1 5674 119 SHARED GENETIC AND EPIGENETIC MECHANISMS BETWEEN CHRONIC PERIODONTITIS AND ORAL SQUAMOUS CELL CARCINOMA. OBJECTIVES: TO ANALYZE BIOINFORMATIC DATASETS FOR DETECTING GENETIC AND EPIGENETIC MECHANISMS SHARED BY CHRONIC PERIODONTITIS (CP) AND ORAL SQUAMOUS CELL CARCINOMA (OSCC). MATERIALS AND METHODS: DATASETS FROM GEO AND TCGA DATABASES REPORTING MRNAS, MIRNAS OR METHYLATION EXPRESSION IN HUMAN CP AND OSCC TISSUES WERE ANALYZED. DIFFERENTIAL EXPRESSION, FUNCTIONAL ENRICHMENT AND PROTEIN-PROTEIN INTERACTION (PPI) NETWORK ANALYSES WERE PERFORMED. DIFFERENTIALLY EXPRESSED MIRNAS (DEMIRNAS) AND GENES (DEG) IN CP AND OSCC WERE DETERMINED. DEMIRNA-TARGET AND DEMIRNA-DEG NETWORKS WERE CONSTRUCTED. DIRECTLY AND INDIRECTLY INTERACTING CROSS-TALK GENES WERE SCREENED, AND THEIR PREDICTION ACCURACY AND ASSOCIATION WITH OSCC PROGNOSIS WAS DETERMINED. RESULTS: 3 DE-MIRNAS (MIR-375, MIR-3609 AND MIR-3652) EXPRESSED IN BOTH CP AND OSCC CRITICALLY REGULATED MOST DEGS. AMONG 12 DIRECTLY INTERACTING CROSS-TALK GENES, NCAPH WAS SIGNIFICANTLY RELATED WITH THE PROGNOSIS OF OSCC. NR2F2 HAD HIGHEST DIFFERENTIAL EXPRESSION IN CP AND OSCC. AMONG 4 CROSS-TALK GENES (FN1, MPPED1, NDEL1, AND NR2F2) DIFFERENTIALLY EXPRESSED IN CP, 3 (FN1, MPPED1, NDEL1) WERE ALSO EXPRESSED IN OSCC. AMONG 12 INDIRECTLY INTERACTING CROSS-TALK GENES DIFFERENTIALLY EXPRESSED IN OSCC, 3 GENES (CDCA8, HIST1H3J, AND RAD51) WERE SIGNIFICANTLY RELATED TO ITS PROGNOSIS. SIGNIFICANT PATHWAYS INVOLVED IN CP AND OSCC INCLUDED: CHEMOKINE RECEPTORS, CLASS I PI3K SIGNALING EVENTS, EPITHELIAL-TO-MESENCHYMAL TRANSITION AND SIGNALING EVENTS BY VEGFR1 AND VEGFR2, EGF RECEPTOR (ERBB1). CONCLUSION: BIOINFORMATIC ANALYSIS OF AVAILABLE DATASETS IMPLICATED 1 DIRECTLY INTERACTING CROSS-TALK GENE (NCAPH), 4 INDIRECTLY INTERACTING CROSS-TALK GENES (NCAPH, NR2F2, FN1, AND MPPED1) AND 3 DE-MIRNAS (HSA-MIR-375, MIR-3609 AND MIR-3652) AS SHARED GENETIC AND EPIGENETIC EXPRESSION PATTERNS BETWEEN CP AND OSCC. 2018 2 5382 23 RECURRENT CHROMOSOMAL AND EPIGENETIC ALTERATIONS IN ORAL SQUAMOUS CELL CARCINOMA AND ITS PUTATIVE PREMALIGNANT CONDITION ORAL LICHEN PLANUS. HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AFFECTS ABOUT 700.000 INDIVIDUALS PER YEAR WORLDWIDE WITH ORAL SQUAMOUS CELL CARCINOMA (OSCC) AS A MAJOR SUBCATEGORY. DESPITE A COMPREHENSIVE TREATMENT CONCEPT INCLUDING SURGERY, RADIATION, AND CHEMOTHERAPY THE 5-YEAR SURVIVAL RATE IS STILL ONLY ABOUT 50 PERCENT. CHRONIC INFLAMMATION IS ONE OF THE HALLMARKS OF CARCINOGENESIS. UNTIL NOW, LITTLE IS KNOWN ABOUT THE PREMALIGNANT STATUS OF ORAL LICHEN PLANUS (OLP) AND MOLECULAR ALTERATIONS IN OLP ARE STILL POORLY CHARACTERIZED. OUR STUDY AIMS TO DELINEATE DIFFERENTIAL DNA METHYLATION PATTERNS IN OLP, OSCC, AND NORMAL ORAL MUCOSA. BY APPLYING A BEAD CHIP APPROACH, WE IDENTIFIED ALTERED CHROMOSOMAL PATTERNS CHARACTERISTIC FOR OSCC WHILE FINDING NO RECURRENT ALTERATIONS IN OLP. IN CONTRAST, WE IDENTIFIED NUMEROUS ALTERATIONS IN THE DNA METHYLATION PATTERN IN OLP, AS COMPARED TO NORMAL CONTROLS, THAT WERE ALSO PRESENT IN OSCC. OUR DATA SUPPORT THE HYPOTHESIS THAT OLP IS A PRECURSOR LESION OF OSCC SHARING MULTIPLE EPIGENETIC ALTERATIONS WITH OSCC. 2019 3 864 28 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 4 5673 33 SHARED EPIGENETIC ALTERATIONS BETWEEN ORAL CANCER AND PERIODONTITIS: A PRELIMINARY STUDY. INTRODUCTION: WE RECENTLY DEVELOPED A NON-INVASIVE SAMPLING PROCEDURE FOR ORAL SQUAMOUS CELL CARCINOMA (OSCC) DETECTION BASED ON DNA METHYLATION ANALYSIS OF A PANEL OF 13 GENES. ORAL CANCER, AS WELL AS ACUTE AND CHRONIC INFLAMMATORY DISEASES, MAY INFLUENCE THE METHYLATION LEVEL OF SEVERAL GENES IN THE ORAL CAVITY. IN THE PRESENT STUDY, WE EVALUATED THE PRESENCE OF PERIODONTAL DISEASE (PD) AND THE METHYLATION STATUS USING OUR 13-GENE PANEL. METHODS: ORAL BRUSHING SPECIMENS WERE COLLECTED FROM THREE