1  5304 124 PROTEOMIC ANALYSIS OF INFLAMMATORY BIOMARKERS ASSOCIATED WITH BREAST CANCER RECURRENCE. INTRODUCTION: BREAST CANCER IS THE MOST FREQUENT CANCER DETECTED FOR WOMEN, AND WHILE OUR ABILITY TO TREAT BREAST CANCER HAS IMPROVED SUBSTANTIALLY OVER THE YEARS, RECURRENCE REMAINS A MAJOR OBSTACLE. STANDARD SCREENING FOR NEW AND RECURRENT BREAST CANCER INVOLVES CLINICAL BREAST IMAGING. HOWEVER, THERE IS NO CLINICALLY APPROVED NONINVASIVE BODY FLUID TEST FOR THE EARLY DETECTION OF RECURRENT BREAST CANCER. MATERIALS AND METHOD: IN THIS STUDY, WE ANALYZED SERUM SAMPLES FROM BOTH RECURRENT AND NONRECURRENT BREAST CANCER PATIENTS BY DIFFERENT PROTEOMICS METHODS TO IDENTIFY BIOMARKERS IN PATIENTS WITH RECURRENCE OF DISEASE. RESULTS: COMPARATIVE DATA ANALYSIS IDENTIFIED SEVERAL HISTONE DEACETYLASE (HDAC) PROTEINS, WHICH WERE FOUND AT SIGNIFICANTLY HIGHER LEVELS IN THE SERUM OF RECURRENT BREAST CANCER PATIENTS: HDAC9 (C-TERM) (P = 0.0035), HDAC5 (C-TERM) (P = 0.013), SMALL UBIQUITIN-LIKE MODIFIER 1 (N-TERM) (P = 0.017), EMBRYONIC STEM CELL-EXPRESSED RAS (INTER) (P = 0.018), AND HDAC7 (C-TERM) (P = 0.020). CHRONIC INFLAMMATION PLAYS A CRITICAL ROLE IN THE DEVELOPMENT OF THE BREAST CANCER RECURRENCE, AND WE IDENTIFIED SEVERAL PROINFLAMMATORY CYTOKINES THAT WERE PRESENT AT ELEVATED LEVELS ONLY IN RECURRENT BREAST CANCER PATIENT SERUM. CONCLUSIONS: OUR DATA INDICATED THAT THE EPIGENETIC REGULATION OF INFLAMMATORY PROCESSES PLAYS A CRITICAL ROLE IN BREAST CANCER RECURRENCE. THE IDENTIFIED PROTEINS COULD LAY THE GROUNDWORK FOR THE DEVELOPMENT OF A SERUM-BASED BREAST CANCER RECURRENCE ASSAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2   497  28 ASSOCIATION BETWEEN BMI AND DNA METHYLATION IN BLOOD OR NORMAL ADULT BREAST TISSUE: A SYSTEMATIC REVIEW. BACKGROUND/AIM: SEVERAL STUDIES HAVE INVESTIGATED THE INFLUENCE OF OBESITY ON DNA METHYLATION (DNAM) TO FIND BIOMARKERS ASSOCIATED WITH THE DETECTION OF CHRONIC DISEASES, INCLUDING BREAST CANCER. THE AIM OF THE STUDY WAS TO SYSTEMATICALLY REVIEW STUDIES EXAMINING THE ASSOCIATION OF BODY MASS INDEX (BMI) AND DNAM IN BLOOD OR NORMAL BREAST TISSUE. MATERIALS AND METHODS: THREE SCIENTIFIC LITERATURE DATABASES (PUBMED, EMBASE AND WEB OF SCIENCE) WERE SCREENED UNTIL MAY 2018. RESULTS: TWENTY-FOUR STUDIES WERE INCLUDED ALONG WITH OURS IN WHICH WE INVESTIGATED THIS RELATION IN THE NORMAL BREAST TISSUE OF 40 BREAST CANCER PATIENTS. CONCLUSION: BMI-ASSOCIATED CPG SITES WERE HIGHLY VARIABLE WITH FEW IDENTIFIED IN LESS THAN HALF OF THE STUDIES. NEVERTHELESS, A FEW GENES POTENTIALLY ASSOCIATED WITH BMI WERE HIGHLIGHTED IN BLOOD (CPT1A, ABCG1, SREBF1 AND LGALS3BP) AND IN NORMAL BREAST TISSUE (PTPRN2 AND ABLIM2). THE VARIABILITY OF THE RESULTS COULD BE EXPLAINED BY THE TISSUE AND CELL-SPECIFICITY OF METHYLATION AND DIFFERENCES IN METHODOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3   935  34 CHRONIC LOW-DOSE EXPOSURE TO XENOESTROGEN AMBIENT AIR POLLUTANTS AND BREAST CANCER RISK: XENAIR PROTOCOL FOR A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH E3N COHORT. BACKGROUND: BREAST CANCER IS THE MOST FREQUENT CANCER IN WOMEN IN INDUSTRIALIZED COUNTRIES. LIFESTYLE AND ENVIRONMENTAL FACTORS, PARTICULARLY ENDOCRINE-DISRUPTING POLLUTANTS, HAVE BEEN SUGGESTED TO PLAY A ROLE IN BREAST CANCER RISK. CURRENT EPIDEMIOLOGICAL STUDIES, ALTHOUGH NOT FULLY CONSISTENT, SUGGEST A POSITIVE ASSOCIATION OF BREAST CANCER RISK WITH EXPOSURE TO SEVERAL INTERNATIONAL AGENCY FOR RESEARCH ON CANCER GROUP 1 AIR-POLLUTANT CARCINOGENS, SUCH AS PARTICULATE MATTER, POLYCHLORINATED BIPHENYLS (PCB), DIOXINS, BENZO[A]PYRENE (BAP), AND CADMIUM. HOWEVER, EPIDEMIOLOGICAL STUDIES REMAIN SCARCE AND INCONSISTENT. IT HAS BEEN PROPOSED THAT THE MENOPAUSAL STATUS COULD MODIFY THE RELATIONSHIP BETWEEN POLLUTANTS AND BREAST CANCER AND THAT THE ASSOCIATION VARIES WITH HORMONE RECEPTOR STATUS. OBJECTIVE: THE XENAIR PROJECT WILL INVESTIGATE THE ASSOCIATION OF BREAST CANCER RISK (OVERALL AND BY HORMONE RECEPTOR STATUS) WITH CHRONIC EXPOSURE TO SELECTED AIR POLLUTANTS, INCLUDING PARTICULATE MATTER, NITROGEN DIOXIDE (NO2), OZONE (O3), BAP, DIOXINS, PCB-153, AND CADMIUM. METHODS: OUR RESEARCH IS BASED ON A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH NATIONAL E3N COHORT OF 5222 INVASIVE BREAST CANCER CASES IDENTIFIED