1 6778 145 [BILIARY TRACT CANCERS : MOLECULAR CHARACTERIZATION AND IDENTIFICATION OF NOVEL PROGNOSTIC MARKERS]. BACKGROUND: BILE DUCT CANCERS (BTCS) ARE HIGHLY AGGRESSIVE TUMORS WITH A DISMAL PROGNOSIS AND AN INCREASING INCIDENCE. BTC IS A TUMORBIOLOGICALLY AND CLINICALLY HETEROGENEOUS TUMOR GROUP AND CAN BE SUBDIVIDED ACCORDING TO ANATOMICAL ASPECTS INTO INTRAHEPATIC CHOLANGIOCARCINOMAS (ICCA), EXTRAHEPATIC CHOLANGIOCARCINOMAS (ECCA) AND GALLBLADDER CARCINOMAS (GBC). NEW THERAPY OPTIONS: CHRONIC INFLAMMATORY PROCESSES OF THE BILIARY SYSTEM SEEM TO PLAY A ROLE IN THE DEVELOPMENT OF THESE TUMORS. INSIGHTS INTO MOLECULAR CHOLANGIOCARCINOGENESIS COULD MAKE AN IMPORTANT CONTRIBUTION TO NOVEL AND MORE PRECISE CLASSIFICATION ATTEMPTS AND TO THE DEVELOPMENT OF NEW, TARGETED THERAPIES FOR BTC. EPIGENETIC AND GENETIC ALTERATIONS IN CHOLANGIOCARCINOMAS: THE FIRST DESCRIPTION OF GENOME-WIDE DNA METHYLATION PATTERNS IN CCA SHOWED DRASTIC GLOBAL METHYLATION DIFFERENCES BETWEEN CCA AND CORRESPONDING NON-NEOPLASTIC TISSUE (MATCHED-PAIR ANALYSES). MOREOVER, SIGNIFICANT METHYLATION DIFFERENCES BETWEEN THE CCA SUBTYPES (ECCA AND ICCA) COULD BE FOUND. USING IMMUNOHISTOCHEMISTRY AND SANGER SEQUENCING, IT WAS SHOWN THAT THE ACTUAL BRAF V600E MUTATION RATE SEEMS TO BE SIGNIFICANTLY LOWER (1.3%) THAN PREVIOUSLY DESCRIBED IN THE LITERATURE. IMMUNEPHENOTYPING IN BILIARY TRACT CANCERS: A COMPREHENSIVE, SUBTYPE-SPECIFIC CHARACTERIZATION OF TUMOR-INFILTRATING IMMUNE CELLS AS WELL AS AN EXPRESSION ANALYSIS OF MAJOR HISTOCOMPATIBILITY COMPLEX I WAS PERFORMED IN A LARGE AND WELL-CHARACTERIZED BTC COHORT. FOR FURTHER STUDIES ON THE EFFICACY OF IMMUNOMODULATORY THERAPY APPROACHES FOR BTC, THE PRESENTED RESULTS PROVIDE A SOLID BASIS. 2017 2 4474 43 MOLECULAR PATHOGENESIS OF GALLBLADDER CANCER: AN UPDATE. GALLBLADDER CARCINOMA (GBC) IS THE MOST AGGRESSIVE GASTROINTESTINAL MALIGNANCY THROUGHOUT THE WORLD, WITH WIDE GEOGRAPHICAL VARIANCE. IT IS THE SUBTYPE OF BILIARY TRACT MALIGNANCY THAT HAS THE POOREST PROGNOSIS AND LOWER SURVIVAL AMONG ALL BILIARY TRACT MALIGNANCIES. VARIOUS FACTORS ARE ASSOCIATED WITH GBC PATHOGENESIS SUCH AS ENVIRONMENTAL, MICROBIAL, METABOLIC AND MOLECULAR. CHRONIC INFLAMMATION OF GALLBLADDER DUE TO PRESENCE OF GALLSTONE OR MICROBIAL INFECTION (EG. SALMONELLA OR H. PYLORI) RESULTS IN SUSTAINED PRODUCTION OF INFLAMMATORY MEDIATORS IN THE TISSUE MICROENVIRONMENT, WHICH CAN CAUSE GENOMIC CHANGES LINKED TO CARCINOGENESIS. GENETIC ALTERATIONS ARE ONE OF THE MAJOR FACTORS, ASSOCIATED WITH