DIFFERENT PATIENT GROUPS: 23 GINGIVAL OSCC PATIENTS, 15 PATIENTS AFFECTED BY PD, AND 15 HEALTHY VOLUNTEERS LACKING EVIDENCE OF PD. DNA METHYLATION ANALYSIS WAS PERFORMED AND EACH SAMPLE WAS DETERMINED TO BE POSITIVE OR NEGATIVE BASED ON A PREDEFINED CUT-OFF VALUE. RESULTS: POSITIVE RESULTS WERE FOUND FOR 23/23 OSCC PATIENTS, 3/15 PD PATIENTS, AND 0/15 SAMPLES FROM HEALTHY VOLUNTEERS. THE GP1BB AND MIR193 GENES IN THE PD GROUP EXHIBITED MEAN METHYLATION LEVELS SIMILAR TO OSCC PATIENTS. ZAP70 SHOWED DIFFERENT METHYLATION LEVELS AMONG THREE GROUPS. CONCLUSION: PRELIMINARY DATA IDENTIFIED SHARED EPIGENETIC ALTERATIONS BETWEEN PD AND OSCC PATIENTS IN TWO INFLAMMATORY GENES (GP1BB AND MIR193). THIS STUDY MAY HELP TO IDENTIFY POTENTIAL LINKS BETWEEN THE TWO DISEASES AND SERVE AS A STARTING POINT FOR THE FUTURE RESEARCH FOCUSED ON PATHOGENESIS. 2023 5 3796 27 INTERLEUKIN-6 PROMOTES TUMORIGENESIS BY ALTERING DNA METHYLATION IN ORAL CANCER CELLS. WORLDWIDE ORAL SQUAMOUS CELL CARCINOMA (OSCC) ACCOUNTS FOR MORE THAN 100,000 DEATHS EACH YEAR. CHRONIC INFLAMMATION CONSTITUTES ONE OF THE KEY RISK FACTORS FOR OSCC. ACCUMULATING EVIDENCE SUGGESTS THAT ABERRANT DNA METHYLATION MAY CONTRIBUTE TO OSCC TUMORIGENESIS. THIS STUDY INVESTIGATED WHETHER CHRONIC INFLAMMATION ALTERS DNA METHYLATION AND EXPRESSION OF CANCER-ASSOCIATED GENES IN OSCC. WE ESTABLISHED AN IN VITRO MODEL OF INTERLEUKIN (IL)-6 MEDIATING CHRONIC INFLAMMATION IN OSCC CELL LINES. THEREAFTER, WE MEASURED THE ABILITY OF IL-6 TO INDUCE GLOBAL HYPOMETHYLATION OF LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) SEQUENCES, AS WELL AS CPG METHYLATION CHANGES USING MULTIPLE METHODOLOGIES INCLUDING QUANTITATIVE PYROSEQUENCING, METHYLATION-SPECIFIC MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION AND SENSITIVE MELTING ANALYSIS AFTER REAL-TIME-METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR). GENE EXPRESSION WAS INVESTIGATED BY QUANTITATIVE REVERSE TRANSCRIPTASE-PCR. IL-6 INDUCED SIGNIFICANT GLOBAL LINE-1 HYPOMETHYLATION (P=0.016) IN OUR IN VITRO MODEL OF INFLAMMATORY STRESS IN OSCC CELL LINES. SIMULTANEOUSLY, IL-6 INDUCED CPG PROMOTER METHYLATION CHANGES IN SEVERAL IMPORTANT PUTATIVE TUMOR SUPPRESSOR GENES INCLUDING CHFR, GATA5 AND PAX6. METHYLATION CHANGES CORRELATED INVERSELY WITH THE CHANGES IN THE EXPRESSION OF CORRESPONDING GENES. OUR RESULTS INDICATE THAT IL-6-INDUCED INFLAMMATION PROMOTES TUMORIGENESIS IN THE ORAL CAVITY BY ALTERING GLOBAL LINE-1 HYPOMETHYLATION. IN ADDITION, CONCURRENT HYPERMETHYLATION OF MULTIPLE TUMOR SUPPRESSOR GENES BY IL-6 SUGGESTS THAT EPIGENETIC GENE SILENCING MAY BE AN IMPORTANT CONSEQUENCE OF CHRONIC INFLAMMATION IN THE ORAL CAVITY. THESE FINDINGS HAVE CLINICAL RELEVANCE, AS BOTH METHYLATION AND INFLAMMATION ARE SUITABLE TARGETS FOR DEVELOPING NOVEL PREVENTIVE AND THERAPEUTIC MEASURES. 2011 6 5157 27 PRE-NEOPLASTIC EPIGENETIC DISRUPTION OF TRANSCRIPTIONAL ENHANCERS IN CHRONIC INFLAMMATION. CHRONIC PERIODONTITIS (CP) IS A CHRONIC INFLAMMATORY DISEASE INDEPENDENTLY ASSOCIATED WITH HIGHER INCIDENCE OF ORAL CAVITY SQUAMOUS CELL CARCINOMA (OSCC). HOWEVER, THE MOLECULAR MECHANISM RESPONSIBLE FOR THIS INCREASED INCIDENCE IS UNKNOWN. HERE WE PROFILED THE DNA METHYLOME OF CP PATIENTS AND HEALTHY CONTROLS AND COMPARED TO A LARGE SET OF OSCC SAMPLES FROM TCGA. WE OBSERVED A SIGNIFICANT OVERLAP BETWEEN THE ALTERED DNA METHYLATION PATTERNS IN CP AND IN OSCC, SUGGESTING AN EMERGENCE OF A PRE-NEOPLASTIC EPIGENOME IN CP. REMARKABLY, THE HYPERMETHYLATED CPGS IN CP WERE SIGNIFICANTLY ENRICHED FOR ENHANCER ELEMENTS. THIS ABERRANT ENHANCER METHYLATION IS FUNCTIONAL AND ABLE TO DISRUPT ENHANCER ACTIVITY BY PREVENTING THE BINDING OF CHROMATIN LOOPING FACTORS. THIS STUDY PROVIDES NEW INSIGHTS ON THE MOLECULAR MECHANISMS LINKING CHRONIC INFLAMMATION AND TUMOR PREDISPOSITION, HIGHLIGHTING THE ROLE OF EPIGENETIC DISRUPTION OF TRANSCRIPTIONAL ENHANCERS. 