DURING FOLLOW-UP FROM 1990 TO 2011, AND 5222 MATCHED CONTROLS. A QUESTIONNAIRE WAS SENT TO ALL PARTICIPANTS TO COLLECT THEIR LIFETIME RESIDENTIAL ADDRESSES AND INFORMATION ON INDOOR POLLUTION. WE WILL ASSESS THESE EXPOSURES USING COMPLEMENTARY MODELS OF LAND-USE REGRESSION, ATMOSPHERIC DISPERSION, AND REGIONAL CHEMISTRY-TRANSPORT (CHIMERE) MODELS, VIA A GEOGRAPHIC INFORMATION SYSTEM. ASSOCIATIONS WITH BREAST CANCER RISK WILL BE MODELED USING CONDITIONAL LOGISTIC REGRESSION MODELS. WE WILL ALSO STUDY THE IMPACT OF EXPOSURE ON DNA METHYLATION AND INTERACTIONS WITH GENETIC POLYMORPHISMS. APPROPRIATE STATISTICAL METHODS, INCLUDING BAYESIAN MODELING, PRINCIPAL COMPONENT ANALYSIS, AND CLUSTER ANALYSIS, WILL BE USED TO ASSESS THE IMPACT OF MULTIPOLLUTANT EXPOSURE. THE FRACTION OF BREAST CANCER CASES ATTRIBUTABLE TO AIR POLLUTION WILL BE ESTIMATED. RESULTS: THE XENAIR PROJECT WILL CONTRIBUTE TO CURRENT KNOWLEDGE ON THE HEALTH EFFECTS OF AIR POLLUTION AND IDENTIFY AND UNDERSTAND ENVIRONMENTAL MODIFIABLE RISK FACTORS RELATED TO BREAST CANCER RISK. CONCLUSIONS: THE RESULTS WILL PROVIDE RELEVANT EVIDENCE TO GOVERNMENTS AND POLICY-MAKERS TO IMPROVE EFFECTIVE PUBLIC HEALTH PREVENTION STRATEGIES ON AIR POLLUTION. THE XENAIR DATASET CAN BE USED IN FUTURE EFFORTS TO STUDY THE EFFECTS OF EXPOSURE TO AIR POLLUTION ASSOCIATED WITH OTHER CHRONIC CONDITIONS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15167.	2020	
                                                                                                                                                                                                                                                                                                                                  
4  2019  34 EPIGENETIC CHANGE IN E-CADHERIN AND COX-2 TO PREDICT CHRONIC PERIODONTITIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES FREQUENTLY OCCURS IN NEOPLASTIC CELLS. ALTHOUGH THE CAUSE REMAINS UNKNOWN, MANY GENES HAVE BEEN IDENTIFIED WITH SUCH ATYPICAL METHYLATION IN NEOPLASTIC CELLS. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION SUCH AS CHRONIC PERIODONTITIS MAY DEMONSTRATE MILD LESION/MUTATION EPIGENETIC LEVEL. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES WHICH ARE OFTEN FOUND IN BREAST CANCER PATIENTS WITH THAT IN CHRONIC PERIODONTITIS. METHODS: TOTAL DNA WAS EXTRACTED FROM THE BLOOD SAMPLES OF 108 SYSTEMICALLY HEALTHY NON-PERIODONTITIS SUBJECTS, AND THE GINGIVAL TISSUES AND BLOOD SAMPLES OF 110 CHRONIC PERIODONTITIS PATIENT AS WELL AS NEOPLASTIC TISSUES OF 106 BREAST CANCER PATIENTS. METHYLATION-SPECIFIC PCR FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PCR PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 38% AND 35% OF THE BREAST CANCER SAMPLES, RESPECTIVELY. IN CHRONIC PERIODONTITIS PATIENTS THE DETECTION RATE WAS 25% AND 19% RESPECTIVELY, AND NONE WAS FOUND IN THE SYSTEMICALLY HEALTHY NON-PERIODONTITIS CONTROL SUBJECTS. THE HYPERMETHYLATION STATUS WAS SHOWN TO BE CORRELATED AMONG THE THREE GROUPS WITH STATISTICAL SIGNIFICANCE (P < 0.0001). THE METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 GENES IN PERIODONTITIS PATIENTS OCCURS MORE FREQUENTLY IN PERIODONTITIS PATIENTS THAN IN THE CONTROL SUBJECTS, BUT OCCURS LESS FREQUENTLY THAN IN THE BREAST CANCER PATIENTS. CONCLUSIONS: THIS SET OF DATA SHOWS THAT THE EPIGENETIC CHANGE IN E-CADHERIN AND CYCLOOXYGENASE-2 IS ASSOCIATED WITH CHRONIC PERIODONTITIS. THE EPIGENETIC CHANGES PRESENTED IN CHRONIC INFLAMMATION PATIENTS MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC PERIODONTITIS TO SOME EXTENT MIGHT BE ASSOCIATED WITH DNA HYPERMETHYLATION WHICH IS RELATED TO CANCER RISK FACTORS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  2749  34 EXPRESSION AND POLYMORPHISM OF MICRO-RNA ACCORDING TO BODY MASS INDEX AND BREAST CANCER PRESENTATION IN TUNISIAN PATIENTS. MICRO-RNAS (MIRS) CONSTITUTE A CLASS OF SMALL NONCODING RNAS IMPLICATED IN THE REGULATION OF GENE EXPRESSION BY BINDING TO TARGET MRNAS. A MIR CAN TARGET SEVERAL MRNAS, BEING INVOLVED IN DIFFERENT BIOLOGIC PROCESSES AND PATHOLOGIES. THIS PLEIOTROPIC FUNCTION MIGHT EXPLAIN THE LINK BETWEEN DISEASES CO-OCCURRENCE. EPIGENETIC ORIGIN OF THE LINK BETWEEN OBESITY AND BREAST CANCER (BC) IS INVESTIGATED IN A COHORT OF TUNISIAN