1 1432 108 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 2 3908 30 LICHEN SCLEROSUS: AN AUTOIMMUNOPATHOGENIC AND GENOMIC ENIGMA WITH EMERGING GENETIC AND IMMUNE TARGETS. LICHEN SCLEROSUS (LS) IS AN INFLAMMATORY DERMATOSIS WITH A PREDILECTION FOR ANOGENITAL SKIN. DEVELOPING LESIONS LEAD TO VULVAR PAIN AND SEXUAL DYSFUNCTION, WITH A SIGNIFICANT LOSS OF STRUCTURAL ANATOMICAL ARCHITECTURE, SCLEROSIS, AND INCREASED RISK OF MALIGNANCY. ONSET MAY OCCUR AT ANY AGE IN BOTH SEXES, BUT TYPICALLY AFFECTS MORE FEMALES THAN MALES, PRESENTING IN A BIMODAL FASHION AMONG PRE-PUBERTAL CHILDREN AND MIDDLE-AGED ADULTS. A DEFINITIVE CURE REMAINS ELUSIVE AS THE EXACT PATHOGENESIS OF LS REMAINS UNKNOWN. A GENERAL REVIEW OF LS, HISTOLOGIC CHALLENGES, ALONG WITH AMOUNTING SUPPORT FOR LS AS AN AUTOIMMUNE DISEASE WITH PREFERENCE FOR A T(H)1 IMMUNE RESPONSE AGAINST A GENETIC BACKGROUND IS SUMMARIZED. IN ADDITION TO THE CLASSICALLY REFERENCED ECM1 (EXTRACELLULAR MATRIX PROTEIN 1), A FOLLOWING DISCUSSION OF OTHER IMMUNE AND GENETIC TARGETS MORE RECENTLY IMPLICATED AS CAUSATIVE OR ACCELERANT AGENTS OF DISEASE, PARTICULARLY MIR-155, DOWNSTREAM TARGETS OF ECM1, GALECTIN-7, P53, AND EPIGENETIC MODIFICATIONS TO CDKN2A, ARE ADDRESSED FROM THE VIEWPOINT OF THEIR INVOLVEMENT IN THREE DIFFERENT, BUT INTERCONNECTED ASPECTS OF LS PATHOLOGY. COLLECTIVELY, THESE EMERGING TARGETS SERVE NOT ONLY AS INHERENTLY POTENTIAL THERAPEUTIC TARGETS FOR TREATMENT, BUT MAY ALSO PROVIDE FURTHER INSIGHT INTO THIS DEBILITATING AND CRYPTIC DISEASE. 2019 3 6381 38 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 4 2974 31 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT. 2022 5 5382 28 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 6 4229 31 METHYLATION OF INK4 AND CIP/KIP FAMILIES OF CYCLIN-DEPENDENT KINASE INHIBITOR IN CHRONIC LYMPHOCYTIC LEUKAEMIA IN CHINESE PATIENTS. BACKGROUND: INK4 (P15, P16, P18 AND P19) AND CIP/KIP (P21, P27 AND P57) ARE TWO FAMILIES OF CYCLIN-DEPENDENT KINASE INHIBITORS (CKI) TARGETING CDK4/6 AND CDK2, RESPECTIVELY. AIM: TO STUDY THE ROLE OF METHYLATION IN THE INACTIVATION OF CKI IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). MATERIALS AND METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WAS CARRIED OUT ON DNA OBTAINED FROM THE BONE MARROW OF 56 NEWLY DIAGNOSED PATIENTS WITH CLL. RESULTS: SIMILAR DEMOGRAPHIC FEATURES AND CLINICAL OUTCOME WERE OBSERVED IN OUR PATIENTS WHEN COMPARED WITH CAUCASIAN PATIENTS, INCLUDING AN INDOLENT CLINICAL COURSE (10-YEAR OVERALL SURVIVAL 51%) AND ADVANCED RAI STAGE (P = 0.006), AND A HIGH-RISK KARYOTYPE SUCH AS TRISOMY 12 AND COMPLEX ABERRATIONS (P = 0.03). IN THE INK4 FAMILY, METHYLATION IN P15 AND P16 OCCURRED IN 20 (35.7%) AND 8 (14.3%) PATIENTS, RESPECTIVELY. IN ALL, 5 (8.9%) CLL SAMPLES HARBOURED CONCURRENT METHYLATION OF BOTH P15 AND P16. APART FROM AN ASSOCIATION OF P16 METHYLATION WITH HIGHER PRESENTING LEUCOCYTE COUNT (64.5 X 10(9)/L IN METHYLATED P16 AND 16.0 X 10(9)/L IN UNMETHYLATED P16 PATIENTS; P = 0.016), THERE WAS NO ASSOCIATION BETWEEN P15 AND P16 METHYLATION AND AGE, SEX AND RAI STAGE. NO DIFFERENCE WAS OBSERVED IN THE OVERALL SURVIVAL FOR PATIENTS WITH AND WITHOUT P15 AND P16 METHYLATION. BY CONTRAST, P18 AND RB WERE UNMETHYLATED IN ALL SAMPLES. IN THE CIP/KIP FAMILY, APART FROM INFREQUENT METHYLATION OF P57 IN 4 (7.1%) PATIENTS, METHYLATION OF P21 AND P27 WAS UNIFORMLY ABSENT. CONCLUSION: P15 AND, LESS FREQUENTLY, P16 OF THE INK4 FAMILY OF CKI, INSTEAD OF THE CIP OR KIP FAMILY, WERE TARGETED BY METHYLATION IN CLL. P16 METHYLATION WAS ASSOCIATED