AGGRESSIVENESS AND PROGNOSIS. RESEARCHES HAVE BEEN DONE TO EXPLORE SUITABLE BIOMARKER FOR EARLY DIAGNOSIS AND IDENTIFY ALTERED MOLECULAR PATHWAYS TO DEVELOP APPROPRIATE BIOMARKERS FOR EARLY DIAGNOSIS, THERAPY AND PREDICTING PROGNOSIS. DIFFERENT AGENTS FOR TARGETED THERAPY AGAINST ACTIONABLE MUTATIONS OF MOLECULES LIKE EGFR, VEGF, MTOR, HER2, PDL-1, PD-1, MET, PI3K, N-CADHERIN, VEGFR, MEK1 AND MEK2 ARE BEING TRIED. DESPITE THESE ADVANCEMENTS, THERE IS DISMAL IMPROVEMENT IN THE SURVIVAL OF GBC PATIENTS. GENETIC ABERRATIONS OTHER THAN ACTIONABLE MUTATIONS AND EPIGENETIC MODIFICATION INCLUDING ABERRANT EXPRESSIONS OF MICRO-RNAS, ARE ALSO BEING STUDIED BOTH AS DIAGNOSTIC BIOMARKER AND THERAPEUTIC TARGETS. COMPLEX PATHOGENESIS OF GBC STILL NEEDS TO BE UNFOLDED. IN THIS REVIEW WE FOCUS ON THE MOLECULAR PATHOGENESIS OF GBC ELUCIDATED TILL DATE ALONG WITH FUTURE DIRECTIONS THAT CAN BE EXPLORED TO ACHIEVE BETTER MANAGEMENT OF GBC PATIENTS. 2019 3 4027 31 LUNG CANCER IN A CF PATIENT: COMBINATION OF BAD LUCK OR IS THERE MORE TO SAY? PATIENTS WITH CYSTIC FIBROSIS HAVE INCREASED RISK FOR GASTROINTESTINAL CANCER, LYMPHOID LEUKEMIA AND TESTICULAR CARCINOMAS. CHRONIC INFLAMMATION DOES NOT SEEM TO BE THE ONLY CONTRIBUTING FACTOR. MUTATIONS AND EPIGENETIC ALTERATIONS IN THE CFTR GENE MAY ALTER SUSCEPTIBILITY TO DEVELOP CANCER. LUNG CANCER IS UP TO NOW NOT FREQUENTLY OBSERVED IN CF PATIENTS. IN LUNG CANCER PATIENTS WITHOUT CF LOW CFTR EXPRESSION IS SIGNIFICANTLY ASSOCIATED WITH ADVANCED STAGING, LYMPH NODE METASTASIS. AS THE MANAGEMENT AND LIFE EXPECTANCY OF PATIENTS WITH CYSTIC FIBROSIS HAVE IMPROVED SUBSTANTIALLY IN RECENT YEARS, WE EXPECT AN INCREASED NUMBER OF THESE PATIENTS DIAGNOSED WITH LUNG CANCER. IN ADDITION, IT IS POSSIBLE THAT THEY, AS A RESULT OF CFTR-DYSFUNCTION, WILL PRESENT WITH MORE AGGRESSIVE LUNG TUMORS. TREATING CANCER IN CF PATIENTS IS A CHALLENGE BECAUSE OF MULTI-ORGAN INVOLVEMENT AND CHRONIC COLONIZATION BY RESISTANT PATHOGENS. THE EFFECTIVENESS AND SAFETY OF IMMUNOTHERAPY IN THIS POPULATION NEEDS TO BE FURTHER EVALUATED. 2021 4 2637 36 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY. 2022 5 1587 38 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS. 2016 6 51 26 A DISTINCT EPIGENETIC PROFILE DISTINGUISHES STENOTIC FROM NON-INFLAMED FIBROBLASTS IN THE ILEAL MUCOSA OF CROHN'S DISEASE PATIENTS. BACKGROUND: THE CHRONIC REMITTING AND RELAPSING INTESTINAL INFLAMMATION CHARACTERISTIC OF CROHN'S DISEASE FREQUENTLY LEADS TO FIBROSIS AND SUBSEQUENT STENOSIS OF THE INFLAMED