2016 7 3561 37 IMPACT OF EPIGENETIC ALTERATIONS IN THE DEVELOPMENT OF ORAL DISEASES. BACKGROUND: EPIGENETIC MECHANISMS ALTER GENE EXPRESSION AND REGULATE VITAL CELLULAR PROCESSES THAT CONTRIBUTE TO THE ONSET AND PROGRESSION OF MAJOR DENTAL DISEASES. THEIR REVERSIBLE CHARACTER MAY PROVE BENEFICIAL FOR THERAPEUTIC TARGETING. THIS REVIEW AIMS TO PROVIDE AN UPDATE ON THE MAIN EPIGENETIC CHANGES THAT CONTRIBUTE TO THE PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA (OSCC), PULPITIS AND PERIODONTITIS AS WELL AS DENTAL CARIES AND CONGENITAL OROFACIAL MALFORMATIONS, IN AN EFFORT TO IDENTIFY POTENTIAL THERAPEUTIC TARGETS. METHODS: WE UNDERTOOK A STRUCTURED SEARCH OF BIBLIOGRAPHIC DATABASES (PUBMED AND MEDLINE) FOR PEER-REVIEWED EPIGENETIC RESEARCH STUDIES FOCUSED ON ORAL DISEASES IN THE LAST TEN YEARS. A QUALITATIVE CONTENT ANALYSIS WAS PERFORMED IN SCREENED PAPERS AND A CRITICAL DISCUSSION OF MAIN FINDINGS IS PROVIDED. RESULTS: SEVERAL EPIGENETIC MODIFICATIONS HAVE BEEN ASSOCIATED WITH OSCC PATHOGENESIS, INCLUDING PROMOTER METHYLATION OF GENES INVOLVED IN DNA REPAIR, CELL CYCLE REGULATION AND PROLIFERATION LEADING TO MALIGNANT TRANSFORMATION. ADDITIONALLY, EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES, OVEREXPRESSION OF HISTONE CHAPERONES AND SEVERAL MICRORNAS ARE IMPLICATED IN OSCC AGGRESSIVENESS. CHANGES IN THE METHYLATION PATTERNS OF IFN-GAMMA AND TRIMETHYLATION OF HISTONE ETA3KAPPA27 HAVE BEEN DETECTED IN PULPITIS, ALONG WITH AN ABERRANT EXPRESSION OF SEVERAL MICRORNAS, MAINLY AFFECTING CYTOKINE PRODUCTION. CHRONIC PERIODONTAL DISEASE HAS BEEN ASSOCIATED WITH MODIFICATIONS IN THE METHYLATION PATTERNS OF TOLL-LIKE RECEPTOR 2, PROSTAGLANDIN SYNTHASE 2, E-CADHERIN AND SOME INFLAMMATORY CYTOKINES, ALONG WITH THE OVEREXPRESSION OF MIR-146A AND MIR155. FURTHERMORE, DNA METHYLATION WAS FOUND TO REGULATE AMELOGENESIS AND HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DENTAL CARIES AS WELL AS IN SEVERAL CONGENITAL OROFACIAL MALFORMATIONS. CONCLUSION: STRONG EVIDENCE INDICATES THAT EPIGENETIC CHANGES PARTICIPATE IN THE PATHOGENESIS OF ORAL DISEASES AND EPIGENETIC TARGETING MAY BE CONSIDERED AS A COMPLEMENTARY THERAPEUTIC SCHEME TO THE CURRENT MANAGEMENT OF ORAL HEALTH. 2021 8 4479 23 MOLECULAR PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR THERAPY. THE DEVELOPMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC) IS A MULTISTEP PROCESS REQUIRING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS, INFLUENCED BY A PATIENT'S GENETIC PREDISPOSITION AS WELL AS BY ENVIRONMENTAL INFLUENCES, INCLUDING TOBACCO, ALCOHOL, CHRONIC INFLAMMATION, AND VIRAL INFECTION. TUMORIGENIC GENETIC ALTERATIONS CONSIST OF TWO MAJOR TYPES: TUMOR SUPPRESSOR GENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN INACTIVATED; AND ONCOGENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN ACTIVATED. TUMOR SUPPRESSOR GENES CAN BE INACTIVATED THROUGH GENETIC EVENTS SUCH AS MUTATION, LOSS OF HETEROZYGOSITY, OR DELETION, OR BY EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION OR CHROMATIN REMODELING. ONCOGENES CAN BE ACTIVATED THROUGH OVEREXPRESSION DUE TO GENE AMPLIFICATION, INCREASED TRANSCRIPTION, OR CHANGES IN STRUCTURE DUE TO MUTATIONS THAT LEAD TO INCREASED TRANSFORMING ACTIVITY. THIS REVIEW FOCUSES ON THE MOLECULAR MECHANISMS OF ORAL CARCINOGENESIS AND THE USE OF BIOLOGIC THERAPY TO SPECIFICALLY TARGET MOLECULES ALTERED IN OSCC. THE RAPID PROGRESS THAT HAS BEEN MADE IN OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS CONTRIBUTING TO THE DEVELOPMENT OF OSCC IS LEADING TO IMPROVEMENTS IN THE EARLY DIAGNOSIS OF TUMORS AND THE REFINEMENT OF BIOLOGIC TREATMENTS INDIVIDUALIZED TO THE SPECIFIC CHARACTERISTICS OF A PATIENT'S TUMOR. 