WITH A HIGHER LYMPHOCYTE COUNT AT PRESENTATION. THIS IS THE FIRST COMPREHENSIVE STUDY OF THE EPIGENETIC DYSREGULATION OF THE INK4 AND CIP/KIP FAMILIES OF CKI IN CHINESE PATIENTS WITH CLL. 2006 7 4540 28 MULTISTEP PATHOGENESIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN PATIENTS. BACKGROUND: A MULTISTEP PATHOGENESIS OF MYELOID LEUKEMIA INCLUDING MUTATIONS IN EPIGENETIC, SPLICEOSOME, AND SIGNALING GENES HAS BEEN RECENTLY DEMONSTRATED IN A PRECLINICAL MODEL BUT IS POORLY VALIDATED IN PATIENTS. METHODS: CLINICAL, PHENOTYPIC, AND BIOLOGIC FEATURES WERE COMPARED BETWEEN THREE DISTINCT MOLECULARLY DEFINED CMML COHORTS INCLUDING TET2 MONOMUTATED PATIENTS (T, N = 10), TET2/SRSF2 BIMUTATED PATIENTS (TS, N = 19), AND PATIENTS WHO HAD NRAS MUTATIONS IN ADDITION TO TET2/SRSF2 COMUTATIONS (TSN, N = 14). RESULTS: MEDIAN SURVIVAL WAS 90, 45, AND 9 MONTHS, RESPECTIVELY (P = .001). WHEREAS NO PATIENT IN THE T AND TS GROUP TRANSFORMED INTO ACUTE MYELOID LEUKEMIA (AML), 6/14 PATIENTS IN THE TSN GROUP HAD AML AT STUDY ENTRY OR TRANSFORMED DURING FOLLOW-UP. LEUKOCYTE COUNTS, BLAST CELL COUNTS, AND LDH LEVELS WERE SIGNIFICANTLY HIGHER IN TSN VS. TS AND T, RESPECTIVELY, WHEREAS HEMOGLOBIN AND PLATELET VALUES WERE NOT SIGNIFICANTLY DIFFERENT. INCREASED GROWTH FACTOR-INDEPENDENT MYELOID COLONY FORMATION WAS RESTRICTED TO TSN BUT NOT FOUND IN T AND TS, RESPECTIVELY. THE PROPORTION OF PATIENTS SHOWING IN VITRO MYELOMONOCYTIC SKEWING IN T, TS, AND TSN WAS 0%, 56%, AND 100%, RESPECTIVELY (P = .010). CONCLUSION: OUR RESULTS DEMONSTRATE THAT THE MODEL OF MULTISTEP PATHOGENESIS IN CMML CAN BE RECAPITULATED IN PATIENTS REGARDING CLINICAL, PHENOTYPIC, AND BIOLOGIC FEATURES. 2022 8 3528 32 IL36G GENETIC VARIANT IS INDEPENDENTLY ASSOCIATED WITH SUSCEPTIBILITY, SEVERITY AND JOINT INVOLVEMENT IN PSORIASIS. PSORIASIS (PSO) IS A CHRONIC, IMMUNE-MEDIATED, INFLAMMATORY AND POLYGENIC DERMATOSIS ASSOCIATED WITH BOTH PHYSICAL AND PSYCHOLOGICAL BURDEN THAT CAN BE TRIGGERED BY INJURY, TRAUMA, INFECTIONS AND MEDICATIONS. THE ETIOLOGY OF PSO IS NOT FULLY ELUCIDATED BUT GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ALL LIKELY TO PLAY A ROLE. A CASE-CONTROL STUDY WAS CARRIED OUT TO EVALUATE THE FREQUENCY OF THE IL36G C>T (RS13392494) AND THE IL36G A>G (RS7584409) VARIANTS AND THEIR ASSOCIATION WITH SUSCEPTIBILITY, JOINT INVOLVEMENT AND SEVERITY OF PSO. THE STUDY INCLUDED 154 PATIENTS WITH PSO AND 154 CONTROLS FROM BRAZILIAN POPULATION. THE SEVERITY OF PSO WAS ASSESSED BY THE PSORIASIS AREA AND SEVERITY INDEX (PASI). THE IL36G (RS13392494 AND RS7584409) VARIANTS WERE GENOTYPED BY ALLELIC DISCRIMINATION ASSAY USING THE REAL-TIME POLYMERASE CHAIN REACTION. THE ASSOCIATION BETWEEN THE IL36G GENETIC VARIANTS AND THE STUDY VARIABLES WAS ANALYZED IN ALLELIC, DOMINANT, CODOMINANT, OVERDOMINANT, RECESSIVE, AND HAPLOTYPE MODELS. THE MAIN RESULTS WERE THAT PSO PATIENTS WERE OLDER (P < 0.001) AND HAD HIGHER BODY MASS INDEX (P < 0.001) THAN CONTROLS; 95.8% OF THE PATIENTS HAD PLAQUE PSO, 16.1% HAD PSORIATIC ARTHRITIS (PSA), AND 27.9% HAD PASI > 10. THE IL36G RS1339294 VARIANT SHOWED NO ASSOCIATION WITH PSO IN ALL GENETIC MODELS WHILE THE IL36G RS7584409 VARIANT SHOWED A PROTECTIVE EFFECT IN PSO. HOWEVER, THE G ALLELE OF THE IL36G RS7584409 IN THE DOMINANT MODEL WAS POSITIVELY ASSOCIATED WITH PASI > 10 (P = 0.031). MOREOVER, PATIENTS WITH THE GG GENOTYPE OF THE IL36G RS7584409 VARIANT HAD ABOUT 5.0 TIMES MORE CHANCE OF PSA THAN THOSE WITH THE AA GENOTYPE (P = 0.014). REGARDING THE HAPLOTYPES, THE C/A IN A RECESSIVE MODEL (CACA VERSUS C/G AND T/A