PATIENTS, FOCUSING ON POLYMORPHISM AT GERMLINE LEVEL (MIR-146A) AND ON EXPRESSION IN MAMMARY TUMORS (MIR-21, MIR-146A, AND MIR-34A), ACCORDING TO BODY MASS INDEX (BMI) AND CLINICO-PATHOLOGIC FEATURES. THE MEASURE OF MIR EXPRESSION IN 60 MAMMARY TUMORS WAS REALIZED USING QUANTITATIVE RT-PCR. STUDY OF RS 2910164 IN MIR-146A WAS PERFORMED BY PCR AND DIRECT SEQUENCING USING BLOOD DNA OF 83 AFFECTED WOMEN AND 50 UNRELATED SUBJECTS FROM GREAT TUNIS. MIR-21, MIR-146A, AND MIR-34A HAVE BEEN QUANTIFIED IN BREAST TUMOR ACCORDING TO BMI. MIR-21 IS SIGNIFICANTLY MORE EXPRESSED IN TUMORS OF OBESE WOMEN COMPARATIVELY TO NONOBESE PATIENTS. ON THE CONTRARY, MIR-34A IS DECREASED IN TUMORS OF OBESE WOMEN. MOREOVER, IN OBESE BC PATIENTS, A SIGNIFICANT INCREASE IN BOTH MIR-21 AND MIR-146A EXPRESSION IS REVEALED IN CASES WITH LYMPH NODE METASTASIS. THE POLYMORPHISM AT RS 2910164 (MIR-146A) LOCUS WAS NOT SHOWN AS A RISK FACTOR FOR BC. HOWEVER THE MUTANT CC GENOTYPE WAS REVEALED TO BE ASSOCIATED WITH A RISK FOR BAD OUTCOME OF THE DISEASE. CHRONIC INFLAMMATION IN OBESE WOMEN WOULD BE LINKED TO AGGRESSIVE BREAST TUMORS VIA INDUCTION OF ONCOMIRS OVEREXPRESSION AND DECREASE OF TUMOR SUPPRESSOR MIRS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6   654  31 BISPHENOL S INDUCED EPIGENETIC AND TRANSCRIPTIONAL CHANGES IN HUMAN BREAST CANCER CELL LINE MCF-7. IN RECENT YEARS, CONCERNS ABOUT USING BISPHENOL A (BPA) IN DAILY CONSUME PRODUCTS AND ITS EFFECTS IN MANY CHRONIC HUMAN DISEASES HAVE PROMPTED THE REMOVAL OF BPA. HOWEVER, THE WIDELY USED BPA ALTERNATIVES, INCLUDING BISPHENOL S (BPS), HAVE A HIGH STRUCTURAL SIMILARITY WITH BPA, SUGGESTING THAT THEY MAY HAVE SIMILAR BIOLOGICAL EFFECTS TOWARDS HUMAN BEINGS. INDEED, BPS WAS ALSO FOUND TO HAVE ENDOCRINE-DISRUPTING EFFECTS. EPIGENETIC MECHANISM WAS REPORTED TO BE INVOLVED IN BPA-INDUCED BIOLOGICAL EFFECTS IN BOTH IN VITRO AND IN VIVO MODELS. HOWEVER, THERE IS NO ASSESSMENT ON WHETHER BPS COULD CAUSE EPIGENETIC CHANGES. IN THIS WORK, WE INVESTIGATED THE POSSIBLE EPIGENETIC EFFECTS OF BPS THAT MIGHT INDUCE IN HUMAN BREAST CANCER CELL LINE MCF-7. WE FOUND THAT BPS COULD CHANGE DNA METHYLATION LEVEL OF TRANSPOSONS. BESIDES, METHYLATION STATUS IN PROMOTER OF BREAST CANCER RELATED GENES CDH1, SFN, TNFRSF10C WERE ALSO CHANGED, WHICH IMPLIED THAT BPS MIGHT PLAY A ROLE IN THE DEVELOPMENT OF BREAST CANCER. GENE EXPRESSION PROFILING SHOWED THAT SOME GENES RELATED TO BREAST CANCER PROGRESSION WERE UPREGULATED, INCLUDING THBS4, PPARGC1A, CREB5, COL5A3. GENE ONTOLOGY (GO) ANALYSIS OF THE DIFFERENTIALLY EXPRESSED GENES REVEALED THE SIGNIFICANTLY CHANGES IN PI3K-AKT SIGNALING PATHWAY AND EXTRACELLULAR MATRIX, WHICH WERE RELATED TO THE PROLIFERATION, MIGRATION AND INVASION OF BREAST CANCER CELLS. THESE RESULTS ILLUSTRATED THAT BPS EXPOSURE MIGHT PLAY ROLES IN THE PROGRESSION OF BREAST CANCER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7   266  32 ADVERSE OUTCOME PATHWAYS FOR IONIZING RADIATION AND BREAST CANCER INVOLVE DIRECT AND INDIRECT DNA DAMAGE, OXIDATIVE STRESS, INFLAMMATION, GENOMIC INSTABILITY, AND INTERACTION WITH HORMONAL REGULATION OF THE BREAST. KNOWLEDGE ABOUT ESTABLISHED BREAST CARCINOGENS CAN SUPPORT IMPROVED AND MODERNIZED TOXICOLOGICAL TESTING METHODS BY IDENTIFYING KEY MECHANISTIC EVENTS. IONIZING RADIATION (IR) INCREASES THE RISK OF BREAST CANCER, ESPECIALLY FOR WOMEN AND FOR EXPOSURE AT YOUNGER AGES, AND EVIDENCE OVERALL SUPPORTS A LINEAR DOSE-RESPONSE RELATIONSHIP. WE USED THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK TO OUTLINE AND EVALUATE THE EVIDENCE LINKING IONIZING RADIATION WITH BREAST CANCER FROM MOLECULAR INITIATING EVENTS TO THE ADVERSE OUTCOME THROUGH INTERMEDIATE KEY EVENTS, CREATING A QUALITATIVE AOP. WE IDENTIFIED KEY EVENTS BASED ON REVIEW ARTICLES, SEARCHED PUBMED FOR RECENT LITERATURE ON KEY EVENTS AND IR, AND IDENTIFIED ADDITIONAL PAPERS USING REFERENCES. WE MANUALLY CURATED PUBLICATIONS AND EVALUATED DATA QUALITY. IONIZING RADIATION DIRECTLY AND INDIRECTLY CAUSES DNA DAMAGE AND INCREASES PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES (RONS). RONS LEAD TO DNA DAMAGE AND EPIGENETIC CHANGES LEADING TO MUTATIONS AND GENOMIC INSTABILITY (GI). PROLIFERATION AMPLIFIES THE EFFECTS OF DNA DAMAGE AND MUTATIONS LEADING TO THE AO OF BREAST