REGION. APPROXIMATELY A THIRD OF ALL CROHN'S DISEASE PATIENTS REQUIRE RESECTION AT SOME STAGE IN THEIR DISEASE COURSE. AS THE PATHOGENESIS OF CROHN'S DISEASE ASSOCIATED FIBROSIS IS LARGELY UNKNOWN, A STRONG NECESSITY EXISTS TO BETTER UNDERSTAND THE PATHOPHYSIOLOGY THEREOF. METHODS: IN THIS STUDY, WE INVESTIGATED CHANGES OF THE DNA METHYLOME AND TRANSCRIPTOME OF ILEUM-DERIVED FIBROBLASTS ASSOCIATED TO THE OCCURRENCE OF CROHN'S DISEASE ASSOCIATED FIBROSIS. EIGHTEEN SAMPLES WERE INCLUDED IN A DNA METHYLATION ARRAY AND TWENTY-ONE SAMPLES WERE USED FOR RNA SEQUENCING. RESULTS: MOST DIFFERENTIALLY METHYLATED REGIONS AND DIFFERENTIALLY EXPRESSED GENES WERE OBSERVED WHEN COMPARING STENOTIC WITH NON-INFLAMED SAMPLES. BY CONTRAST, FEW DIFFERENCES WERE OBSERVED WHEN COMPARING CROHN'S DISEASE WITH NON-CROHN'S DISEASE, OR INFLAMED WITH NON-INFLAMED TISSUE. INTEGRATIVE METHYLATION AND GENE EXPRESSION ANALYSES REVEALED DYSREGULATION OF GENES ASSOCIATED TO THE PRKACA AND E2F1 NETWORK, WHICH IS INVOLVED IN CELL CYCLE PROGRESSION, ANGIOGENESIS, EPITHELIAL TO MESENCHYMAL TRANSITION, AND BILE METABOLISM. CONCLUSION: OUR RESEARCH PROVIDES EVIDENCE THAT THE METHYLOME AND THE TRANSCRIPTOME ARE SYSTEMATICALLY DYSREGULATED IN STENOSIS-ASSOCIATED FIBROBLASTS. 2018 7 2653 39 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES. 2008 8 5211 35 PRENEOPLASTIC LESIONS IN HUMAN HEPATOCARCINOGENESIS. THE EARLY STAGES OF HEPATOCARCINOGENESIS IN HUMAN CHRONIC LIVER DISEASES ARE CHARACTERIZED BY THE EMERGENCE OF PRENEOPLASTIC LESIONS OF WHICH SOME WILL EVENTUALLY DEVELOP INTO HEPATOCELLULAR CARCINOMA (HCC). BASIC STUDIES ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THESE PRENEOPLASTIC LESIONS MAY EVENTUALLY LEAD TO NEW THERAPEUTIC STRATEGIES. CLINICOPATHOLOGICAL STUDIES ARE ALSO IMPORTANT IN ORDER TO DETERMINE OPTIMAL MANAGEMENT OF PATIENTS WITH A PRENEOPLASTIC LESION. THIS ARTICLE AIMS TO PROVIDE A COMPREHENSIVE REVIEW OF THE CURRENT CONCEPTS OF PRENEOPLASTIC LESION IN CHRONIC LIVER DISEASES. THE MICROSCOPICAL SMALL-CELL DYSPLASTIC FOCUS IS THE SMALLEST MORPHOLOGICALLY RECOGNIZABLE PRECURSOR LESION OF HCC AND THEREFORE IS A LOGICAL TARGET OF STUDY TO ELUCIDATE THE EARLIEST EVENTS IN HEPATOCARCINOGENESIS. IN CONTRAST, LARGE-CELL DYSPLASIA IS NOT A PRECURSOR LESION, BUT APPEARS TO BE OF CLINICAL VALUE BECAUSE OF ITS GOOD PREDICTIVE VALUE FOR DEVELOPMENT OF HCC. DYSPLASTIC NODULES (DNS) ARE MACROSCOPICALLY RECOGNIZABLE PRECURSOR LESIONS OF HCC AND HIGH-GRADE DNS (HGDNS) HAVE A RISK OF MALIGNANT TRANSFORMATION. DETECTION