CARRIERS) WAS ASSOCIATED WITH PSO (P = 0.035) WHILE THE C/G HAPLOTYPE IN A DOMINANT MODEL (C/A CARRIERS VERSUS C/G AND T/A CARRIERS) SHOWED A PROTECTIVE EFFECT FOR PSO (P = 0.041). IN CONCLUSION, THE G ALLELE OF THE IL36G RS7584409 VARIANT WAS ASSOCIATED WITH PROTECTION TO PSO; HOWEVER, IN PATIENTS WITH PSO, THIS SAME ALLELE WAS ASSOCIATED WITH MODERATE TO SEVERE DISEASE AND PSA. THESE RESULTS SUGGEST THAT THE IL36G RS7584409 VARIANT MAY BE USED AS A POSSIBLE GENETIC BIOMARKER TO PREDICT SEVERITY AND JOINT INVOLVEMENT OF PSO. 2023 9 3879 33 KERATIN 19-EXPRESSING HEPATOCELLULAR CARCINOMA AND SMALL-DUCT TYPE INTRAHEPATIC CHOLANGIOCARCINOMA SHOW A SIMILAR POSTOPERATIVE CLINICAL COURSE BUT HAVE DISTINCT GENETIC FEATURES. AIMS: THE PRESENT STUDY AIMED TO SYSTEMATICALLY COMPARE CLINICOPATHOLOGICAL AND GENETIC FEATURES BETWEEN KERATIN 19 (K19)-EXPRESSING HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICCA). METHODS AND RESULTS: CONSECUTIVE CASES OF HCC (N = 430) WERE CLASSIFIED INTO K19(+) AND K19(-) USING IMMUNOHISTOCHEMISTRY. ICCA CASES WERE ALSO SEPARATED INTO SMALL-(S-ICCA; N = 36) AND LARGE-DUCT TYPES (N = 22) BASED ON RECENTLY PROPOSED CRITERIA, WITH THE FORMER BEING USED IN THE PRESENT STUDY. MUTATIONAL HOT-SPOTS IN TERT, CTNNB1, KRAS AND IDH1 WERE SEQUENCED. TWENTY-SIX CASES (6%) OF HCC EXPRESSED K19. K19(+) HCC WAS MORE STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B THAN K19(-) HCC AND S-ICCA (46% VERSUS 17% AND 6%; BOTH P < 0.001). LYMPH NODE METASTASIS WAS OBSERVED IN K19(+) HCC (8%) AND S-ICCA (22%), BUT WAS EXCEPTIONAL IN K19(-) HCC (1%). K19(+) HCC HAD TERT PROMOTER MUTATIONS LESS FREQUENTLY THAN K19(-) HCC (31% VERSUS 59%; P = 0.022), AND LACKED ALTERATIONS IN KRAS AND IDH1. CTNNB1 MUTATIONS WERE SIMILARLY OBSERVED IN K19(+) AND K19(-) HCC (23% AND 19%, RESPECTIVELY), BUT RARE IN S-ICCA (3%). THE POSTOPERATIVE SURVIVAL CURVE OF K19(+) HCC WAS ALMOST IDENTICAL TO THAT OF S-ICCA IN THE FIRST 5 YEARS (APPROXIMATELY 50% AT 5 YEARS), AND SIGNIFICANTLY WORSE THAN THAT OF K19(-) HCC (P = 0.040). EXTRAHEPATIC RECURRENCE WAS MORE COMMON IN K19(+) HCC (50%) AND S-ICCA (35%) THAN IN K19(-) HCC (15%) (P = 0.001). CONCLUSIONS: ALTHOUGH K19(+) HCC AND S-ICCA SHOWED SIMILAR BIOLOGICAL BEHAVIOURS, THEY DID NOT SHARE ANY DRIVER GENE MUTATIONS, SUGGESTING THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ICCA-LIKE FEATURES OF K19(+) HCC. 2019 10 514 30 ASSOCIATION OF SHMT1, MAZ, ERG, AND L3MBTL3 GENE POLYMORPHISMS WITH SUSCEPTIBILITY TO MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS THE MOST COMMON INFLAMMATORY AND CHRONIC DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS). A COMPLEX INTERACTION BETWEEN GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS IS INVOLVED IN THE PATHOGENESIS OF MS. WITH THE ADVANCEMENT OF GWAS, VARIOUS VARIANTS ASSOCIATED WITH MS HAVE BEEN IDENTIFIED. THIS STUDY AIMED TO EVALUATE THE ASSOCIATION OF SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS) RS4925166 AND RS1979277 IN THE SHMT1, MAZ RS34286592, ERG RS2836425, AND L3MBTL3 RS4364506 WITH MS. IN THIS CASE-CONTROL STUDY, THE ASSOCIATION OF FIVE SNPS IN SHMT1, MAZ, ERG, AND L3MBTL3 GENES WITH RELAPSING-REMITTING MS (RR-MS) WAS INVESTIGATED IN 190 PATIENTS AND 200 HEALTHY INDIVIDUALS. FOUR SNPS INCLUDING SHMT1 RS4925166, SHMT1 RS1979277, MAZ RS34286592, AND L3MBTL3 RS4364506 WERE GENOTYPED USING PCR-RFLP AND GENOTYPING OF ERG RS2836425 WAS PERFORMED BY TETRA-PRIMER ARMS PCR. OUR FINDINGS SHOWED A SIGNIFICANT DIFFERENCE IN THE ALLELIC FREQUENCIES FOR THE FOUR SNPS OF SHMT1 RS4925166, SHMT1 