CANCER. SEPARATELY, RONS AND DNA DAMAGE ALSO INCREASE INFLAMMATION. INFLAMMATION CONTRIBUTES TO DIRECT AND INDIRECT EFFECTS (EFFECTS IN CELLS NOT DIRECTLY REACHED BY IR) VIA POSITIVE FEEDBACK TO RONS AND DNA DAMAGE, AND SEPARATELY INCREASES PROLIFERATION AND BREAST CANCER THROUGH PRO-CARCINOGENIC EFFECTS ON CELLS AND TISSUE. FOR EXAMPLE, GENE EXPRESSION CHANGES ALTER INFLAMMATORY MEDIATORS, RESULTING IN IMPROVED SURVIVAL AND GROWTH OF CANCER CELLS AND A MORE HOSPITABLE TISSUE ENVIRONMENT. ALL OF THESE EVENTS OVERLAP AT MULTIPLE POINTS WITH EVENTS CHARACTERISTIC OF "BACKGROUND" INDUCTION OF BREAST CARCINOGENESIS, INCLUDING HORMONE-RESPONSIVE PROLIFERATION, OXIDATIVE ACTIVITY, AND DNA DAMAGE. THESE OVERLAPS MAKE THE BREAST PARTICULARLY SUSCEPTIBLE TO IONIZING RADIATION AND REINFORCE THAT THESE BIOLOGICAL ACTIVITIES ARE IMPORTANT CHARACTERISTICS OF CARCINOGENS. AGENTS THAT INCREASE THESE BIOLOGICAL PROCESSES SHOULD BE CONSIDERED POTENTIAL BREAST CARCINOGENS, AND PREDICTIVE METHODS ARE NEEDED TO IDENTIFY CHEMICALS THAT INCREASE THESE PROCESSES. TECHNIQUES ARE AVAILABLE TO MEASURE RONS, DNA DAMAGE AND MUTATION, CELL PROLIFERATION, AND SOME INFLAMMATORY PROTEINS OR PROCESSES. IMPROVED ASSAYS ARE NEEDED TO MEASURE GI AND CHRONIC INFLAMMATION, AS WELL AS THE INTERACTION WITH HORMONALLY DRIVEN DEVELOPMENT AND PROLIFERATION. SEVERAL METHODS MEASURE DIVERSE EPIGENETIC CHANGES, BUT IT IS NOT CLEAR WHICH CHANGES ARE RELEVANT TO BREAST CANCER. IN ADDITION, MOST TOXICOLOGICAL ASSAYS ARE NOT CONDUCTED IN MAMMARY TISSUE, AND SO IT IS A PRIORITY TO EVALUATE IF RESULTS FROM OTHER TISSUES ARE GENERALIZABLE TO BREAST, OR TO CONDUCT ASSAYS IN BREAST TISSUE. DEVELOPING AND APPLYING THESE ASSAYS TO IDENTIFY EXPOSURES OF CONCERN WILL FACILITATE EFFORTS TO REDUCE SUBSEQUENT BREAST CANCER RISK.	2020	

8  2656  22 EPIMUTATION AND CANCER: A NEW CARCINOGENIC MECHANISM OF LYNCH SYNDROME (REVIEW). EPIMUTATION IS DEFINED AS ABNORMAL TRANSCRIPTIONAL REPRESSION OF ACTIVE GENES AND/OR ABNORMAL ACTIVATION OF USUALLY REPRESSED GENES CAUSED BY ERRORS IN EPIGENETIC GENE REPRESSION. EPIMUTATION ARISES IN SOMATIC CELLS AND THE GERMLINE, AND CONSTITUTIONAL EPIMUTATION MAY ALSO OCCUR. EPIMUTATION IS THE FIRST STEP OF TUMORIGENESIS AND CAN BE A DIRECT CAUSE OF CARCINOGENESIS. CANCERS ASSOCIATED WITH EPIMUTATION INCLUDE LYNCH SYNDROME (HEREDITARY NON-POLYPOSIS COLORECTAL CANCER, HNPCC), CHRONIC LYMPHOCYTIC LEUKEMIA, BREAST CANCER AND OVARIAN CANCER. EPIMUTATION HAS BEEN SHOWN FOR MANY TUMOR SUPPRESSOR GENES, INCLUDING RB, VHL, HMLH1, APC AND BRCA1, IN SPORADIC CANCERS. METHYLATION HAS RECENTLY BEEN SHOWN IN DNA FROM NORMAL TISSUES AND PERIPHERAL BLOOD IN CASES OF SPORADIC COLORECTAL CANCER AND MANY STUDIES SHOW CONSTITUTIVE EPIMUTATION IN CANCERS. EPIMUTATION OF DNA MISMATCH REPAIR (MMR) GENES (BRCA1, HMLH1 AND HMSH2) INVOLVED IN DEVELOPMENT FAMILIAL CANCERS HAS ALSO BEEN FOUND. THESE RESULTS HAVE LED TO A FOCUS ON EPIMUTATION AS A NOVEL ONCOGENIC MECHANISM.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9   519  30 ASSOCIATIONS BETWEEN GENETIC AND EPIGENETIC VARIATIONS IN CYTOKINE GENES AND MILD PERSISTENT BREAST PAIN IN WOMEN FOLLOWING BREAST CANCER SURGERY. PERSISTENT PAIN FOLLOWING BREAST CANCER SURGERY IS A SIGNIFICANT PROBLEM. BOTH INHERITED AND ACQUIRED MECHANISMS OF INFLAMMATION APPEAR TO PLAY A ROLE IN THE DEVELOPMENT AND MAINTENANCE OF PERSISTENT PAIN. IN THIS LONGITUDINAL STUDY, GROWTH MIXTURE MODELING WAS USED TO IDENTIFY PERSISTENT BREAST PAIN PHENOTYPES BASED ON PAIN ASSESSMENTS OBTAINED PRIOR TO AND MONTHLY FOR 6MONTHS FOLLOWING BREAST CANCER SURGERY. ASSOCIATIONS BETWEEN THE "NO PAIN" AND "MILD PAIN" PHENOTYPES AND SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) SPANNING 15 CYTOKINE GENES WERE EVALUATED. THE METHYLATION STATUS OF THE CPG SITES FOUND IN THE PROMOTERS OF GENES ASSOCIATED WITH PAIN GROUP MEMBERSHIP WAS DETERMINED USING BISULFITE SEQUENCING. IN THE MULTIVARIATE ANALYSIS, THREE SNPS (I.E., INTERLEUKIN 6 (IL6) RS2069840, C-X-C MOTIF CHEMOKINE LIGAND 8 (CXCL8) RS4073, TUMOR NECROSIS FACTOR (TNF) RS1800610) AND TWO TNF CPG SITES (I.E., C.-350C, C.