSLOCATIONS AND FUSIONS. IN ITS EARLIEST STAGE, THE PROCESS IS REVERSIBLE BY DEMETHYLATION OF THE SILENCED SUPPRESSOR GENE PROMOTERS (TO REACTIVATE THEM), OR RE-ACETYLATION OF THE HISTONES OF THE ONCOGENE PROMOTERS, THUS DE-ACTIVATING THEM. THE EXTERNAL ADMINISTRATION OF HISTONE DEACETYLASE INHIBITORS USUALLY LEADS TO THE RESTORATION OF HISTONE ACETYLATION. IN TIME, THE UNCORRECTED PROCESSES SOLIDIFY INTO CONSTITUTIVE AND IRREVERSIBLE GENE MUTATIONS. SOME OF THE PATHOGENS INDUCING INFLAMMATIONS WITH CONSQUENTIAL MALIGNANT TRANSFORMATION CONTAIN ONCOGENIC GENE SEQUENCES (PAPILLOMA VIRUSES, EPSTEIN-BARR VIRUS, KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS, HEPATITIS B AND C VIRUSES, MERKEL CELL POLYOMA VIRUS, HELICOBACTER PYLORI, ENTEROTOXIGENIC BACTEROIDES FRAGILIS). THESE INDUCED MALIGNANCIES MAY BE MULTIFOCAL. OTHER PATHOGENS ARE DEVOID OF ANY KNOWN ONCOGENIC GENOMIC SEQUENCES (MYCOPLASMA VAV-CARCINOGENESIS, CHLAMYDIA MALT-LYMPHOMA GENESIS). IN THESE CASES THE HOST'S INFLAMMATORY REACTIONS INDUCE THE MALIGNANT TRANSFORMATION IN SERIAL SEQUENCES OF GENE ALTERATIONS INITIATED BY HYPOXIA AND REACTIVE OXYGEN AND NITROGEN SPECIES GENERATION. CARCINOGENIC INTRINSIC INFLAMMATORY PROCESSES ENDOGENOUSLY INITIATED WITHOUT A PATHOGEN ARE RECOGNIZED. CHRONIC INFLAMMATORY PROCESSES SIGNAL THE RNA/DNA COMPLEX. IN RESPONSE, THE DNA MAY REVERT INTO ITS ANCIENT PRIMORDIAL 'IMMORTAL' FORMAT, WHICH THE CLINICS RECOGNIZE AS 'ONCOGENESIS'. THE DNA REMAINS THE ULTIMATE MASTER OF BIOENGINEERING IN ORDER TO SUSTAIN LIFE. A DISCUSSION ON THE MOST VERSATILE AND RESISTANT PRIMORDIAL RNA/DNA COMPLEX AND THE PRE-, PROTO-, AND UNICELLULAR WORLD IN WHICH THEY CO-EXISTED IS INCLUDED.	2012	
                                                                                                           
15  6415  30 THE STUDY OF P16 AND P15 GENE METHYLATION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA AND THEIR QUANTITATIVE EVALUATION IN PLASMA BY REAL-TIME PCR. EPIGENETIC SILENCING OF THE P16 AND P15 GENES BY PROMOTER METHYLATION ARE COMMONLY OBSERVED IN HUMAN EPITHELIAL MALIGNANCIES, INCLUDING HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC). IN THIS STUDY, A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) WAS USED TO EVALUATE THE METHYLATION STATUS OF THE P16 AND P15 GENES IN 73 HNSCC SURGICAL SPECIMENS. P16 AND P15 GENE METHYLATION WAS ALSO EXAMINED IN 29 PAIRED METASTATIC LYMPH NODES AND 29 PAIRED HISTOLOGICALLY, NORMAL RESECTION MARGIN MUCOSAE. THE QUANTITY OF CELL-FREE METHYLATED P16 AND P15 DNA IN THE PLASMA SAMPLES OF 20 HNSCC PATIENTS AND 24 