RS1979277, MAZ RS34286592, AND ERG RS2836425, WHILE THERE WERE NO DIFFERENCES IN THE ALLELE AND GENOTYPE FREQUENCIES FOR L3MBTL3 RS4364506. THESE SIGNIFICANT ASSOCIATIONS WERE OBSERVED FOR THE FOLLOWING GENOTYPES: TT AND GG GENOTYPES OF SHMT1 RS4925166 (OR 0.47 AND 1.90, RESPECTIVELY) GENOTYPE GG OF SHMT1 RS1979277 (OR 0.63), GENOTYPE GG OF MAZ RS34286592 (OR 0.61), TC AND CC GENOTYPES OF ERG RS2836425 (OR 1.89 AND 0.50, RESPECTIVELY). OUR STUDY HIGHLIGHTED THAT PEOPLE WHO ARE CARRYING GENOTYPES INCLUDING GG (SHMT1 RS4925166) AND TC (ERG RS2836425) HAVE THE HIGHEST SUSCEPTIBILITY CHANCE FOR MS, RESPECTIVELY. HOWEVER, GENOTYPES TT (SHMT1 RS4925166), CC (ERG RS2836425), GG (MAZ RS34286592), AND GG (SHMT1 RS1979277) HAD THE HIGHEST NEGATIVE ASSOCIATION (PROTECTIVE EFFECT) WITH MS, RESPECTIVELY. L3MBTL3 RS4364506 WAS FOUND NEITHER AS A PREDISPOSING NOR A PROTECTIVE VARIANT. 2019 11 1575 39 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 12 2948 31 GENETIC AND EPIGENETIC CHARACTERISTICS OF INFLAMMATORY BOWEL DISEASE-ASSOCIATED COLORECTAL CANCER. BACKGROUND & AIMS: INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC, RELAPSING INFLAMMATORY DISORDER ASSOCIATED WITH AN ELEVATED RISK OF COLORECTAL CANCER (CRC). IBD-ASSOCIATED CRC (IBD-CRC) MAY REPRESENT A DISTINCT PATHWAY OF TUMORIGENESIS COMPARED TO SPORADIC CRC (SCRC). OUR AIM WAS TO COMPREHENSIVELY CHARACTERIZE IBD-ASSOCIATED TUMORIGENESIS INTEGRATING MULTIPLE HIGH-THROUGHPUT APPROACHES, AND TO COMPARE THE RESULTS WITH IN-HOUSE DATA SETS FROM SCRCS. METHODS: WHOLE-GENOME SEQUENCING, SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS, RNA SEQUENCING, GENOME-WIDE METHYLATION ANALYSIS, AND IMMUNOHISTOCHEMISTRY WERE PERFORMED USING FRESH-FROZEN AND FORMALIN-FIXED TISSUE SAMPLES OF TUMOR AND CORRESPONDING NORMAL TISSUES FROM 31 PATIENTS WITH IBD-CRC. RESULTS: TRANSCRIPTOME-BASED TUMOR SUBTYPING REVEALED THE COMPLETE ABSENCE OF CANONICAL EPITHELIAL TUMOR SUBTYPE ASSOCIATED WITH WNT SIGNALING IN IBD-CRCS, DOMINATED INSTEAD BY MESENCHYMAL STROMA-RICH SUBTYPE. NEGATIVE WNT REGULATORS AXIN2 AND RNF43 WERE STRONGLY DOWN-REGULATED IN IBD-CRCS AND CHROMOSOMAL GAINS AT HNF4A, A NEGATIVE REGULATOR OF WNT-INDUCED EPITHELIAL-MESENCHYMAL TRANSITION (EMT), WERE LESS FREQUENT COMPARED TO SCRCS. ENRICHMENT OF HYPOMETHYLATION AT HNF4ALPHA BINDING SITES WAS DETECTED SOLELY IN SCRC GENOMES. PIGR AND OSMR INVOLVED IN MUCOSAL IMMUNITY WERE DYSREGULATED VIA EPIGENETIC MODIFICATIONS IN IBD-CRCS. GENOME-WIDE ANALYSIS SHOWED SIGNIFICANT ENRICHMENT OF NONCODING MUTATIONS TO 5'UNTRANSLATED REGION OF TP53 IN IBD-CRCS. AS REPORTED PREVIOUSLY, SOMATIC MUTATIONS IN APC AND KRAS WERE LESS FREQUENT IN IBD-CRCS COMPARED TO SCRCS. CONCLUSIONS: DISTINCT MECHANISMS OF WNT PATHWAY DYSREGULATION SKEW IBD-CRCS TOWARD MESENCHYMAL TUMOR SUBTYPE, WHICH MAY AFFECT PROGNOSIS AND TREATMENT OPTIONS. INCREASED OSMR SIGNALING MAY FAVOR THE ESTABLISHMENT OF MESENCHYMAL TUMORS IN PATIENTS WITH IBD. 2021 13 2037 37 EPIGENETIC CHANGES OF TIMP-3, GSTP-1 AND 14-3-3 SIGMA GENES AS INDICATION OF STATUS OF CHRONIC INFLAMMATION AND CANCER. OBJECTIVES: THIS STUDY AIMED TO COMPARE THE EPIGENETIC CHANGES VIA HYPERMETHYLATION STATUS OF TIMP-3, GSTP-1 AND 14-3-3SIGMA GENES, BETWEEN HEALTHY SUBJECTS AND PATIENTS WITH REVERSIBLE CHRONIC INFLAMMATORY DISEASE, AND BETWEEN HEALTHY SUBJECTS AND PATIENTS WITH IRREVERSIBLE MALIGNANT DISEASE, TO HIGHLIGHT THE GENETIC CHANGES THAT OCCUR IN THE PROGRESSION FROM AN INFLAMMATORY CONDITION TO IRREVERSIBLE GENETIC CHANGES COMMONLY OBSERVED IN CANCER PATIENTS. METHODS: DNA WAS EXTRACTED FROM THE BLOOD OF 680 HEALTHY SUBJECTS, AND TISSUES AND BLOOD OF 110 PATIENTS WITH CHRONIC INFLAMMATION DISEASE OF THE GUMS, AS WELL AS NEOPLASTIC TISSUES OF 108 BREAST CANCER PATIENTS. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) FOR TIMP-3, GSTP-1 AND 14-3-3SIGMA WAS PERFORMED, AND HYPERMETHYLATION STATUS WAS ANALYZED AND COMPARED BETWEEN THE 3 GROUPS. RESULTS: THE HYPERMETHYLATION FREQUENCIES OF TIMP-3 AND GSTP-1 OF REVERSIBLE CHRONIC INFLAMMATORY GUM DISEASE AND THE CONTROL GROUP WERE SIMILAR, BUT BOTH WERE SIGNIFICANTLY LOWER THAN THOSE FOR MALIGNANT DISEASE PATIENTS (P<0.0001). THE METHYLATION FREQUENCY OF 14-3-3SIGMA IN CHRONIC INFLAMMATORY GUM DISEASE WAS HIGHER THAN IN THE CANCER AND CONTROL GROUPS (P<0.0001). THE METHYLATION OF CPG ISLANDS IN TIMP-3 AND GSTP-1 IN CHRONIC INFLAMMATION PATIENTS OCCURRED AS FREQUENTLY AS IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN BREAST CANCER PATIENTS. HOWEVER, THE EPIGENETIC SILENCING OF 14-3-3SIGMA OCCURRED MORE FREQUENTLY IN THE CHRONIC INFLAMMATION GROUP THAN IN CANCER PATIENTS AND HEALTHY CONTROLS. CONCLUSIONS: THE EPIGENETIC SILENCING OF 14-3-3SIGMA MIGHT BE ESSENTIAL FOR CHRONIC INFLAMMATORY GUM DISEASE. THE EPIGENETIC CHANGES PRESENTED IN CHRONIC INFLAMMATION PATIENTS MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO CANCER. 2014 14 388 32 AN INTEGRATED ANALYSIS OF SOCS1 DOWN-REGULATION IN HBV INFECTION-RELATED HEPATOCELLULAR CARCINOMA. PERSISTENT INFLAMMATION TOGETHER WITH GENETIC/EPIGENETIC ABERRATIONS IS STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B VIRUS (HBV) INFECTION-RELATED HEPATOCARCINOGENESIS. HERE, WE INVESTIGATED THE ALTERATIONS OF THE SUPPRESSOR OF CYTOKINE SIGNALLING (SOCS) FAMILY GENES IN HBV-RELATED HEPATOCELLULAR CARCINOMA (HCC). A TOTAL OF 116 PATIENTS WITH HCC WERE ENROLLED IN THIS STUDY. THE METHYLATION STATUSES OF SOCS1-7 AND CISH GENES WERE QUANTITATIVELY MEASURED AND CLINICOPATHOLOGICAL SIGNIFICANCE OF SOCS1 METHYLATION WAS STATISTICALLY ANALYSED. THE GENE COPY NUMBER VARIATION WAS ASSAYED BY ACGH. LUCIFERASE REPORTER ASSAY AND WESTERN BLOT WERE USED TO DETECT THE INVOLVEMENT OF SOCS1 IN P53 SIGNALLING. WE FOUND HIGH FREQUENCIES OF SOCS1 GENE HYPERMETHYLATION IN BOTH TUMOUR (56.03%) AND ADJACENT NONTUMOUR TISSUES (54.31%), BUT TUMOUR TISSUES EXHIBITED INCREASED METHYLATION INTENSITY (24.01% VS 13.11%, P < 0.0001), PARTICULARLY IN PATIENTS WITH LARGER TUMOUR SIZE OR CIRRHOSIS BACKGROUND (P < 0.0001). IN ADDITION, THE FREQUENCY AND INTENSITY OF SOCS1 HYPERMETHYLATION IN TUMOUR TISSUES WERE BOTH SIGNIFICANTLY HIGHER THAN THOSE IN NONTUMOUR TISSUES IN MALE GENDER PATIENTS AND IN PATIENTS >/=45 YEARS OLD (P = 0.0214 AND P < 0.0001, P = 0.0232 AND P < 0.0001, RESPECTIVELY). SOCS1 GENE DELETION WAS FOUND IN 8 OF 25 ACGH ASSAYED TUMOUR SPECIMENS, WHICH WAS ASSOCIATED WITH LOWER SOCS1 MRNA EXPRESSION (P = 0.0448). FURTHERMORE, ECTOPIC SOCS1 OVEREXPRESSION COULD ACTIVATE THE P53 SIGNALLING PATHWAY IN HCC CELL LINES. HYPERMETHYLATION OF SOCS2-7 AND CISH GENES WAS SELDOM FOUND IN HCC. OUR RESULTS SUGGESTED THAT THE GENE LOSS AND EPIGENETIC SILENCING OF SOCS1 WERE STRONGLY ASSOCIATED WITH HBV-RELATED HCC. 2014 15 1044 28 CLINICAL CHARACTERISTICS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKIN B-CELL LYMPHOMA: A MULTICENTER RETROSPECTIVE STUDY. BACKGROUND: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATED WITH B-CELL LYMPHOMA IS A HIGHLY AGGRESSIVE DISEASE WITH UNCLEAR CLINICAL FEATURES AND HAS NO STANDARD TREATMENT. PATIENTS AND METHODS: WE ANALYZED THE CLINICAL CHARACTERISTICS OF 31 PATIENTS FROM TWO INDIVIDUAL CENTERS. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS ONLY 1.5 MONTHS. BOTH UNIVARIATE AND MULTIVARIATE ANALYSES, BASED ON LYMPHOMA OR HLH-RELATED CHARACTERISTICS, REVEALED THAT PATIENTS WITH HIGH EPSTEIN-BARR VIRUS (EBV) DNA LOAD AND >/= 2 EXTRANODAL LESIONS, OR HYPOFIBRINOGENEMIA, RESPECTIVELY, SHOWED SIGNIFICANTLY POORER OVERALL SURVIVAL. INTERESTINGLY, SOME PATIENTS WITH HIGH EBV DNA LOAD HAD EBV-POSITIVE NATURAL KILLER (NK) AND/OR T CELLS, WHICH MAY BE RELATED TO THE COEXISTENCE OF IMMUNODEFICIENCY AND/OR CHRONIC ACTIVE EBV INFECTION. MOLECULAR GENETICS EXAMINATION CONFIRMED THAT 47.4% (9/19) OF PATIENTS HAD COMPLEX KARYOTYPES, 37.5% (3/8) OF PATIENTS HAD TP53 DELETIONS, AND 21.34% (3/14) OF PATIENTS HAD TP53 MUTATION OR ALTERATION OF MALIGNANCY-RELATED PATHWAYS, INCLUDING BCR/NF-KAPPAB, JAK-STAT, AND EPIGENETIC REGULATORY PATHWAYS, WHICH MAY PROVIDE CLUES TO CHOOSE TARGETS FOR THERAPY. TREATMENT REGIMENS CONTAINING ETOPOSIDE, ANTI-CD20 MONOCLONAL ANTIBODIES, OR ANTHRACYCLINES IMPROVED PATIENT PROGNOSIS (P = .0183, .025, AND .0436, RESPECTIVELY). PATIENTS WITH INFECTIONS HAD SIGNIFICANTLY SHORTER SURVIVAL THAN THOSE WITHOUT INFECTIONS (P = .00019). CONCLUSION: THE PATIENTS' PERFORMANCE STATUS, NUMBER OF EXTRANODAL LESIONS, HIGH EBV DNA LOAD, AND HYPOFIBRINOGENEMIA ARE POOR PROGNOSTIC FACTORS FOR HLH ASSOCIATED WITH B-CELL LYMPHOMA. MOLECULAR GENETIC HIGH-RISK FACTORS ARE OF PARTICULAR IMPORTANCE BECAUSE THESE FACTORS CAN PROVIDE INFORMATION FOR PROGNOSIS PREDICTION, TREATMENT DECISIONS, AND DISEASE SURVEILLANCE. 2021 16 5289 35 PROSTANOID RECEPTOR GENES CONFER POOR PROGNOSIS IN HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA EPIGENETIC INACTIVATION. BACKGROUND: CHRONIC INFLAMMATION IS A RISK FACTOR FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AND OTHER DISEASES. PROSTANOID RECEPTORS ARE CLEARLY INVOLVED IN THE DEVELOPMENT OF MANY TYPES OF CANCER. HOWEVER, THEIR ROLE IS NOT SIMPLE AND IS POORLY UNDERSTOOD IN HNSCC. METHODS: METHYLATION PROFILES OF PROSTANOID RECEPTOR FAMILY GENES WERE GENERATED FOR TUMOUR SAMPLES OBTAINED FROM 274 PATIENTS WITH HNSCC, INCLUDING 69 HYPOPHARYNX, 51 LARYNX, 79 ORAL CAVITY, AND 75 OROPHARYNX TUMOUR SAMPLES, BY QUANTITATIVE METHYLATION-SPECIFIC PCR. PROMOTER METHYLATION WAS THEN EVALUATED WITH RESPECT TO VARIOUS CLINICAL CHARACTERISTICS AND PATIENT SURVIVAL. RESULTS: THE MEAN NUMBER OF METHYLATED GENES PER SAMPLE WAS 2.05 +/- 2.59 (RANGE 0 TO 9). PROMOTERS OF PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, AND TBXA2R WERE METHYLATED IN 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, AND 11.3% OF THE SAMPLES, RESPECTIVELY. METHYLATION INDICES FOR PROSTANOID RECEPTOR FAMILY GENES TENDED TO BE HIGHER AS THE NUMBER OF TET METHYLATION EVENTS INCREASED. PATIENTS WITH 5-9 METHYLATED GENES HAD A SIGNIFICANTLY LOWER SURVIVAL RATE THAN THAT OF PATIENTS WITH 0-4 METHYLATED GENES (LOG-RANK TEST, P= 0.007). IN MULTIVARIATE ANALYSES, PTGDR1 METHYLATION WAS MOST HIGHLY CORRELATED WITH RECURRENCE IN PATIENTS WITH HYPOPHARYNGEAL CANCER (P = 0.014). A SIMILAR CORRELATION WAS OBSERVED FOR PTGER4 IN PATIENTS WITH LARYNGEAL CANCER (P = 0.046). METHYLATION OF THE PTGIR AND TBXA2R PROMOTERS WAS POSITIVELY CORRELATED WITH RECURRENCE IN OROPHARYNGEAL CANCER (P = 0.028 AND P = 0.006, RESPECTIVELY). MOREOVER, PATIENTS WITH 5-9 METHYLATED GENES WERE EXTREMELY LOWER OF 5HMC LEVELS (P = 0.035) AND WAS CORRELATED WITH INCREASING EXPRESSION OF DNMT3A AND DNMT3B (P < 0.05 AND P < 0.05, RESPECTIVELY). CONCLUSION: WE CHARACTERISED THE RELATIONSHIP BETWEEN THE METHYLATION STATUS OF PROSTANOID RECEPTOR GENES AND RECURRENCE IN HNSCC. THESE RESULTS PROVIDE NEW PERSPECTIVES FOR THE DEVELOPMENT OF MOLECULAR TARGETED TREATMENT APPROACHES. 