2008 9 4859 24 ORAL SQUAMOUS CELL CARCINOMA: DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS. OSCC IS THE MOST FREQUENT MALIGNANT TUMOUR OF THE ORAL CAVITY, ACCOUNTING FOR MORE THAN 90% OF MALIGNANT TUMOURS OF THIS ANATOMIC REGION AND IT OFTEN ARISES FROM PRECURSOR LESIONS. ASIDE FROM TOBACCO AND ALCOHOL CONSUMPTION, FURTHER DETERMINANTS HAVE BEEN CONSIDERED TO INCREASE THE RISK OF OSCC DEVELOPMENT, SUCH AS MICRONUTRIENT DEFICIENCIES, CHRONIC TRAUMATISM, POOR ORAL HYGIENE AND VIRUSES. RECURRENCE, SURVIVAL AND CONVERSELY, MORTALITY DEPENDS ON NUMEROUS AND DIFFERENT BIOLOGICAL, HISTOLOGICAL, MACROSCOPIC AND MICROSCOPIC FACTORS THAT HAVE BEEN INVESTIGATED IN ORDER TO DEFINE CAUSES, TO HELP DIAGNOSIS AND TO REFINE APPROPRIATE TREATMENTS THAT PERFECTLY FIT WITH THE DIFFERENT FEATURES OF OSCCS. FOR THIS PURPOSE, DURING THE LAST DECADES, THE IMPROVEMENT OF SCIENTIFIC TECHNOLOGIES AND MOLECULAR ANALYSES HAVE ALLOWED TO INVESTIGATE MARKERS AND GENETIC AND EPIGENETIC FACTORS, IN ORDER TO CLARIFY THEIR RESPONSIBILITIES RELATED TO EARLY DIAGNOSIS AND OSCC PROGRESSION AND PROGNOSIS IN ORDER TO ADDRESS THEM AS TARGETS IN FUTURE SELECTIVE AND INDIVIDUALLY-SHAPED THERAPIES. THIS REVIEW WILL FOCUS ON THE ETIOLOGY, ADVANCES IN DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS FOR ORAL CANCERS. 2016 10 2975 21 GENETIC AND MOLECULAR ALTERATIONS ASSOCIATED WITH ORAL SQUAMOUS CELL CANCER (REVIEW). THE DEVELOPMENT OF ORAL SQUAMOUS CELL CANCER (OSCC) IS A MULTISTEP PROCESS INVOLVING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS MODULATED BY GENETIC PRE-DISPOSITION AND ENVIRONMENTAL INFLUENCES SUCH AS TOBACCO AND ALCOHOL USE, CHRONIC INFLAMMATION, AND VIRAL INFECTIONS. ALL OF THESE FACTORS CAN LEAD TO A WIDE RANGE OF GENETIC AND MOLECULAR ALTERATIONS THAT CAN BE DETECTED USING A RANGE OF MOLECULAR STUDIES. THE ALTERATIONS MOSTLY AFFECT TWO LARGE GROUPS OF GENES: ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH CAN BE EITHER INACTIVATED OR OVEREXPRESSED THROUGH MUTATIONS, LOSS OF HETEROZYGOSITY, DELETIONS, OR EPIGENETIC MODIFICATIONS SUCH AS METHYLATION. OTHER MOLECULES THAT ARE CLOSELY ASSOCIATED WITH TUMOR PATHOGENESIS AND PROGNOSIS ALSO EXIST AND WARRANT FURTHER STUDY. IMPORTANT ADVANCES IN MOLECULAR BIOLOGY ARE HELPING TO SHED LIGHT ON ORAL CANCER AND THUS AIDING IN THE EARLY DIAGNOSIS AND DEVELOPMENT OF NEW PERSONALIZED TREATMENT APPROACHES. THE PURPOSE OF THE REVIEW IS TO EXPLORE THE GENETIC AND MOLECULAR ALTERATIONS ASSOCIATED WITH OSCC. 2009 11 6759 19 WNT SIGNALLING PATHWAY IN ORAL LESIONS. WINGLESS-INTEGRATED/BETA-CATENIN (WNT/?-CATENIN) SIGNALLING PATHWAY IS ONE OF THE PRINCIPAL INTERCELLULAR SIGNALLING PATHWAYS IN HUMANS. IT PLAYS AN INTRINSIC ROLE IN THE CELLULAR PROLIFERATION, DIFFERENTIATION AND REGENERATION ALONG WITH MANY OTHER CELLULAR FUNCTIONS. EPIGENETIC DEOXYRIBONUCLEIC ACID METHYLATIONS AND SILENCING OF WNT SIGNALLING PATHWAY GENES HAVE A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION OF ORAL LESIONS SUCH AS ORAL SUBMUCOUS FIBROSIS, ORAL LEUKOPLAKIA, ORAL LICHEN PLANUS AND ERYTHROPLAKIA. THE INCREASE IN WNT INHIBITORY PROTEINS ALONG WITH INFLAMMATORY FACTORS CAUSE BONE LOSS IN PERIAPICAL LESIONS, SUCH AS CHRONIC APICAL PERIODONTITIS. THIS REVIEW DISCUSSES THE MOLECULAR GENETICS OF POTENTIALLY MALIGNANT ORAL LESIONS, SHEDS LIGHT ON OUR UNDERSTANDING OF WNT/?-CATENIN SIGNALLING IN BONE LOSS PERTAINING TO PERIAPICAL LESIONS, AND ALTERATION OF THIS PATHWAY FOR THERAPEUTIC BENEFITS. 