HEALTHY CONTROLS WAS ALSO EXAMINED USING A FLUORESCENCE-BASED REAL-TIME PCR ASSAY. THE FREQUENCIES OF P16 AND P15 METHYLATION IN THE PRIMARY TUMOUR WERE 49% AND 60%, RESPECTIVELY. CONCORDANT METHYLATION OF P16 AND P15 IN TUMOUR SAMPLES AND METASTATIC LYMPH NODES WAS FOUND IN 59 AND 38% OF CASES, RESPECTIVELY. A SIGNIFICANTLY HIGHER PREVALENCE OF P15 METHYLATION WAS FOUND IN HISTOLOGICALLY-NORMAL SURGICAL MARGIN EPITHELIA OF HNSCC PATIENTS WITH CHRONIC SMOKING AND DRINKING HABITS COMPARED WITH NON-SMOKERS AND NON-DRINKERS. IN ADDITION, METHYLATED P16 AND P15 DNA LEVELS WERE SIGNIFICANTLY HIGHER IN THE PLASMA OF HNSCC PATIENTS (MEAN 56 COPIES/ML PLASMA AND 65 COPIES/ML PLASMA, RESPECTIVELY) COMPARED WITH NORMAL CONTROLS (MEAN 6 COPIES/ML PLASMA AND 16 COPIES/ML PLASMA, RESPECTIVELY). IN CONCLUSION, PROMOTER METHYLATION OF THE P16 AND P15 GENES IS INVOLVED IN THE PATHOGENESIS OF HNSCC AND MAY BE RELATED TO CHRONIC SMOKING AND DRINKING. THE DIFFERENTIAL LEVELS OF METHYLATED P16 AND P15 DNA IN PLASMA MIGHT BE POTENTIAL USEFUL MARKERS IN SCREENING HIGH-RISK POPULATIONS FOR EARLY HNSCC AND MONITORING THEIR TREATMENT RESPONSE.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  5885  29 SYSTEMIC LUPUS ERYTHEMATOSUS FOLLOWING HUMAN PAPILLOMAVIRUS VACCINATION: A CASE-BASED REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS SYSTEMIC AUTOIMMUNE DISEASES (AIDS) WITH MANY PATHOGENIC FACTORS, RANGING FROM GENETIC TO EPIGENETIC TO ENVIRONMENTAL. THE HUMAN PAPILLOMAVIRUS (HPV), A VIRAL INFECTIOUS AGENT, IS A COMMON CONTRIBUTOR TO THE ONSET AND EXACERBATION OF SLE. HPV INFECTIONS ARE MORE PREVALENT AMONG SLE PATIENTS THAN HEALTHY INDIVIDUALS, BRINGING ABOUT A SUBSTANTIAL NEED FOR TREATMENT. WHILE HPV RECOMBINANT GENE VACCINES ARE ACCEPTED AS A UNIVERSAL METHOD FOR INFECTION PREVENTION, THEY POSE A RISK FOR ADVERSE EVENTS SUCH AS FEVER, JOINT PAIN, AND RASHES. IN RARE CASES, THEY MIGHT EVEN TRIGGER AIDS SUCH AS SLE, ESPECIALLY IN PATIENTS WITH A PERSONAL OR FAMILY HISTORY OF SUCH DISEASES. IN THIS ARTICLE, WE PROVIDE A REPORT OF A CASE OF SLE ONSET FOLLOWING HPV VACCINATION AND A REVIEW OF 11 SIMILAR CASES. AN ANALYSIS OF 12 PATIENTS REVEALED THAT 7 CASES OF SLE DEVELOPED BETWEEN 3 WEEKS AND 2 MONTHS POST-VACCINATION. SYMPTOMS OF SLE GENERALLY MANIFEST AS FATIGUE, FEVER, JOINT PAIN, AND MYALGIA. TWO PATIENTS HAD LUPUS NEPHRITIS, 2 SHOWED CENTRAL NERVOUS SYSTEM INVOLVEMENT, INCLUDING ABNORMAL BEHAVIOR AND EPILEPTIC SEIZURES, AND 1 HAD INTESTINAL PSEUDO-OBSTRUCTION. ALL PATIENTS SHOWED RAPID REMISSION WITH GLUCOCORTICOID AND IMMUNOSUPPRESSIVE THERAPY AND REMAINED STABLE DURING SEVERAL MONTHS OF FOLLOW-UP.