-344C) WERE ASSOCIATED WITH PAIN GROUP MEMBERSHIP. THESE FINDINGS SUGGEST THAT VARIATIONS IN IL6, CXCL8, AND TNF ARE ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF MILD PERSISTENT BREAST PAIN. CPG METHYLATION WITHIN THE TNF PROMOTER MAY PROVIDE AN ADDITIONAL MECHANISM THROUGH WHICH TNF ALTERS THE RISK FOR MILD PERSISTENT BREAST PAIN AFTER BREAST CANCER SURGERY. THESE GENETIC AND EPIGENETIC VARIATIONS MAY HELP TO IDENTIFY INDIVIDUALS WHO ARE PREDISPOSED TO THE DEVELOPMENT OF MILD LEVELS OF PERSISTENT BREAST PAIN FOLLOWING BREAST CANCER SURGERY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  4811  28 OBESITY-ASSOCIATED ALTERATIONS IN INFLAMMATION, EPIGENETICS, AND MAMMARY TUMOR GROWTH PERSIST IN FORMERLY OBESE MICE. USING A MURINE MODEL OF BASAL-LIKE BREAST CANCER, WE TESTED THE HYPOTHESIS THAT CHRONIC OBESITY, AN ESTABLISHED BREAST CANCER RISK AND PROGRESSION FACTOR IN WOMEN, INDUCES MAMMARY GLAND EPIGENETIC REPROGRAMMING AND INCREASES MAMMARY TUMOR GROWTH. MOREOVER, WE ASSESSED WHETHER THE OBESITY-INDUCED EPIGENETIC AND PROTUMOR EFFECTS ARE REVERSED BY WEIGHT NORMALIZATION. OVARIECTOMIZED FEMALE C57BL/6 MICE WERE FED A CONTROL DIET OR DIET-INDUCED OBESITY (DIO) REGIMEN FOR 17 WEEKS, RESULTING IN A NORMAL WEIGHT OR OBESE PHENOTYPE, RESPECTIVELY. MICE ON THE DIO REGIMEN WERE THEN RANDOMIZED TO CONTINUE THE DIO DIET OR WERE SWITCHED TO THE CONTROL DIET, RESULTING IN FORMERLY OBESE (FOB) MICE WITH WEIGHTS COMPARABLE WITH CONTROL MICE. AT WEEK 24, ALL MICE WERE ORTHOTOPICALLY INJECTED WITH MMTV-WNT-1 MOUSE MAMMARY TUMOR CELLS. MEAN TUMOR VOLUME, SERUM IL6 LEVELS, EXPRESSION OF PROINFLAMMATORY GENES IN THE MAMMARY FAT PAD, AND MAMMARY DNA METHYLATION PROFILES WERE SIMILAR IN DIO AND FOB MICE AND HIGHER THAN IN CONTROLS. MANY OF THE GENES FOUND TO HAVE OBESITY-ASSOCIATED HYPERMETHYLATION IN MICE WERE ALSO FOUND TO BE HYPERMETHYLATED IN THE NORMAL BREAST TISSUE OF OBESE VERSUS NONOBESE HUMAN SUBJECTS, AND NEARLY ALL OF THESE CONCORDANT GENES REMAINED HYPERMETHYLATED AFTER SIGNIFICANT WEIGHT LOSS IN THE FOB MICE. OUR FINDINGS SUGGEST THAT WEIGHT NORMALIZATION MAY NOT BE SUFFICIENT TO REVERSE THE EFFECTS OF CHRONIC OBESITY ON EPIGENETIC REPROGRAMMING AND INFLAMMATORY SIGNALS IN THE MICROENVIRONMENT THAT ARE ASSOCIATED WITH BREAST CANCER PROGRESSION. CANCER PREV RES; 9(5); 339-48. (C)2016 AACR.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  5858  26 SULFORAPHANE AND EPIGALLOCATECHIN GALLATE RESTORE ESTROGEN RECEPTOR EXPRESSION BY MODULATING EPIGENETIC EVENTS IN THE BREAST CANCER CELL LINE MDA-MB-231: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND/AIMS: EPIGENETICS REFERS TO MODIFICATIONS IN GENE ACTIVITY AND EXPRESSION WITHOUT ALTERATION AT THE DNA SEQUENCE. ENVIRONMENT AND DIET COULD INFLUENCE GENE EXPRESSION. DIET MODIFICATIONS MAY BE MEANINGFUL IN PREVENTING AND TREATING CHRONIC DISEASES, CANCER INCLUDED. DIETARY BIOACTIVE COMPOUNDS, SUCH AS POLYPHENOLS (E.G., CURCUMIN, RESVERATROL, OR EPIGALLOCATECHIN GALLATE [EGCG]) OR ISOTHIOCYANATE (E.G., SULFORAPHANE [SFN]), CAN REGULATE HISTONE ACETYLATION. THE AIM OF THIS SYSTEMATIC REVIEW AND META-ANALYSIS WAS TO EVALUATE THE EFFECT OF SFN AND EGCG ON BREAST CANCER (BC) CELLS CULTURED IN VITRO. METHODS: DUE TO THE ENORMOUS VARIABILITY OBSERVED IN STUDY PROTOCOLS AND THE INNUMERABLE GENES INVOLVED, ONLY STUDIES ANALYZING THE NUMBER OF APOPTOTIC CELLS IN THE MDA-MB-231 CELL LINE WERE EVALUATED. THE EFFECT SIZE (ES) WAS COMPUTED AS THE RATIO OF MEANS. RESULTS: WE IDENTIFIED 7 STUDIES, 4 REGARDING THE EFFECT OF 10 MICROM SFN ON MDA-MB-231 CELLS (ES = 4.59, 95% CONFIDENCE INTERVAL 4.05-5.20) AND 3 FOCUSING ON THE IMPACT OF 20 MICROM EGCG (ES = 2.84, 95% CONFIDENCE INTERVAL 2.60-3.10). CONCLUSION: THE FINDINGS SUGGEST BENEFICIAL EFFECTS OF DIETARY BIOACTIVE COMPOUNDS SUCH AS SFN AND EGCG AND THEIR EFFECT ON BC CELLS BY RESTORING ESTROGEN RECEPTOR GENE EXPRESSION, MODULATING EPIGENETIC CHANGES AND EVENTS, AND INTERFERING WITH TUMOR GROWTH RATE. PUBLICATION BIAS LIMITS THE GENERALIZABILITY OF THE CONCLUSIONS. HIGH-QUALITY STUDIES ARE NEEDED.