2019 12 1575 31 DNA METHYLATION PATTERNS OF GENES RELATED TO IMMUNE RESPONSE IN THE DIFFERENT CLINICAL FORMS OF ORAL LICHEN PLANUS. BACKGROUND: THE ORAL LICHEN PLANUS IS A CHRONIC INFLAMMATORY DISEASE. ALTHOUGH ITS AETIOLOGY IS NOT WELL UNDERSTOOD, THE ROLE OF T LYMPHOCYTES IN ITS INFLAMMATORY EVENTS IS RECOGNISED. IDENTIFYING THE EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF THIS IMMUNE-MEDIATED CONDITION IS FUNDAMENTAL FOR UNDERSTANDING THE INFLAMMATORY REACTION THAT OCCURS IN THE DISEASE. THE PURPOSE OF THIS WORK WAS TO EVALUATE THE METHYLATION PATTERN OF 21 IMMUNE RESPONSE-RELATED GENES IN THE DIFFERENT CLINICAL FORMS OF ORAL LICHEN PLANUS. METHODS: A CROSS-SECTIONAL STUDY WAS PERFORMED TO ANALYSE THE DNA METHYLATION PATTERNS IN THREE DISTINCT GROUPS OF ORAL LICHEN PLANUS: (I) RETICULAR/PLAQUE LESIONS; (II) EROSIVE LESIONS; (III) NORMAL ORAL MUCOSA (CONTROL GROUP). AFTER DNA EXTRACTION FROM BIOPSIES, THE SAMPLES WERE SUBMITTED TO DIGESTIONS BY METHYLATION-SENSITIVE AND METHYLATION-DEPENDENT ENZYMES AND DOUBLE DIGESTION. THE RELATIVE PERCENTAGE OF METHYLATED DNA FOR EACH GENE WAS PROVIDED USING REAL-TIME POLYMERASE CHAIN REACTION ARRAYS. RESULTS: HYPERMETHYLATION OF THE STAT5A GENE WAS OBSERVED ONLY IN THE CONTROL GROUP (59.0%). A HIGHER HYPERMETHYLATION OF THE ELANE GENE WAS FOUND IN RETICULAR/PLAQUE LESIONS (72.1%) COMPARED TO THE EROSIVE LESIONS (50.0%). CONCLUSION: OUR RESULTS SHOW VARIATIONS IN THE METHYLATION PROFILE OF IMMUNE RESPONSE-RELATED GENES, ACCORDING TO THE CLINICAL TYPE OF ORAL LICHEN PLANUS AFTER COMPARING WITH THE NORMAL ORAL MUCOSA. FURTHER STUDIES ARE NECESSARY TO VALIDATE THESE FINDINGS USING GENE EXPRESSION ANALYSIS. 2018 13 152 22 ABERRANT METHYLATION OF DAPK IN LONG-STANDING ULCERATIVE COLITIS AND ULCERATIVE COLITIS-ASSOCIATED CARCINOMA. DEATH-ASSOCIATED PROTEIN KINASE (DAPK) HAS PRO-APOPTOTIC FUNCTIONS AND PARTICIPATES IN VARIOUS APOPTOTIC SYSTEMS. DAPK ACTS AS A TUMOR SUPPRESSOR, AND ITS INACTIVATION BY PROMOTER HYPERMETHYLATION HAS BEEN FREQUENTLY OBSERVED IN VARIOUS HUMAN CANCERS. AS ALTERATIONS OF PRO-APOPTOTIC GENES MIGHT CAUSE INSTABILITY IN THE BALANCE OF CELL-TURNOVER DURING CHRONIC INFLAMMATORY PROCESSES, EPIGENETIC SILENCING OF DAPK MIGHT BE INVOLVED IN THE CARCINOGENESIS OF ULCERATIVE COLITIS-ASSOCIATED CARCINOMA (UCC). TO EVALUATE THE ROLE OF DAPK IN THE INFLAMMATION-DRIVEN CARCINOGENESIS OF ULCERATIVE COLITIS (UC), WE ANALYZED PROMOTER HYPERMETHYLATION AND PROTEIN EXPRESSION OF DAPK USING METHYLATION-SPECIFIC PCR AND IMMUNOHISTOCHEMISTRY IN 43 UCCS AND PAIRED UC-BACKGROUND MUCOSA, AS WELL AS IN UC-BACKGROUND MUCOSA OF 50 PATIENTS WITHOUT UCC. THE FREQUENCY OF METHYLATION OF DAPK IN UCCS WAS LOW (27.6%) COMPARED TO OVERALL NON-NEOPLASTIC UC-BACKGROUND MUCOSA (48.3%; P=0.02) AND SPORADIC COLORECTAL CARCINOMA (57.4%, P=0.019). THE DIFFERENCE IN THE METHYLATION FREQUENCY IN UC-BACKGROUND MUCOSA IN PATIENTS WITHOUT UCC (54.2%), COMPARED TO THOSE WITH UCC (40.0%), WAS NOT SIGNIFICANT (P=0.141). PROMOTER METHYLATION CORRELATED SIGNIFICANTLY WITH DECREASED DAPK PROTEIN EXPRESSION (P<0.001) AND SEVERITY OF INFLAMMATORY ACTIVITY (P=0.024). IN UNMETHYLATED UC-BACKGROUND MUCOSA, DAPK PROTEIN EXPRESSION INCREASED WITH ACTIVITY OF UC-ASSOCIATED INFLAMMATION, SUGGESTING A PROTECTIVE ROLE OF THE PRO-APOPTOTIC DAPK DURING THE CHRONIC INFLAMMATORY PROCESS OF UC. THUS, INACTIVATION OF DAPK BY PROMOTER HYPERMETHYLATION MIGHT BE CRUCIAL FOR ACCUMULATION OF DNA DAMAGE IN INFLAMED MUCOSA OF UC, AND MIGHT THEREFORE CONTRIBUTE TO THE INITIATION OF THE NEOPLASTIC PROCESS AND DEVELOPMENT OF UC-ASSOCIATED CARCINOMA. 2010 14 2996 17 GENETIC PROFILE AND MICROSATELLITE INSTABILITY IN A CASE OF SECONDARY ESOPHAGEAL SQUAMOUS CELL CARCINOMA 12 YEARS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR APLASTIC ANEMIA. WE REPORT ON A 16-YEAR-OLD JAPANESE BOY IN WHOM AN ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) DEVELOPED 12 YEARS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WAS PERFORMED FOR APLASTIC ANEMIA. A HIGH FREQUENCY OF MICROSATELLITE INSTABILITY WAS DETECTED IN SAMPLES OF ESCC. MOREOVER, THE DETECTION OF PATHOGENIC VARIANTS, INCLUDING SINGLE NUCLEOTIDE SUBSTITUTION OF TP53 (C.346C>T) AND BRCA2 (C.6952C>T) AND SPLICING OF KDM6A (C.1194+2T>G), SUGGEST THAT THE DEVELOPMENT OF ESCC IN THE PATIENT WAS TRIGGERED BY IMPAIRMENT OF CHECKPOINT AND REPAIR FOR DNA DAMAGE AND EPIGENETIC MODIFICATION THROUGH ACCUMULATION OF GENE MUTATIONS INDUCED BY CHRONIC GRAFT-VERSUS-HOST DISEASE AND PROLONGED ADMINISTRATION OF TACROLIMUS. 