2020 17 2893 20 GAS5 RS2067079 AND MIR-137 RS1625579 FUNCTIONAL SNPS AND RISK OF CHRONIC HEPATITIS B VIRUS INFECTION AMONG EGYPTIAN PATIENTS. HEPATITIS B VIRUS (HBV) INFECTION IS A SIGNIFICANT HEALTH ISSUE WORLDWIDE.. WE ATTEMPTED TO FULFILL THE MOLECULAR MECHANISMS OF EPIGENETIC AND GENETIC FACTORS ASSOCIATED WITH CHRONIC HBV (CHBV). EXPRESSION LEVELS OF THE LNCRNA GROWTH ARREST-SPECIFIC 5 (GAS5) AND MIR-137 AND THEIR CORRESPONDING SNPS, RS2067079 (C/T) AND RS1625579 (G/T) WERE ANALYZED IN 117 CHBV PATIENTS AND 120 CONTROLS TO INVESTIGATE THE PROBABLE ASSOCIATION BETWEEN THESE BIOMARKERS AND CHBV PATHOGENESIS IN THE EGYPTIAN POPULATION. SERUM EXPRESSION LEVELS OF GAS5 AND MIR-137 WERE SIGNIFICANTLY DOWN-REGULATED IN CASES VS CONTROLS. REGARDING GAS5 (RS2067079), THE MUTANT TT GENOTYPE SHOWED AN INCREASED RISK OF CHBV (P < 0.001), WHILE THE DOMINANT CC WAS A PROTECTIVE FACTOR (P = 0.004). REGARDING MIR-137 RS1625579, THE MUTANT GENOTYPE TT WAS REPORTED AS A RISK FACTOR FOR CHBV (P < 0.001) AND THE NORMAL GG GENOTYPE WAS A PROTECTIVE FACTOR, P < 0.001. THE SERUM GAS5 WAS SIGNIFICANTLY HIGHER IN THE MUTANT TT GENOTYPE OF GAS5 SNP AS COMPARED TO THE OTHER GENOTYPES (P = 0.007). CONCERNING MIR-137 RS1625579, THE MUTANT TT GENOTYPE WAS SIGNIFICANTLY ASSOCIATED WITH A LOWER SERUM EXPRESSION LEVEL OF MIR-137 (P = 0.018). WE REVEALED THE DYSREGULATED EXPRESSION LEVELS OF GAS5 AND MIR-137 LINKED TO THEIR FUNCTIONING SNPS WERE ASSOCIATED WITH CHBV RISK AND MIGHT ACT AS POTENTIAL THERAPEUTIC TARGETS. 2021 18 6248 28 THE METHYLATION STATUS OF THE DDX43 PROMOTER IN CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION IS A COMMON EPIGENETIC ALTERATION AND AN IMPORTANT FEATURE IN HUMAN CANCERS. THE DEAD BOX POLYPEPTIDE 43 (DDX43) HAS BEEN FOUND TO BE OVEREXPRESSED IN VARIOUS SOLID TUMORS AND SOME HEMATOLOGIC MALIGNANCIES. IN THE PRESENT STUDY, WE INVESTIGATED THE METHYLATION STATUS OF THE DDX43 PROMOTER IN 87 CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) USING REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION AND EXAMINED THE DDX43 TRANSCRIPT IN 35 PATIENTS USING REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION. DDX43 PROMOTER HYPOMETHYLATION WAS OBSERVED IN 22 (25.3%) CML PATIENTS. NO SIGNIFICANT CORRELATION WAS FOUND BETWEEN THE HYPOMETHYLATION OF THE DDX43 PROMOTER WITH THE AGE, SEX, WHITE BLOOD CELL COUNTS, HEMOGLOBIN CONCENTRATION, PLATELET COUNTS, AND CHROMOSOMAL ABNORMALITIES OF CML PATIENTS (P>0.05). THE FREQUENCY OF DDX43 HYPOMETHYLATION IN PATIENTS IN THE CHRONIC PHASE, IN THE ACCELERATED PHASE, AND IN BLAST CRISIS WAS 23.4% (15/64), 25.0% (2/8), AND 33.3% (5/15), RESPECTIVELY (P>0.05). THERE WAS A SIGNIFICANT CORRELATION BETWEEN DDX43 HYPOMETHYLATION AND DDX43 TRANSCRIPT (R=0.469, P=0.004). OUR DATA SUGGEST THAT HYPOMETHYLATION OF THE DDX43 PROMOTER MAY BE AN EARLY AND FREQUENT MOLECULAR EVENT IN THE DEVELOPMENT OF CML IN CHINESE PATIENTS. 