OF DNS AND CORRECT DIFFERENTIATION FROM SMALL HCC (<2 CM) IS SOMETIMES DIFFICULT, ESPECIALLY WHEN ONLY IMAGING TECHNIQUES ARE USED. ADDITIONAL CLINICOPATHOLOGICAL STUDIES ON IDENTIFICATION AND OPTIMAL TREATMENT OF DNS ARE NECESSARY. MOLECULAR STUDIES ON HGDNS AND SMALL HCCS MAY YIELD MUCH INFORMATION ON THE GENETIC MECHANISMS INVOLVED IN THE TRANSITION FROM SEVERE DYSPLASIA TO EARLY MALIGNANCY. IN CONTRAST, CURRENTLY AVAILABLE DATA INDICATE THAT (LARGE) REGENERATIVE NODULES DO NOT REPRESENT A DISTINCT STEP IN HEPATOCARCINOGENESIS. ANIMAL MODELS WILL BE HELPFUL IN THE FURTHER UNRAVELLING OF HUMAN HCC DEVELOPMENT, PROVIDED THAT STUDIES ARE PERFORMED ON MODELS THAT ARE GOOD REPRESENTATIVES OF HUMAN HEPATOCARCINOGENESIS. WE PROPOSE THREE CRITERIA BY WHICH GOOD MIMICKERS CAN BE IDENTIFIED. 2005 9 1519 30 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS. 2021 10 5785 33 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 11 6468 25 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL. 2015 12 1545 36 DNA METHYLATION IN LIVER TUMORIGENESIS IN FISH FROM THE ENVIRONMENT. THE LINK BETWEEN ENVIRONMENT, ALTERATION IN DNA METHYLATION AND CANCER HAS BEEN WELL ESTABLISHED IN HUMANS; YET, IT IS UNDER-STUDIED IN UNSEQUENCED NON-MODEL ORGANISMS. THE OCCURRENCE OF LIVER TUMORS IN THE FLATFISH DAB COLLECTED AT CERTAIN UK SAMPLING SITES EXCEEDS 20%, YET THE CAUSATIVE AGENTS AND THE MOLECULAR MECHANISMS OF TUMOR FORMATION ARE NOT KNOWN, ESPECIALLY REGARDING THE BALANCE BETWEEN EPIGENETIC AND GENETIC FACTORS. METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) COMBINED WITH DE NOVO HIGH-THROUGHPUT DNA SEQUENCING WERE USED TO INVESTIGATE DNA METHYLATION CHANGES IN DAB HEPATOCELLULAR ADENOMA TUMORS FOR THE FIRST TIME IN AN UNSEQUENCED SPECIES. NOVEL CUSTOM-MADE DAB GENE EXPRESSION ARRAYS WERE DESIGNED AND USED TO DETERMINE THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION. IN ADDITION, THE CONFIRMATORY TECHNIQUES OF BISULFITE SEQUENCING PCR (BSP) AND RT-PCR WERE APPLIED. GENES INVOLVED IN PATHWAYS RELATED TO CANCER, INCLUDING APOPTOSIS, WNT/BETA-CATENIN SIGNALING AND GENOMIC AND NON-GENOMIC ESTROGEN RESPONSES, WERE ALTERED BOTH IN METHYLATION AND TRANSCRIPTION. GLOBAL METHYLATION WAS STATISTICALLY SIGNIFICANTLY 1.8-FOLD REDUCED IN HEPATOCELLULAR ADENOMA AND NON-CANCEROUS SURROUNDING TISSUES COMPARED WITH LIVER FROM NON-CANCER BEARING DAB. BASED ON THE IDENTIFIED CHANGES AND CHEMICAL EXPOSURE DATA, OUR STUDY SUPPORTS THE EPIGENETIC MODEL OF CANCER. WE HYPOTHESIZE THAT CHRONIC EXPOSURE TO A MIXTURE OF ENVIRONMENTAL CONTAMINANTS CONTRIBUTES TO A GLOBAL HYPOMETHYLATION FOLLOWED BY FURTHER EPIGENETIC AND GENOMIC CHANGES. THE FINDINGS SUGGEST A LINK BETWEEN ENVIRONMENT, EPIGENETICS AND CANCER IN FISH TUMORS IN THE WILD AND SHOW THE UTILITY OF THIS METHODOLOGY FOR STUDIES IN NON-MODEL ORGANISMS. 