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  1540  40 DNA METHYLATION IN GASTRIC CANCER, RELATED TO HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS. GASTRIC CANCER IS A LEADING CAUSE OF CANCER DEATH WORLDWIDE, AND SIGNIFICANT EFFORT HAS BEEN FOCUSED ON CLARIFYING THE PATHOLOGY OF GASTRIC CANCER. IN PARTICULAR, THE DEVELOPMENT OF GENOME-WIDE ANALYSIS TOOLS HAS ENABLED THE DETECTION OF GENETIC AND EPIGENETIC ALTERATIONS IN GASTRIC CANCER; FOR EXAMPLE, ABERRANT DNA METHYLATION IN GENE PROMOTER REGIONS IS THOUGHT TO PLAY A CRUCIAL ROLE IN GASTRIC CARCINOGENESIS. THE ETIOLOGICAL VIEWPOINT IS ALSO ESSENTIAL FOR THE STUDY OF GASTRIC CANCERS, AND TWO DISTINCT PATHOGENS, HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV), ARE KNOWN TO PARTICIPATE IN GASTRIC CARCINOGENESIS. CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM DUE TO H. PYLORI INFECTION INDUCES ABERRANT POLYCLONAL METHYLATION THAT MAY LEAD TO AN INCREASED RISK OF GASTRIC CANCER. IN ADDITION, EBV INFECTION IS KNOWN TO CAUSE EXTENSIVE METHYLATION, AND EBV-POSITIVE GASTRIC CANCERS DISPLAY A HIGH METHYLATION EPIGENOTYPE, IN WHICH ABERRANT METHYLATION EXTENDS TO NOT ONLY POLYCOMB REPRESSIVE COMPLEX (PRC)-TARGET GENES IN EMBRYONIC STEM CELLS BUT ALSO NON-PRC-TARGET GENES. HERE, WE REVIEW ABERRANT DNA METHYLATION IN GASTRIC CANCER AND THE ASSOCIATION BETWEEN METHYLATION AND INFECTION WITH H. PYLORI AND EBV.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18  1582  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  6820  38 [GASTRIC CARCINOMA AND CHRONIC GASTRITIS: EPIGENETIC REGULATION OF CDH1 (E-CADHERIN), CDKN2A (P16INK4A), PTGS2 (COX-2) AND EGFR GENES THROUGH METHYLATION]. THE GENETIC AND EPIGENETIC ALTERATIONS ARE BEING STUDIED AS ONE OF THE CAUSES OF GASTRIC CANCER (GC) PROGRESSION AND DEVELOPMENT. DNA METHYLATION IS AN EPIGENETIC ALTERATION WHICH LEADS TO SUPPRESSOR GENE SILENCING AND PROTO-ONCOGENE ACTIVATION, PLAYING AN IMPORTANT ROLE IN CARCINOGENESIS. THE HISTOLOGICAL TYPES OF GASTRIC CARCINOMA HAVE DIFFERENT GENETIC PATHS AND THE KNOWLEDGE OF THE MOLECULAR BASES OF TUMORAL PROGRESSION LEADS TO DIAGNOSTIC ACCURACY AND ATTEMPTED THERAPY. CDH1 (E-CADHERIN) AND CDKN2A (P16(INK4A)) GENES ARE THOUGHT TO BE TUMORAL SUPPRESSOR GENES AND PTGS2 (COX-2) AND GENES ARE INVOLVED IN TUMOUR REGULATION AND GROWTH. IN ONE HAND, GENE SILENCING AS AN EPIGENETIC PHENOMENON, AND IN THE OTHER HAND, GENE EXPRESSION ENHANCEMENT DUE TO POSSIBLE DEMETHYLATION, SIMULTANEOUSLY, CAN FACILITATE CARCINOGENESIS AND TUMORAL PROGRESSION. OUR