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  1484  24 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13   507  35 ASSOCIATION OF INCREASED DNA METHYLTRANSFERASE EXPRESSION WITH CARCINOGENESIS AND POOR PROGNOSIS IN PANCREATIC DUCTAL ADENOCARCINOMA. INTRODUCTION: EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN MULTISTAGE CARCINOGENESIS. THE ROLE OF THE THREE FUNCTIONAL DNA METHYLTRANSFERASES (DNMTS) IN PANCREATIC CARCINOGENESIS HAS NOT BEEN FULLY UNDERSTOOD. THE MAIN GOAL OF THIS STUDY WAS TO EXAMINE DNMT EXPRESSION IN DIFFERENT STAGES OF PANCREATIC DUCTAL ADENOCARCINOMA (PDAC), AND EVALUATE THEIR PROGNOSTIC SIGNIFICANCE IN PDAC. MATERIALS AND METHODS: A LARGE NUMBER OF PREMALIGNANT AND MALIGNANT PANCREATIC LESIONS WERE OBTAINED BY MANUAL MICRODISSECTION. QUANTITATIVE REAL-TIME RT-PCR WAS USED TO DETECT DNMTS MRNA EXPRESSION. NONPARAMETRIC TEST, LOGRANK TEST AND COX REGRESSION ANALYSIS WERE USED TO EVALUATE THE CLINICAL SIGNIFICANCE OF DNMT EXPRESSION. RESULTS: THE MRNA EXPRESSION OF THE THREE DNMTS INCREASED WITH THE DEVELOPMENT OF PANCREATIC CANCER FROM NORMAL DUCT TO PANCREATIC INTRADUCTAL NEOPLASIA AND FURTHER TO PDAC, AND WERE STATISTICALLY CORRELATED WITH EACH OTHER. EXPRESSION OF THE THREE DNMTS WAS STATISTICALLY CORRELATED WITH TNM STAGING AND HISTORY OF CHRONIC PANCREATITIS. DNMT3A AND DNMT3B, BUT NOT DNMT1 EXPRESSION, WAS STATISTICALLY CORRELATED WITH TUMOUR SIZE. PATIENTS WITH HIGHER LEVELS OF DNMT1, DNMT3A AND/OR DNMT3B EXPRESSION HAD AN OVERALL LOWER SURVIVAL THAN THOSE WITH LOWER LEVELS OF EXPRESSION. UNIVARIATE ANALYSIS SHOWED THAT HIGH EXPRESSION LEVELS OF DNMTS, ALCOHOL CONSUMPTION, TUMOUR DIFFERENTIATION AND TNM STAGING WERE STATISTICALLY SIGNIFICANT RISK FACTORS. MULTIVARIATE ANALYSIS SHOWED THAT HIGH LEVEL OF DNMT3B EXPRESSION AND TUMOUR DIFFERENTIATION WERE STATISTICALLY SIGNIFICANT INDEPENDENT POOR PROGNOSTIC FACTORS. CONCLUSIONS: THESE RESULTS SUGGESTED THAT PANCREATIC CARCINOGENESIS INVOLVES AN INCREASED MRNA EXPRESSION OF THREE DNMTS, AND THEY MAY BECOME VALUABLE DIAGNOSTIC AND PROGNOSTIC MARKERS AS WELL AS POTENTIAL THERAPEUTIC TARGETS FOR PANCREATIC CANCER.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  5435  31 RELATIVE ROLE OF METHYLATOR AND TUMOR SUPPRESSOR PATHWAYS IN ULCERATIVE COLITIS-ASSOCIATED COLON CANCER. BACKGROUND: CHRONIC ULCERATIVE COLITIS (UC) IS ASSOCIATED WITH AN INCREASED COLORECTAL CANCER RISK WHICH MAY BE SECONDARY TO REPETITIVE MUCOSAL INJURY. BOTH EPIGENETIC METHYLATION AND THE CLASSIC ADENOMA-TO-CARCINOMA SEQUENCE HAVE BEEN IMPLICATED IN THIS MALIGNANT TRANSFORMATION, BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN POORLY DEFINED. THIS STUDY COMPARES THE MOLECULAR CHARACTERISTICS OF COLITIS-ASSOCIATED AND COMMON COLORECTAL CANCERS. METHODS: NINETEEN PATIENTS WITH COLORECTAL ADENOCARCINOMAS ARISING WITHIN UC WERE MATCHED FOR AGE AND CANCER SITE WITH 54 PATIENTS WITH SPORADIC ADENOCARCINOMAS. TUMOR TISSUE WAS EXAMINED FOR BRAF MUTATIONS, CPG ISLAND METHYLATOR PHENOTYPE (CIMP), AND MLH1 PROMOTER METHYLATION. MUTATIONS OF KRAS AND P53 WERE ASSESSED BY SEQUENCING. RESULTS: PATIENT DEMOGRAPHICS WERE SIMILAR FOR THE TWO GROUPS. CIMP WAS OBSERVED IN 22% OF SPORADIC COLORECTAL CANCERS AND IN 5% OF UC CANCERS (P = 0.162). RATES OF BRAF MUTATION (4% VS 5%, P = 1.0), MLH1 METHYLATION (9% VERSUS 5%, P = 0.682), AND KRAS MUTATIONS (24% VERSUS 32%, P = 0.552) WERE SIMILAR BETWEEN THE GROUPS. HOWEVER, COLITIS-ASSOCIATED COLORECTAL CANCERS WERE MORE LIKELY TO HAVE A P53 MUTATION COMPARED TO SPORADIC ADENOCARCINOMAS (95% VERSUS 53%, P = 0.001). THE DOMINANT MUTATION FOR COLITIS-ASSOCIATED CANCERS WAS A MUTATION IN CODON 4, REPRESENTING HALF OF THE MUTATIONS. FURTHERMORE, COLITIS-ASSOCIATED CANCERS HAD A HIGHER RATE OF MUTATION IN CODON 8 (48% VERSUS 6%, P < 0.001) THAN SPORADIC COUNTERPARTS. CONCLUSIONS: UNLIKE OTHER INFLAMMATORY GASTROINTESTINAL CANCERS, COLITIS-ASSOCIATED COLORECTAL CANCERS DO NOT PREFERENTIALLY ARISE VIA A METHYLATOR PATHWAY WHEN COMPARED TO SPORADIC COLORECTAL CANCERS. CHROMOSOMAL INSTABILITY REMAINS AN IMPORTANT ETIOLOGY, BUT WITH A UNIQUE P53 FREQUENCY AND MUTATION PATTERN.