2020 15 1432 27 DIFFERENTIAL GENE HYPERMETHYLATION IN GENITAL LICHEN SCLEROSUS AND CANCER: A COMPARATIVE STUDY. AIMS: LICHEN SCLEROSUS (LS) IS A CHRONIC INFLAMMATORY DISEASE OF THE GENITAL SKIN OF UNKNOWN AETIOLOGY. THE ROLE OF LS IN PENILE SQUAMOUS CELL CARCINOGENESIS IS NOT WELL CHARACTERIZED. HPV HAS BEEN IMPLICATED IN BOTH, AS HAVE EPIGENETIC CHANGES. THE PRESENCE OF HPV AND HYPERMETHYLATION OF THE MGMT, P16, RASSF1, RASSF2, TSLC1 AND TSP1 GENES WERE STUDIED IN PENILE LS; MGMT, RASSF2 AND TSLC1 HYPERMETHYLATION IN PENILE CANCER AND TSLC1 HYPERMETHYLATION IN VULVAR LS AND CANCER EXTENDS PREVIOUS RESULTS REPORTED BY OUR GROUP. METHODS AND RESULTS: THIRTY-SEVEN HPV GENOTYPES AND HYPERMETHYLATION WERE EVALUATED BY PCR/REVERSE-LINE-BLOT AND METHYLATION-SPECIFIC PCR RESPECTIVELY, IN 27 PREPUTIAL LS, 24 PENILE SCC, 30 VULVAR SCC, 21 VULVAR LS AND 22 NORMAL SKIN CASES. HPV66 WAS PRESENT IN 3.7% OF PENILE LS CASES, AND P16 AND RASSF2 HYPERMETHYLATION WERE MORE FREQUENT IN PENILE CANCER THAN IN PENILE LS. P16, RASSF1, RASSF2 AND TSP1 HYPERMETHYLATION WERE SIMILAR IN PENILE AND VULVAR LS. CONCLUSIONS: GENE HYPERMETHYLATION IS A COMMON EVENT IN PENILE LS, AND OCCURS APPROXIMATELY AS FREQUENTLY AS IN VULVAR LS. CERTAIN GENES CAN BE HYPERMETHYLATED AS AN EARLY OR LATE EVENT IN LS OR CANCER, RESPECTIVELY. THIS SUGGESTS A POSSIBLE SEQUENTIAL ROLE FOR THESE ALTERATIONS IN THE TRANSITION FROM BENIGN TO MALIGNANT LESIONS. 2013 16 3298 30 HIGH-DEFINITION CPG METHYLATION OF NOVEL GENES IN GASTRIC CARCINOGENESIS IDENTIFIED BY NEXT-GENERATION SEQUENCING. GASTRIC CANCERS ARE THE MOST FREQUENT GASTRIC MALIGNANCY AND USUALLY ARISE IN THE SEQUENCE OF HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS. CPG METHYLATION IS A CENTRAL MECHANISM OF EPIGENETIC GENE REGULATION AFFECTING CANCER-RELATED GENES, AND OCCURS EARLY IN GASTRIC CARCINOGENESIS. DNA SAMPLES FROM NON-METAPLASTIC GASTRIC MUCOSA WITH VARIABLE LEVELS OF GASTRITIS (NON-METAPLASTIC MUCOSA), INTESTINAL METAPLASIA, OR GASTRIC CANCER WERE SCREENED WITH METHYLATION ARRAYS FOR CPG METHYLATION OF CANCER-RELATED GENES AND 30 GENE TARGETS WERE FURTHER CHARACTERIZED BY HIGH-DEFINITION BISULFITE NEXT-GENERATION SEQUENCING. IN ADDITION, DATA FROM THE CANCER GENOME ATLAS WERE ANALYZED FOR CORRELATION OF METHYLATION WITH GENE EXPRESSION. OVERALL, 13 GENES HAD SIGNIFICANTLY INCREASED CPG METHYLATION IN GASTRIC CANCER VS NON-METAPLASTIC MUCOSA (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, AND SNRPN). FURTHER, MOST OF THESE GENES HAD CORRESPONDING REDUCED EXPRESSION LEVELS IN GASTRIC CANCER COMPARED WITH INTESTINAL METAPLASIA, INCLUDING NOVEL HYPERMETHYLATED GENES IN GASTRIC CANCER (FLI1, GALR1, SGCE, AND SNRPN), SUGGESTING THAT THEY MAY REGULATE NEOPLASTIC TRANSFORMATION FROM NON-MALIGNANT INTESTINAL METAPLASIA TO CANCER. OUR DATA SUGGEST A TUMOR-SUPPRESSOR ROLE FOR FLI1 IN GASTRIC CANCER, CONSISTENT WITH RECENTLY REPORTED DATA IN BREAST CANCER. FOR THE GENES WITH STRONGEST METHYLATION/EXPRESSION CORRELATION, NAMELY FLI1, THE EXPRESSION WAS LOWEST IN MICROSATELLITE-UNSTABLE TUMORS COMPARED WITH OTHER GASTRIC CANCER MOLECULAR SUBTYPES. IMPORTANTLY, REDUCED EXPRESSION OF HYPERMETHYLATED BRINP1 AND SGCE WAS SIGNIFICANTLY ASSOCIATED WITH FAVORABLE SURVIVAL IN GASTRIC CANCER. IN SUMMARY, WE REPORT NOVEL METHYLATION GENE TARGETS THAT MAY HAVE FUNCTIONAL ROLES IN DISCRETE STAGES OF GASTRIC CARCINOGENESIS AND MAY SERVE AS BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF GASTRIC CANCER. 