AIM WAS TO RELATE CDH1, P16(INK4A), COX-2 AND EGFR GENES DNA METHYLATION WITH THE SEVERAL HISTOLOGICAL TYPES OF GASTRIC CARCINOMA AND CHRONIC GASTRITIS. WE STUDIED 55 FORMALIN FIXED PARAFFIN EMBEDDED GASTRIC BIOPSIES: 35 WERE GC SPECIMENS (12 DIFFUSE TYPE, 15 INTESTINAL TYPE AND 8 INDETERMINATE TYPE, ACCORDING TO LAUREN'S CLASSIFICATION) AND 20 SAMPLES HAD CHRONIC GASTRITIS (CG). THE DNA WAS TREATED WITH SODIUM BISULFITE AFTER EXTRACTION AND THEN PERFORMED METHYLATION SPECIFIC PCR (MSP). STATISTICAL ANALYSIS WAS BASED ON CHI-SQUARE TEST AND EXACT FISHER'S TEST. CPG ISLAND METHYLATION WAS DETECTED IN 94% OF THE GC SAMPLES FOR CDH1, 91% FOR COX-2, 80% FOR P16(INK4A) AND NO METHYLATION WAS DETECTED IN EGFR GENE (0%). IN CG, CPG ISLAND METHYLATION WAS FOUND IN 100% FOR CDH1 AND COX-2 GENES, 90% FOR P16(INK4A) AND 20% FOR EGFR. THESE RESULTS REVEAL SIGNIFICANT DIFFERENCES IN EGFR GENE METHYLATION DISTINGUISHING GC FROM CG (P < 0, 01), SUGGESTING THAT GENE DEMETHYLATION LEADS TO MALIGNANT TRANSFORMATION AND FAVOURS THE USE OF TYROSINE-KINASE INHIBITORS IN ITS TREATMENT. GENES COX2 E P16INK4A LOWER METHYLATION IN INTESTINAL AND DIFFUSE TYPES OF GC, FAVOURS THEIR DIFFERENT ROLE IN RESPECTIVE HISTOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20   563  38 BARRETT'S ESOPHAGUS: CAN BIOMARKERS PREDICT PROGRESSION TO MALIGNANCY? BARRETT'S ESOPHAGUS (BE) IS ONE OF THE MOST COMMON PREMALIGNANT LESIONS AND CAN PROGRESS TO ESOPHAGEAL ADENOCARCINOMA. IT IS CHARACTERIZED HISTOLOGICALLY BY A SPECIALIZED INTESTINAL METAPLASIA THAT REPLACES THE SQUAMOUS EPITHELIUM OF THE DISTAL ESOPHAGUS, AND IS ASSOCIATED WITH CHRONIC GASTROESOPHAGEAL REFLUX DISEASE AND OBESITY. SIMILAR TO THE ADENOMA-CARCINOMA SEQUENCE OF COLORECTAL CARCINOMAS, ESOPHAGEAL ADENOCARCINOMA DEVELOPS THROUGH PROGRESSION FROM BE TO LOW- AND HIGH-GRADE DYSPLASIA, THEN TO ADENOCARCINOMA WITH ACCUMULATION OF GENETIC AND EPIGENETIC ABNORMALITIES. THE EXACT MALIGNANCY POTENTIAL OF BE IS UNCERTAIN. DYSPLASIA IS THE MOST PREDICTIVE MARKER FOR RISK OF ESOPHAGEAL ADENOCARCINOMA, WHEREAS ENDOSCOPIC AND HISTOLOGICAL DIAGNOSES ARE STILL THE GOLD STANDARD FOR SURVEILLANCE OF PATIENTS WITH BE. HOWEVER, BOTH ARE LIMITED, EITHER BY SAMPLING ERRORS IN BIOPSIES OR BY DIFFERENCES IN HISTOLOGICAL INTERPRETATION. SEVERAL STUDIES HAVE IDENTIFIED CANDIDATE BIOMARKERS THAT MAY HAVE PREDICTIVE VALUE AND MAY SERVE AS ADDITIONAL FACTORS FOR THE RISK ASSESSMENT OF ESOPHAGEAL ADENOCARCINOMA. THIS REVIEW DISCUSSES THE ROLE OF BIOMARKERS IN THE PROGRESSION FROM BE TO ADENOCARCINOMA, FOCUSING ON CLINICAL AND MOLECULAR MARKERS.	2008