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  3148  28 GLUCOCORTICOID INDUCED LOSS OF OESTROGEN RECEPTOR ALPHA GENE METHYLATION AND RESTORATION OF SENSITIVITY TO FULVESTRANT IN TRIPLE NEGATIVE BREAST CANCER. THE RESPONSE TO PSYCHOLOGICAL STRESS CAN DIFFER DEPENDING ON THE TYPE AND DURATION OF THE STRESSOR. ACUTE STRESS CAN FACILITATE A "FIGHT OR FLIGHT RESPONSE" AND AID SURVIVAL, WHEREAS CHRONIC LONG-TERM STRESS WITH THE PERSISTENT RELEASE OF STRESS HORMONES SUCH AS CORTISOL HAS BEEN SHOWN TO BE DETRIMENTAL TO HEALTH. WE ARE NOW BEGINNING TO UNDERSTAND HOW THIS STRESS HORMONE RESPONSE IMPACTS IMPORTANT PROCESSES SUCH AS DNA REPAIR AND CELL PROLIFERATION PROCESSES IN BREAST CANCER. HOWEVER, IT IS NOT KNOWN WHAT EPIGENETIC CHANGES STRESS HORMONES INDUCE IN BREAST CANCER. EPIGENETIC MECHANISMS INCLUDE MODIFICATION OF DNA AND HISTONES WITHIN CHROMATIN THAT MAY BE INVOLVED IN GOVERNING THE TRANSCRIPTIONAL PROCESSES IN CANCER CELLS IN RESPONSE TO CHANGES BY ENDOGENOUS STRESS HORMONES. THE CONTRIBUTION OF ENDOGENOUS ACUTE OR LONG-TERM EXPOSURE OF GLUCOCORTICOID STRESS HORMONES, AND EXOGENOUS GLUCOCORTICOIDS TO METHYLATION PATTERNS IN BREAST CANCER TISSUES WITH DIFFERENT AETIOLOGIES REMAINS TO BE EVALUATED. IN VITRO AND IN VIVO MODELS WERE DEVELOPED TO INVESTIGATE THE EPIGENETIC MODIFICATIONS AND THEIR CONTRIBUTION TO BREAST CANCER PROGRESSION AND AETIOLOGY. A PANEL OF TRIPLE NEGATIVE BREAST CANCER CELL LINES WERE TREATED WITH THE GLUCOCORTICOID, CORTISOL WHICH RESULTED IN EPIGENETIC ALTERATION CHARACTERISED BY LOSS OF METHYLATION ON PROMOTER REGIONS OF TUMOUR SUPPRESSOR GENES INCLUDING ESR1, AND LOSS OF METHYLATION ON LINE-1 REPETITIVE ELEMENT USED AS A SURROGATE MARKER FOR GLOBAL METHYLATION. THIS WAS VERIFIED IN VIVO IN MDA-MB-231 XENOGRAFTS; THE MODEL VERIFIED THE LOSS OF METHYLATION ON ESR1 PROMOTER, AND SUBSEQUENT INCREASE IN ESR1 EXPRESSION IN PRIMARY TUMOURS IN MICE SUBJECTED TO RESTRAINT STRESS. OUR STUDY HIGHLIGHTS THAT DNA METHYLATION LANDSCAPE IN BREAST CANCER CAN BE ALTERED IN RESPONSE TO STRESS AND GLUCOCORTICOID TREATMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  1844  35 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  1431  32 DIFFERENTIAL FREQUENCIES OF P16(INK4A) PROMOTER HYPERMETHYLATION, P53 MUTATION, AND K-RAS MUTATION IN EXFOLIATIVE MATERIAL MARK THE DEVELOPMENT OF LUNG CANCER IN SYMPTOMATIC CHRONIC SMOKERS. PURPOSE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE FREQUENCY OF THREE (EPI)GENETIC ALTERATIONS (P53 AND K-RAS MUTATIONS AND P16(INK4A) PROMOTER HYPERMETHYLATION) IN SYMPTOMATIC CHRONIC SMOKERS COMPARED WITH PATIENTS WITH LUNG CANCER AND TO EVALUATE THE USE OF EXFOLIATIVE MATERIAL FOR SUCH ANALYSES. PATIENTS AND METHODS: FIFTY-ONE PATIENTS WITH HISTOLOGICALLY CONFIRMED LUNG CANCER AND 25 CHRONIC SMOKERS (> 20 PACK-YEARS) WERE INVESTIGATED FOR MUTATIONS IN THE K-RAS (CODON 12) AND P53 (CODONS 248, 249, AND 273) GENES AND FOR ALLELIC HYPERMETHYLATION OF THE P16(INK4A) GENE. DNA WAS ISOLATED FROM SPUTUM AND BILATERAL BRONCHIAL LAVAGE, AND BRUSHINGS WERE TAKEN AT BRONCHOSCOPY. RESULTS: FORTY-ONE GENETIC LESIONS WERE DETECTED WITHIN EXFOLIATIVE MATERIAL FROM THE GROUP OF 51 PATIENTS WITH LUNG CANCER AND 10 LESIONS IN THE CHRONIC SMOKER GROUP. K-RAS MUTATIONS OCCURRED EXCLUSIVELY IN THE LUNG CANCER GROUP, WHEREAS P53 MUTATIONS AND P16(INK4A) PROMOTER HYPERMETHYLATION WERE ALSO FOUND IN CHRONIC SMOKERS. THREE OF EIGHT CHRONIC SMOKERS WHO HARBORED AN (EPI)GENETIC ALTERATION WERE SUBSEQUENTLY DIAGNOSED WITH LUNG CANCER. ANALYSIS OF SPUTUM YIELDED INFORMATION EQUIVALENT TO THAT OF SAMPLES OBTAINED DURING BRONCHOSCOPY. CONCLUSION: P16(INK4A) PROMOTER HYPERMETHYLATION AND P53 MUTATIONS CAN OCCUR IN CHRONIC SMOKERS BEFORE ANY CLINICAL EVIDENCE OF NEOPLASIA AND MAY BE INDICATIVE OF AN INCREASED RISK OF DEVELOPING LUNG CANCER OR OF EARLY DISEASE. K-RAS MUTATIONS OCCUR EXCLUSIVELY IN THE PRESENCE OF CLINICALLY DETECTABLE NEOPLASTIC TRANSFORMATION. MOLECULAR ANALYSIS OF SPUTUM FOR SUCH MARKERS MAY PROVIDE AN EFFECTIVE MEANS OF SCREENING CHRONIC SMOKERS TO ENABLE EARLIER DETECTION AND THERAPEUTIC INTERVENTION OF LUNG CANCER.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  6539  28 TRANSCRIPTIONAL VARIATIONS IN THE WIDER PERITUMORAL TISSUE ENVIRONMENT OF PANCREATIC CANCER. TRANSCRIPTIONAL PROFILING WAS PERFORMED ON 452 RNA PREPARATIONS ISOLATED FROM VARIOUS TYPES OF PANCREATIC TISSUE FROM TUMOUR PATIENTS AND HEALTHY DONORS, WITH A PARTICULAR FOCUS ON PERITUMORAL SAMPLES. PANCREATIC DUCTAL ADENOCARCINOMAS (PDAC) AND CYSTIC TUMOURS WERE MOST DIFFERENT IN THESE NON-TUMOROUS TISSUES SURROUNDING THEM, WHEREAS THE ACTUAL TUMOURS EXHIBITED RATHER SIMILAR TRANSCRIPT PATTERNS. THE ENVIRONMENT OF CYSTIC TUMOURS WAS TRANSCRIPTIONALLY NEARLY IDENTICAL TO NORMAL PANCREAS TISSUE. IN CONTRAST, THE