2011 13 5905 31 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 14 6488 42 TP53 R72P POLYMORPHISM MODULATES DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS CHARACTERIZED BY WIDESPREAD EPIDEMIOLOGICAL AND MOLECULAR HETEROGENEITY. PREVIOUS WORK SHOWED THAT IN THE WESTERN PART OF NORTH AFRICA, A REGION OF LOW INCIDENCE OF HCC, MUTATIONS ARE SCARCE FOR THIS TUMOR TYPE. AS EPIGENETIC CHANGES ARE CONSIDERED POSSIBLE SURROGATES TO MUTATIONS IN HUMAN CANCERS, WE DECIDED, THUS, TO CHARACTERIZE DNA METHYLATION IN HCC FROM NORTH-AFRICAN PATIENTS. METHODS: A SET OF 11 LOCI WAS INVESTIGATED IN A SERIES OF 45 TUMOR SPECIMENS USING METHYLATION-SPECIFIC AND COMBINED-BISULFITE RESTRICTION ASSAY PCR. RESULTS OBTAINED ON CLINICAL SAMPLES WERE SUBSEQUENTLY VALIDATED IN LIVER CANCER CELL LINES. RESULTS: DNA METHYLATION AT TUMOR SUPPRESSOR LOCI IS SIGNIFICANTLY HIGHER IN SAMPLES DISPLAYING CHROMOSOME INSTABILITY. MORE IMPORTANTLY, DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN ARG/ARG WHEN COMPARED TO PRO/PRO GENOTYPE CARRIERS AT CODON 72 RS1042522 OF TP53 (65% VS 20% METHYLATED LOCI, P = 0.0006), A POLYMORPHISM ALREADY KNOWN TO AFFECT SOMATIC MUTATION RATE IN HUMAN CARCINOMAS. IN VITRO EXPERIMENTS IN CELL LINES INDICATED THAT ENZYMES CONTROLLING DNA METHYLATION WERE DIFFERENTIALLY REGULATED BY CODON 72 ARG OR PRO ISOFORMS OF P53. FURTHERMORE, THE ARG72-CARRYING VERSION OF P53 WAS SHOWN TO RE-METHYLATE DNA MORE RAPIDLY THAN THE PRO-HARBORING ISOFORM. FINALLY, PRO-CARRYING CELL LINES WERE SHOWN TO BE SIGNIFICANTLY MORE RESISTANT TO DECITABINE TREATMENT (TWO-FOLD, P = 0.005). CONCLUSIONS: OUR DATA SUGGEST THAT ARG72PRO POLYMORPHISM IN A WT P53 CONTEXT MAY ACT AS A PRIMARY DRIVER OF EPIGENETIC CHANGES IN HCC. IT SUGGESTS, IN ADDITION, THAT RS1042522 GENOTYPE MAY PREDICT SENSITIVITY TO EPIGENETIC-TARGETED THERAPY. THIS MODEL OF LIVER TUMORIGENESIS THAT ASSOCIATES LOW PENETRANCE GENETIC PREDISPOSITION TO EPIGENETIC CHANGES EMERGES FROM A REGION OF LOW HCC INCIDENCE AND IT MAY, THEREFORE, APPLY ESSENTIALLY TO POPULATION LIVING IN SIMILAR AREAS. SURVEYS ON POPULATIONS SUBMITTED TO HIGHLY MUTAGENIC CONDITIONS AS PERINATALLY-ACQUIRED CHRONIC HEPATITIS B OR AFLATOXIN B1 EXPOSURE REMAINED TO BE CONDUCTED TO VALIDATE OUR OBSERVATIONS AS A GENERAL MODEL. 