2016 17 2943 20 GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES IN GASTRIC CANCER. BOTH GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES INVOLVED IN THE PATHOGENESIS OF GASTRIC CANCER ARE REVIEWED HERE, AND MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS ARE PROPOSED. GASTRIC CARCINOMAS ARE BELIEVED TO EVOLVE FROM NATIVE GASTRIC MUCOSA OR INTESTINAL METAPLASTIC MUCOSA THAT UNDERGOES GENETIC AND EPIGENETIC ALTERATIONS INVOLVING EITHER THE SUPPRESSOR PATHWAY (DEFECTS IN TUMOR SUPPRESSOR GENES) OR MUTATOR PATHWAY (DEFECTS IN DNA MISMATCH REPAIR GENES). METHYLATION OF E-CADHERIN IN NATIVE GASTRIC MUCOSA RESULTS IN UNDIFFERENTIATED CARCINOMAS (SUPPRESSOR PATHWAY), WHILE METHYLATION OF HMLHI RESULTS IN DIFFERENTIATED FOVEOLAR-TYPE CARCINOMAS (MUTATOR PATHWAY). THE MAJORITY OF DIFFERENTIATED GASTRIC CARCINOMAS HOWEVER, ARISE FROM INTESTINAL METAPLASTIC MUCOSA AND EXHIBIT STRUCTURAL ALTERATIONS OF TUMOR SUPPRESSOR GENES, ESPECIALLY P53. THEY APPEAR TO BE RELATED TO CHRONIC INJURY, PERHAPS DUE TO HELICOBACTER PYLORI INFECTION. APPROXIMATELY 20% OF DIFFERENTIATED CARCINOMAS (ORDINARY-TYPE) HAVE EVIDENCE OF MUTATOR PATHWAY TUMORIGENESIS. MUTATIONS OF E-CADHERIN ARE MAINLY INVOLVED IN THE PROGRESSION OF DIFFERENTIATED CARCINOMAS TO UNDIFFERENTIATED TUMORS. THE MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS DEPEND ON THE HISTOLOGICAL BACKGROUND, AND GASTRIC CARCINOMAS SHOW DISTINCT BIOLOGICAL BEHAVIORS AS A RESULT OF DISCERNIBLE CELLULAR GENETIC AND EPIGENETIC ALTERATIONS. 2002 18 2843 25 FREQUENT CPG ISLAND METHYLATION IN PRECURSOR LESIONS AND EARLY GASTRIC ADENOCARCINOMAS. GASTRIC CARCINOGENESIS INVOLVES MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC SILENCING OF TUMOR-RELATED GENES DUE TO CPG ISLAND METHYLATION (CIM) HAS BEEN RECENTLY REPORTED IN GASTRIC CANCER, BUT THE ROLE IN PRECURSOR LESIONS IS NOT WELL UNDERSTOOD. WE ANALYSED THE METHYLATION STATUS OF THE TUMOR SUPPRESSOR GENE P16, THE DNA MISMATCH REPAIR GENE HMLH1, AND FOUR CPG ISLANDS (MINT1, MINT2, MINT25, AND MINT31) USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION IN 35 POLYPOID ADENOMAS AND 46 FLAT DYSPLASIAS UNASSOCIATED WITH CARCINOMA, 34 EARLY ADENOCARCINOMAS (T1N0M0) AND ASSOCIATED ADENOMAS/DYSPLASIAS, AND CORRESPONDING ADJACENT NON-NEOPLASTIC MUCOSA. THE EXTENT OF CIM WAS DEFINED BY THE FRACTION OF METHYLATED LOCI (METHYLATION INDEX), AND COMPARED WITH PREVIOUSLY CHARACTERIZED GENETIC ALTERATIONS (MICROSATELLITE INSTABILITY (MSI) AND APC GENE MUTATION). WE FOUND THAT METHYLATION OF P16 WAS MORE FREQUENT IN ADENOCARCINOMA-ASSOCIATED DYSPLASIAS/ADENOMAS (29%) AND ADENOCARCINOMAS (44%) AS COMPARED TO FLAT DYSPLASIAS (4%) AND ADENOMAS (18%) UNASSOCIATED WITH ADENOCARCINOMA (P=0.001). THE MEAN METHYLATION INDEX INCREASED FROM NORMAL/CHRONIC GASTRITIS (CG) MUCOSA (0.09) TO INTESTINAL METAPLASIA (IM) (0.16), FLAT DYSPLASIAS (0.40) OR POLYPOID ADENOMAS (0.41) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH CARCINOMA (0.44), AND ADENOCARCINOMAS (0.44). THERE WAS NO DIFFERENCE IN FREQUENCIES OF HIGH-LEVEL CPG ISLAND METHYLATION (CIM-H, METHYLATION INDEX > OR =0.5) AMONG FLAT DYSPLASIAS (50%) AND POLYPOID ADENOMAS (51%) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH ADENOCARCINOMA (47%), AND ADENOCARCINOMA (47%). CIM-H WAS PRESENT IN 15% OF IM, BUT NOT IN NORMAL/CG MUCOSA. THERE WAS A SIGNIFICANT CORRELATION BETWEEN METHYLATION OF HMLH1 AND HIGH-LEVEL OF MICROSATELLITE INSTABILITY (MSI-H): METHYLATION OF HMLH1 WAS PRESENT IN 71% OF MSI-H TUMORS, BUT ONLY 8% OF MSI-LOW TUMORS AND 13% OF MICROSATELLITE-STABLE TUMORS (P=0.0001). THERE WAS NO STATISTICAL DIFFERENCE BETWEEN METHYLATION INDEX AND APC MUTATION. OUR RESULTS INDICATE THAT CONCURRENT PROMOTER METHYLATION IS AN EARLY AND FREQUENT EVENT IN GASTRIC TUMORIGENESIS, INCLUDING BOTH MSI-H AND MICROSATELLITE-STABLE NEOPLASMS. METHYLATION OF THE P16 GENE MAY CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF GASTRIC PRECURSOR LESIONS. 