TISSUE AROUND PDAC BEHAVED A LOT LIKE THE TUMOUR, INDICATING SOME KIND OF FIELD DEFECT, WHILE SHOWING FAR LESS MOLECULAR RESEMBLANCE TO BOTH CHRONIC PANCREATITIS AND HEALTHY TISSUE. THIS SUGGESTS THAT THE MAJOR PATHOGENIC DIFFERENCE BETWEEN CYSTIC AND DUCTAL TUMOURS MAY BE DUE TO THEIR CELLULAR ENVIRONMENT RATHER THAN THE FEW VARIATIONS BETWEEN THE TUMOURS. LACK OF CORRELATION BETWEEN DNA METHYLATION AND TRANSCRIPT LEVELS MAKES IT UNLIKELY THAT THE OBSERVED FIELD DEFECT IN THE PERITUMORAL TISSUE OF PDAC IS CONTROLLED TO A LARGE EXTENT BY SUCH EPIGENETIC REGULATION. FUNCTIONALLY, A STRIKINGLY LARGE NUMBER OF AUTOPHAGY-RELATED TRANSCRIPTS WAS CHANGED IN BOTH PDAC AND ITS PERITUMORAL TISSUE, BUT NOT IN OTHER PANCREATIC TUMOURS. A TRANSCRIPTION SIGNATURE OF 15 AUTOPHAGY-RELATED GENES WAS ESTABLISHED THAT PERMITS A PROGNOSIS OF SURVIVAL WITH HIGH ACCURACY AND INDICATES THE ROLE OF AUTOPHAGY IN TUMOUR BIOLOGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19   902  25 CHRONIC EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION CAUSES INCREASED GROWTH AND TRANSFORMATION IN HUMAN PROSTATE EPITHELIAL CELLS POTENTIALLY BY HYPERMETHYLATION-MEDIATED SILENCING OF MLH1. BACKGROUND: CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN IS ASSOCIATED WITH RISK OF PROSTATE CANCER, BUT THEIR MECHANISM IS NOT FULLY UNDERSTOOD. ADDITIONALLY, THE CARCINOGENIC EFFECTS OF THEIR CO-EXPOSURE ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION, ON CELL GROWTH AND TRANSFORMATION, AND IDENTIFY THE MECHANISM BEHIND THESE EFFECTS. METHODS: RWPE-1 HUMAN PROSTATE EPITHELIAL CELLS WERE CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION. CELL GROWTH WAS MEASURED BY CELL COUNT AND CELL CYCLE, WHEREAS CELL TRANSFORMATION WAS EVALUATED BY COLONY FORMATION ASSAY. GENE EXPRESSION WAS MEASURED BY QUANTITATIVE REAL-TIME PCR AND CONFIRMED AT PROTEIN LEVEL BY WESTERN BLOT ANALYSIS. MLH1 PROMOTER METHYLATION WAS DETERMINED BY PYROSEQUENCING METHOD. RESULTS: EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATIONS INCREASES CELL GROWTH AND TRANSFORMATION IN RWPE-1 CELLS. INCREASED EXPRESSION OF CYCLIN D1 AND BCL2, WHEREAS DECREASED EXPRESSION OF MISMATCH REPAIR GENES MSH4, MSH6, AND MLH1 WAS ALSO OBSERVED. HYPERMETHYLATION OF MLH1 PROMOTER FURTHER SUGGESTED THE EPIGENETIC INACTIVATION OF MLH1 EXPRESSION IN ARSENIC AND ESTROGEN TREATED CELLS. ARSENIC AND ESTROGEN COMBINATION CAUSED GREATER CHANGES THAN THEIR INDIVIDUAL TREATMENTS. CONCLUSIONS: FINDINGS OF THIS STUDY FOR THE FIRST TIME SUGGEST THAT ARSENIC AND ESTROGEN EXPOSURES CAUSE INCREASED CELL GROWTH AND SURVIVAL POTENTIALLY THROUGH EPIGENETIC INACTIVATION OF MLH1 RESULTING IN DECREASED MLH1-MEDIATED APOPTOTIC RESPONSE, AND CONSEQUENTLY INCREASED CELLULAR TRANSFORMATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  6386  38 THE ROLE OF QUANTITATIVE NPTX2 HYPERMETHYLATION AS A NOVEL SERUM DIAGNOSTIC MARKER IN PANCREATIC CANCER. OBJECTIVES: THE MAJORITY OF PANCREATIC CANCERS ARE FOUND TO BE UNRESECTABLE, AND THE ONLY CHANCE FOR CURE LIES ON EARLY DETECTION AND COMPLETE RESECTION. SEVERAL GENES HAVE BEEN DISCOVERED TO BE ABERRANTLY METHYLATED IN PRIMARY PANCREATIC CANCER TISSUE, AND THIS CANCER DNA CAN BE DETECTED IN THE PLASMA. THE AIMS OF THIS STUDY WERE TO DEVELOP A NOVEL DIAGNOSTIC MARKER BASED ON EPIGENETIC CHARACTERISTICS OF PANCREATIC CANCER. METHODS: WE ENROLLED 104 PATIENTS WITH PANCREATIC CANCER, 60 WITH CHRONIC PANCREATITIS, AND 5 WITH BENIGN BILIARY STONE DISEASES. THE BLOOD SAMPLES WERE COLLECTED BEFORE SURGERY OR ANY KINDS OF TREATMENT MODALITIES. DNA WAS EXTRACTED FROM THE PLASMA OF EACH PATIENT, AND NPTX2 (NEURONAL PENTRAXIN II) CPG ISLAND HYPERMETHYLATION WAS EXAMINED QUANTITATIVELY BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NPTX2 HYPERMETHYLATION LEVELS WERE SIGNIFICANTLY HIGHER COMPARED WITH CHRONIC PANCREATITIS (P = 0.016). THE SENSITIVITY AND SPECIFICITY WERE 80% AND 76%, RESPECTIVELY (CUTOFF = 0.015). NPTX2 GENE HYPERMETHYLATION LEVEL WAS SIGNIFICANTLY ELEVATED IN CORRELATION WITH HIGHER AMERICAN JOINT COMMITTEE ON CANCER STAGES. CONCLUSIONS: THE ABERRANTLY METHYLATED NPTX2 GENE MAY HELP TO DISTINGUISH BETWEEN CHRONIC PANCREATITIS AND PANCREATIC CANCER WITH CONVENTIONAL DIAGNOSTIC TOOLS AND COULD BECOME A VALUABLE DIAGNOSTIC MARKER.	2012