2015 15 1508 46 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH. 2014 16 4028 42 LUNG TUMORS, COPD AND IMMUNE RESPONSE: IS EPIGENETICS THE BOTTOM LINE? NSCLC IS A HETEROGENEOUS DISORDER CONSISTING OF DISTINCT MOLECULAR SUBTYPES WHICH CAN BE TREATED BY USING SPECIFIC DRUGS TARGETED TO DISTINCT GENETIC LESIONS. IT IS WELL KNOWN THAT NSCLS INCIDENCE IS HIGHER IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS BECAUSE THEY SHARE A COMMON RISK FACTOR (CIGARETTE SMOKING) AND IT IS BELIEVED THAT THE TYPICAL INFLAMMATORY MICROENVIRONMENT OBSERVED IN COPD MAY INFLUENCE THE MOLECULAR MECHANISMS RESPONSIBLE OF CARCINOGENESIS. IN THE LAST YEARS, THE ROLE OF EPIGENETIC PROCESSES IN CELL BIOLOGY AND TISSUE PATHOLOGY HAS BEEN EXTENSIVELY STUDIED BOTH IN COPD AND NSCLC. THE RECENT PAPER BY WAUTERS ET AL. SHOWED A SPECIFIC PATTERN OF DRIVER MUTATIONS AND MOLECULAR FEATURES IN NSCLC RAISING IN THE CONTEXT OF COPD. ALL THESE FINDINGS HAVE SHOWN FOR THE FIRST TIME THAT LUNG TUMORS FOUND IN COPD PATIENTS DIFFER FROM THOSE OBSERVED IN PATIENT WITHOUT COPD DUE TO THE PRESENCE OF A SPECIFIC TUMOR MICROENVIRONMENT WHICH IS CHARACTERIZED BY REDUCED CD4+ TREG CELLS. ON THIS BASIS, THE PRESENT WORK AIMS AT DISCUSSING AND ANALYZING THE CONTEXT-SPECIFIC MECHANISMS OF CLONAL SELECTION AND EVOLUTION MAINLY FOCUSING ON THE EPIGENETIC ALTERATIONS AND AT POINTING OUT THE POTENTIAL THERAPEUTIC IMPLICATIONS. 2016 17 6595 29 TUMOR-SPECIFIC GROWTH FACTOR (TSGF): A FUTURISTIC TUMOR BIOMARKER IN EARLY DIAGNOSIS OF CANCER. DESPITE THE SIGNIFICANT IMPROVEMENT IN THE TREATMENT MODALITIES, CANCER IS ONE OF THE FASTEST-GROWING CHRONIC DISEASE CONDITIONS ALL OVER THE WORLD. GENETIC AND EPIGENETIC ALTERATIONS IN THE NORMAL PHYSIOLOGY OF THE CELL ARE THE KEY FACTOR FOR TUMOR DEVELOPMENT. THESE CHANGES CAN TRIGGER THE PRODUCTION OF ABNORMAL PROTEIN EXPRESSIONS THROUGH STIMULATION OF DIFFERENT SIGNALING PATHWAYS AND CAN DEEPLY AFFECT NORMAL CELL GROWTH AND PROLIFERATION. ANY ALTERED PROTEIN EXPRESSION, GENETIC VARIATION, MICRO-RNA OR POST-TRANSLATIONAL PROTEIN MODIFICATIONS THAT INDICATE TUMORIGENESIS CAN ACT AS AN EARLY SIGNAL TERMED AS BIOMARKER. CANCER, BEING A MULTISTEP PROCESS WITH ACCUMULATING GENETIC AND EPIGENETIC ALTERATIONS, COULD BE DETECTED EARLY WITH SUITABLE BIOMARKERS. THERE ARE SEVERAL PROTEINS SUCH AS AFP, CA-125, PSA, TROPONIN, CEA, OSTEOPONTIN, CA 19-9 THAT ACT AS BIOMARKERS WHICH HELP IN EARLY