2013 19 471 27 ARISTOLOCHIC ACID CONTAINING HERBS INDUCE GENDER-RELATED ONCOLOGICAL DIFFERENCES IN UPPER TRACT UROTHELIAL CARCINOMA PATIENTS. BACKGROUND: IN CHINA, UPPER TRACT UROTHELIAL CARCINOMA (UTUC) IS LESS PREVALENT BUT MORE MALIGNANT IN MALES. THIS STUDY INVESTIGATES THE PROGNOSTIC FACTORS AND CAUSES OF GENDER-BASED DIFFERENCES IN CHINESE POPULATIONS. METHODS: BETWEEN 1999 AND 2011, 687 UTUC PATIENTS WHO UNDERWENT SURGERY WERE UTILIZED FOR THIS STUDY. WE EVALUATED THE DIFFERENCES IN ONCOLOGICAL CHARACTERISTICS, EPIGENETIC BIOMARKERS, CANCER-SPECIFIC SURVIVAL (CSS), BLADDER RECURRENCE (BR) RATE, AND CONTRALATERAL UPPER TRACT RECURRENCE (CUTR) RATE. SMOKING HISTORY, BENZENE EXPOSURE HISTORY, AND THE HISTORY OF USING ARISTOLOCHIC ACID (AA) CONTAINING HERBS WERE ANALYZED IN DETAIL. RESULTS: COMPARED WITH MALE PATIENTS, FEMALE PATIENTS SHOWED POORER RENAL FUNCTION, LOWER PROPORTIONS OF TUMOR STAGE III/IV, AND SMALLER TUMOR DIAMETERS. THE CSS IN MALE PATIENTS WAS LOWER THAN THAT IN FEMALE PATIENTS. SIGNIFICANT GENDER-RELATED DIFFERENCES WERE OBSERVED CONCERNING VARIOUS PROGNOSTIC FACTORS. IN FEMALE PATIENTS, POORER SURVIVAL RATES WERE ATTRIBUTED TO THE PRIMARY TUMOR LOCATION IN THE URETER, LARGE DIAMETER PRIMARY TUMORS, SEVERE CHRONIC KIDNEY DISEASE, PAPILLARY TUMOR ARCHITECTURE, HIGH TUMOR STAGES, POSITIVE N STATUS, AND METHYLATED ABCC6 PROMOTERS. IN MALE PATIENTS, OLDER AGE, IPSILATERAL HYDRONEPHROSIS, LARGE TUMOR DIAMETERS, SESSILE TUMOR ARCHITECTURE, HIGH TUMOR STAGES, AND METHYLATED TMEFF2 PROMOTERS WERE ASSOCIATED WITH HIGHER CANCER-SPECIFIC MORTALITY. AA MIGHT BE THE MAIN CAUSE OF THESE GENDER-BASED DIFFERENCES. THE AA-INDUCED UTUC PATIENTS PRESENTED SMALLER TUMOR DIAMETERS, LOWER TUMOR STAGES, FEWER POSITIVE N STATUSES, MORE MULTIFOCAL TUMORS, LOWER METHYLATION INDICES, AND POORER RENAL FUNCTION. ALTHOUGH AA-INDUCED UTUC PATIENTS EXHIBITED BETTER SURVIVAL RATES, BR AND CUTR RATES WERE SIGNIFICANTLY WORSE. CONCLUSION: IN CHINA, THERE EXIST SIGNIFICANT AA-INDUCED DIFFERENCES BETWEEN MALE AND FEMALE UTUC PATIENTS. THE BLADDERS AND CONTRALATERAL UPPER URINARY TRACTS OF AA-INDUCED UTUC PATIENTS SHOULD BE CAREFULLY MONITORED AFTER SURGERY. 2018 20 2746 25 EXPRESSION ANALYSIS OF LONG NON-CODING RNAS AND THEIR TARGET GENES IN MULTIPLE SCLEROSIS PATIENTS. MULTIPLE SCLEROSIS (MS) IS A PROGRESSIVE CHRONIC AUTOIMMUNE-MEDIATED DISEASE. RECENTLY, LONG NON-CODING RNAS (LNCRNAS) ARE CHARACTERIZED TO PARTICIPATE IN THE ADJUSTMENT OF IMMUNE RESPONSES. HERE, WE EVALUATED THE EXPRESSION LEVELS OF GSTT1-AS1 AND IFNG-AS1 LNCRNAS AND THEIR TARGETS (TNF AND IFNG, RESPECTIVELY) IN IRANIAN MS PATIENTS.IN THIS CASE-CONTROL STUDY, 50 RELAPSING-REMITTING MS PATIENTS AND 50 HEALTHY SUBJECTS WERE RECRUITED. EXPRESSIONS OF GSTT1-AS1 AND IFNG-AS1 LNCRNAS, AS WELL AS TNF AND IFNG GENES, WERE ASSESSED IN THEIR PERIPHERAL BLOOD SAMPLES BY SYBR GREEN-BASED REAL-TIME QUANTITATIVE PCR.EXPRESSION LEVELS OF GSTT1-AS1 AND IFNG-AS1 LNCRNAS WERE BOTH SIGNIFICANTLY DOWNREGULATED (P VALUES 0.032 AND 0.013, RESPECTIVELY). ON THE OTHER HAND, THE EXPRESSION OF TNF AND IFNG SHOWED INCREASED LEVELS, HOWEVER, DID NOT REACH STATISTICAL SIGNIFICANCE AFTER OUR ANALYSIS (P > 0.05). SPEARMAN CORRELATION ANALYSIS SHOWED THAT GSTT1-AS1 HAD A SIGNIFICANT POSITIVE MODERATE CORRELATION WITH IFNG-AS1 (R = 0.541, P < 0.0001), IFNG (R = 0.329, P = 0.001), AND TNF (R = 0.204, P = 0.041). ALSO, IFNG-AS1 REVEALED THE SAME CORRELATION WITH IFNG (R = 0.475, P < 0.0001) AS WELL AS TNF (R = 0.399, P < 0.0001). FURTHERMORE, GSTT1-AS1 (R = 0.313, P = 0.027) AND (IFNG R = 0.478, P < 0.0001) DEMONSTRATED A SIGNIFICANT POSITIVE CORRELATION WITH AGE AT ONSET.BRIEFLY, THE CURRENT STUDY PROVIDED FOR THE FIRST TIME DYSREGULATION OF GSTT1-AS1 AND IFNG-AS LNCRNAS NETWORK IN MS, WHICH HIGHLIGHTS THE SIGNIFICANT ROLE OF EPIGENETIC PATHWAYS IN THIS AUTOIMMUNE DISORDER. LARGER SAMPLE SIZE AND FURTHER INVESTIGATION ASSAYS COULD SHED LIGHT ON THE UNDERLYING MECHANISMS IN THIS AREA OF SCIENCE. 2019