2004 19 6746 28 WHOLE EXOME SEQUENCING OF ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER BASED ON NOVEL SOMATIC MUTATIONS IDENTIFIED IN CHINESE PATIENTS. BACKGROUND: CARCINOGENESIS IS A SEVERE CONSEQUENCE OF CHRONIC ULCERATIVE COLITIS. WE INVESTIGATED THE SOMATIC MUTATIONS AND PATHWAY ALTERATIONS IN ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER (CRC) IN CHINESE PATIENTS COMPARED WITH SPORADIC CRCS TO REVEAL POTENTIAL THERAPEUTIC TARGETS IN ULCERATIVE COLITIS-ASSOCIATED CRC. METHODS: WHOLE EXOME SEQUENCING WAS PERFORMED ON ARCHIVAL TUMOR TISSUES AND PAIRED ADJACENT NONDYSPLASTIC MUCOSA FROM 10 ULCERATIVE COLITIS-ASSOCIATED CRC PATIENTS AT A HIGH RISK OF CARCINOGENESIS. GENOMIC ALTERATION PROFILES FROM 223 PRIMARY CRCS FROM THE CANCER GENOME ATLAS SERVED AS SPORADIC CRC CONTROLS. A META-ANALYSIS WAS PERFORMED TO INVESTIGATE DIFFERENCES IN MAJOR GENETIC MUTATIONS BETWEEN ULCERATIVE COLITIS-ASSOCIATED AND CROHN'S DISEASE-ASSOCIATED CRCS. RESULTS: WE IDENTIFIED 44 NONSILENT RECURRENT SOMATIC MUTATIONS VIA WHOLE EXOME SEQUENCING, INCLUDING 25 DELETERIOUS MUTATIONS INVOLVED IN APOPTOSIS AND THE PI3K-AKT PATHWAY (COL6A3, FN1), AUTOPHAGY (ULK1), CELL ADHESION (PODXL, PTPRT, ZFHX4), AND EPIGENETIC REGULATION (ARID1A, NCOR2, KMT2D, NCOA6, MECP2, SUPT6H). IN TOTAL, 11 OF THE 25 MUTATED GENES SIGNIFICANTLY DIFFERED BETWEEN ULCERATIVE COLITIS-ASSOCIATED CRC AND SPORADIC CRC (APC, APOB, MECP2, NCOR2, NTRK2, PODXL, RABGAP1, SIK3, SUPT6H, ULK1, USP48). SOMATIC TP53 MUTATIONS OCCURRED IN 33% OF ULCERATIVE COLITIS-ASSOCIATED CRCS. SUBSEQUENT META-ANALYSIS REVEALED DISTINCT MUTATION PROFILES FOR CROHN'S DISEASE- AND ULCERATIVE COLITIS-ASSOCIATED CRCS. MUTATIONS INVOLVING THE NF-KB PATHWAY AND EPIGENETIC REGULATION WERE MORE COMMON IN ULCERATIVE COLITIS-ASSOCIATED CRCS THAN IN SPORADIC CRCS. CONCLUSION: DISTINCT GENOMIC ALTERATION PROFILES OF DELETERIOUS SOMATIC MUTATIONS WERE FOUND IN ULCERATIVE COLITIS-ASSOCIATED AND SPORADIC CRCS. MUTATIONS OF EPIGENETIC REGULATORS, SUCH AS KMT2D AND NCOA6, WERE COMMON, SUGGESTING AN EPIGENETIC PATHOMECHANISM FOR COLITIS-ASSOCIATED CARCINOMA IN CHINESE PATIENTS. 2019 20 4373 32 MIRNAS: IMPORTANT TARGETS FOR ORAL CANCER PAIN RESEARCH. PAIN IS A SYMPTOM SHARED BY AN INCREDIBLE NUMBER OF DISEASES. IT IS ALSO ONE OF THE PRIMARY CONDITIONS THAT PROMPT INDIVIDUALS TO SEEK MEDICAL TREATMENT. HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) CORRESPONDS TO A HETEROGENEOUS DISEASE THAT MAY ARISE FROM MANY DISTINCT STRUCTURES OF A LARGE, HIGHLY COMPLEX, AND INTRICATE REGION. HNSCC AFFECTS A GREAT NUMBER OF PATIENTS WORLDWIDE AND IS DIRECTLY ASSOCIATED WITH CHRONIC PAIN, WHICH IS ESPECIALLY PROMINENT DURING THE ADVANCED STAGES OF ORAL SQUAMOUS CELL CARCINOMA (OSCC), AN ANATOMICAL AND CLINICAL SUBTYPE THAT CORRESPONDS TO THE GREAT MAJORITY ORAL CANCERS. ALTHOUGH THE CELLULAR AND MOLECULAR BASES OF ORAL CANCER PAIN HAVE NOT BEEN FULLY ESTABLISHED YET, THE RESULTS OF RECENT STUDIES SUGGEST THAT DIFFERENT EPIGENETIC MECHANISMS MAY CONTRIBUTE TO THIS PROCESS. FOR INSTANCE, THERE IS STRONG SCIENTIFIC EVIDENCE THAT MICRORNAS (MIRNAS), SMALL RNA MOLECULES THAT DO NOT ENCODE PROTEINS, MIGHT ACT BY REGULATING THE MECHANISMS UNDERLYING CANCER-RELATED PAIN. AMONG THE MIRNAS THAT COULD POSSIBLY INTERFERE IN PAIN-SIGNALING PATHWAYS, MIR-125B, MIR-181, AND MIR-339 EMERGE AS SOME OF THE MOST PROMISING CANDIDATES. IN FACT, SUCH MOLECULES APPARENTLY CONTRIBUTE TO INFLAMMATORY PAIN. MOREOVER, THESE MOLECULES POSSIBLY INFLUENCE THE ACTIVITY OF ENDOGENOUS PAIN CONTROL SYSTEMS (E.G., OPIOIDERGIC AND SEROTONERGIC SYSTEMS), WHICH COULD ULTIMATELY RESULT IN PERIPHERAL AND CENTRAL SENSITIZATION, CENTRAL NERVOUS SYSTEM (CNS) PHENOMENA INNATELY ASSOCIATED WITH CHRONIC PAIN. THIS REVIEW PAPER FOCUSES ON THE CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE INVOLVEMENT OF MIRNAS IN CANCER PAIN, WITH SPECIAL ATTENTION DEDICATED TO OSCC-RELATED PAIN. 2017