DETECTION, PROGNOSIS, AND MONITORING OF DISEASE PROGRESSION, A HUNT FOR NEWER BIOMARKERS WITH HIGHER SPECIFICITY AND SENSITIVITY IS STILL ONGOING. TUMOR-SPECIFIC GROWTH FACTOR (TSGF) IS ONE SUCH BUDDING AND PREVAILING TUMOR BIOMARKER USED FOR THE EARLY-STAGE DETECTION OF SEVERAL TYPES OF CARCINOMAS. TSGF IS A GENE THAT HELPS IN TUMOR ANGIOGENESIS AND GETS RELEASED DURING THE PRELIMINARY STAGES FROM CANCER CELLS THAT ENSURE THE VASCULAR PROLIFERATION OF THE SAME. IN THIS REVIEW, THE CLINICAL INVESTIGATIONS OF TSGF IN DIFFERENT KINDS OF MALIGNANCY IS DISCUSSED IN DETAIL AND SUGGESTS THE POSSIBILITY OF USING TSGF AS A BIOMARKER IN EARLY DIAGNOSIS OF CANCER. 2023 18 3693 36 INFLAMMATORY CELLS CAN ALTER THE LEVELS OF H3K9AC AND GAMMAH2AX IN DYSPLASTIC CELLS AND FAVOR TUMOR PHENOTYPE. ORAL POTENTIALLY MALIGNANT DISORDERS (OPMD) ARE CLINICAL PRESENTATIONS THAT CARRY AN INCREASED RISK OF CANCER DEVELOPMENT. CURRENTLY, EPITHELIAL DYSPLASIA GRADE IS BASED ON ARCHITECTURAL AND CYTOLOGICAL EPITHELIAL CHANGES AND IS USED TO PREDICT THE MALIGNANT TRANSFORMATION OF THESE LESIONS. HOWEVER, PREDICTING WHICH OPMD WILL PROGRESS TO A MALIGNANT TUMOR IS VERY CHALLENGING. INFLAMMATORY INFILTRATES CAN FAVOR CANCER DEVELOPMENT, AND RECENT STUDIES SUGGEST THAT THIS ASSOCIATION WITH OPMD LESIONS MAY BE RELATED TO THE ETIOLOGY AND/OR AGGRESSIVE CLINICAL BEHAVIOR OF THESE LESIONS. EPIGENETIC CHANGES SUCH AS HISTONE MODIFICATIONS MAY MEDIATE CHRONIC INFLAMMATION AND ALSO FAVOR TUMOR CELLS IN IMMUNE RESISTANCE AND EVASION. THIS STUDY AIMED TO EVALUATE THE RELATIONSHIP BETWEEN HISTONE ACETYLATION (H3K9AC) AND DNA DAMAGE IN THE CONTEXT OF DYSPLASTIC LESIONS WITH PROMINENT CHRONIC INFLAMMATION. IMMUNOFLUORESCENCE OF "LOW-RISK" AND "HIGH-RISK" OPMD LESIONS (N = 24) AND INFLAMMATORY FIBROUS HYPERPLASIA (N = 10) AS THE CONTROL GROUP WAS PERFORMED TO ASSESS HISTONE ACETYLATION LEVELS AND DNA DAMAGE THROUGH THE PHOSPHORYLATION OF H2AX (GAMMAH2AX). CELL CO-CULTURE ASSAYS WITH PBMCS AND ORAL KERATINOCYTE CELL LINES (NOK-SI, DOK, AND SCC-25) WERE PERFORMED TO ASSESS PROLIFERATION, ADHESION, MIGRATION, AND EPITHELIAL-MESENCHYMAL TRANSITION (EMT). ORAL DYSPLASTIC LESIONS SHOWED A HYPOACETYLATION OF H3K9 AND LOW LEVELS OF GAMMAH2AX COMPARED TO CONTROL. THE CONTACT OF DYSPLASTIC ORAL KERATINOCYTES WITH PBMCS FAVORED EMT AND THE LOSS OF CELL-CELL ADHESION. ON THE OTHER HAND, P27 LEVELS INCREASED AND CYCLIN E DECREASED IN DOK, INDICATING CELL CYCLE ARREST. WE CONCLUDE THAT THE PRESENCE OF CHRONIC INFLAMMATION ASSOCIATED TO DYSPLASTIC LESIONS IS CAPABLE OF PROMOTING EPIGENETIC ALTERATIONS, WHICH IN TURN CAN FAVOR THE PROCESS OF MALIGNANT TRANSFORMATION. 2023 19 2820 27 FINE-MAPPING INFLAMMATORY BOWEL DISEASE LOCI TO SINGLE-VARIANT RESOLUTION. INFLAMMATORY BOWEL DISEASES ARE CHRONIC GASTROINTESTINAL INFLAMMATORY DISORDERS THAT AFFECT MILLIONS OF PEOPLE WORLDWIDE. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED 200 INFLAMMATORY BOWEL DISEASE-ASSOCIATED LOCI, BUT FEW HAVE BEEN CONCLUSIVELY RESOLVED TO SPECIFIC FUNCTIONAL VARIANTS. HERE WE REPORT FINE-MAPPING OF 94 INFLAMMATORY BOWEL DISEASE LOCI USING HIGH-DENSITY GENOTYPING IN 67,852 INDIVIDUALS. WE PINPOINT 18 ASSOCIATIONS TO A SINGLE CAUSAL VARIANT WITH GREATER THAN 95% CERTAINTY, AND AN ADDITIONAL 27 ASSOCIATIONS TO A SINGLE VARIANT WITH GREATER THAN 50% CERTAINTY. THESE 45 VARIANTS ARE SIGNIFICANTLY ENRICHED FOR PROTEIN-CODING CHANGES (N = 13), DIRECT DISRUPTION OF TRANSCRIPTION-FACTOR BINDING SITES (N = 3), AND TISSUE-SPECIFIC EPIGENETIC MARKS (N = 10), WITH THE LAST CATEGORY SHOWING ENRICHMENT IN SPECIFIC IMMUNE CELLS AMONG ASSOCIATIONS STRONGER IN CROHN'S DISEASE AND IN GUT MUCOSA AMONG ASSOCIATIONS STRONGER IN ULCERATIVE COLITIS. THE RESULTS OF THIS STUDY SUGGEST THAT HIGH-RESOLUTION FINE-MAPPING IN LARGE SAMPLES CAN CONVERT MANY DISCOVERIES FROM GENOME-WIDE ASSOCIATION STUDIES INTO STATISTICALLY CONVINCING CAUSAL VARIANTS, PROVIDING A POWERFUL SUBSTRATE FOR EXPERIMENTAL ELUCIDATION OF DISEASE MECHANISMS. 2017 20 6222 19 THE LANDSCAPE OF SOMATIC MUTATIONS IN LYMPHOBLASTOID CELL LINES. SOMATIC MUTATIONS HAVE IMPORTANT BIOLOGICAL RAMIFICATIONS WHILE EXERTING SUBSTANTIAL RATE, TYPE, AND GENOMIC LOCATION HETEROGENEITY. YET, THEIR SPORADIC OCCURRENCE MAKES THEM DIFFICULT TO STUDY AT SCALE AND ACROSS INDIVIDUALS. LYMPHOBLASTOID CELL LINES (LCLS), A MODEL SYSTEM FOR HUMAN POPULATION AND FUNCTIONAL GENOMICS, HARBOR LARGE NUMBERS OF SOMATIC MUTATIONS AND HAVE BEEN EXTENSIVELY GENOTYPED. BY COMPARING 1,662 LCLS, WE REPORT THAT THE MUTATIONAL LANDSCAPE OF THE GENOME VARIES ACROSS INDIVIDUALS IN TERMS OF THE NUMBER OF MUTATIONS, THEIR GENOMIC LOCATIONS, AND THEIR SPECTRA; THIS VARIATION MAY ITSELF BE MODULATED BY SOMATIC TRANS-ACTING MUTATIONS. MUTATIONS ATTRIBUTED TO THE TRANSLESION DNA POLYMERASE ETA FOLLOW TWO DIFFERENT MODES OF FORMATION, WITH ONE MODE ACCOUNTING FOR THE HYPERMUTABILITY OF THE INACTIVE X CHROMOSOME. NONETHELESS, THE DISTRIBUTION OF MUTATIONS ALONG THE INACTIVE X CHROMOSOME APPEARS TO FOLLOW AN EPIGENETIC MEMORY OF THE ACTIVE FORM. 2023