1  3294 141 HIGH INCIDENCE OF MGMT AND RARBETA PROMOTER METHYLATION IN PRIMARY GLIOBLASTOMAS: ASSOCIATION WITH HISTOPATHOLOGICAL CHARACTERISTICS, INFLAMMATORY MEDIATORS AND CLINICAL OUTCOME. GLIOBLASTOMAS, THE MOST FREQUENT PRIMARY BRAIN TUMORS IN ADULTS, ARE CHARACTERIZED BY A HIGHLY AGGRESSIVE, INFLAMMATORY AND ANGIOGENIC PHENOTYPE. METHYLATION OF CPG ISLANDS IN CANCER-RELATED GENES MAY SERVE AS AN EPIGENETIC BIOMARKER FOR GLIOBLASTOMA DIAGNOSIS AND PROGNOSIS. THE AIM OF THIS STUDY WAS TO ANALYZE THE METHYLATION STATUS OF FOUR CRITICAL TUMOR-ASSOCIATED GENES (MGMT, RARBETA, RASSF1A, CDH13), AND INVESTIGATE POSSIBLE LINKS WITH INFLAMMATORY (INTERLEUKIN [IL]-6, IL-8) AND ANGIOGENIC MEDIATORS (VASCULAR ENDOTHELIAL GROWTH FACTOR [VEGF], CYCLOOXYGENASE [COX]-2) AND CLINICAL OUTCOME IN 23 GLIOMA SAMPLES (6 GRADE II ASTROCYTOMAS, 17 GRADE IV GLIOBLASTOMAS). RARBETA AND MGMT GENES WERE MORE FREQUENTLY METHYLATED IN 70.58% AND 58.8% OF GLIOBLASTOMAS, RESPECTIVELY. RASSF1A AND CDH13 DISPLAYED A SIMILAR METHYLATION FREQUENCY (23.52%) IN GLIOBLASTOMAS. NO GENE METHYLATION WAS OBSERVED IN GRADE II ASTROCYTOMAS. TUMOR GRADE CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION (P = 0.005 AND P = 0.019, RESPECTIVELY) AND THE EXTENT OF NECROSIS (P = 0.001 AND P = 0.003). INTERESTINGLY, THE MARKER OF CHRONIC INFLAMMATION, IL-6, WAS POSITIVELY ASSOCIATED WITH METHYLATION OF MGMT (P = 0.004), RARBETA (P = 0.002), AND RASSF1A (P = 0.0081) AS WELL AS THE TOTAL NUMBER OF METHYLATED GENES (P < 0.0001), INDICATING THE IMPORTANT ROLE OF IL-6 IN MAINTAINING PROMOTER METHYLATION OF THESE GENES. VEGF EXPRESSION CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION ALTHOUGH THESE RELATIONSHIPS WERE OF MARGINAL SIGNIFICANCE (P = 0.0679 AND P = 0.0757). KAPLAN-MEIER UNIVARIATE SURVIVAL ANALYSIS INDICATED AN UNFAVORABLE SURVIVAL PERIOD IN PATIENTS WITH MGMT METHYLATION COMPARED WITH THOSE WITHOUT METHYLATION (P = 0.0474). OUR STUDY HIGHLIGHTS THE IMPLICATION OF MGMT AND RARBETA METHYLATION IN THE AGGRESSIVE PHENOTYPE OF PRIMARY GLIOBLASTOMAS. THE ASSOCIATION OF MGMT METHYLATION WITH CLINICAL OUTCOME INDICATES ITS POTENTIAL PROGNOSTIC VALUE.	2010	
                                                                                                                                                                                                                                
2  1056  30 CLINICAL MANIFESTATIONS AND EPIGENETIC MECHANISMS OF GASTRIC MUCOSA ASSOCIATED LYMPHOID TISSUE LYMPHOMA AND LONG-TERM FOLLOW-UP FOLLOWING HELICOBACTER PYLORI ERADICATION. THE CURRENT STUDY AIMED TO SUMMARIZE THE CLINICAL MANIFESTATIONS AND IDENTIFY THE EPIGENETIC MECHANISMS OF GASTRIC MUCOSA ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA, AS WELL AS EVALUATE THE LONG-TERM EFFECTS OF HELICOBACTER PYLORI (H. PYLORI) ERADICATION. A TOTAL OF 122 PATIENTS WITH MARGINAL ZONE B-CELL LYMPHOMA OF PRIMARY GASTRIC MALT LYMPHOMA WERE ENROLLED IN THE PRESENT STUDY. THE CLINICAL MANIFESTATIONS OF GASTRIC MALT LYMPHOMA, INCLUDING SYMPTOMS, H. PYLORI STATE AND ENDOSCOPIC TYPE, WERE SUMMARIZED. THE RESPONSE TO THERAPY WAS EVALUATED IN PATIENTS THAT UNDERWENT H. PYLORI ERADICATION. SURVIVAL ANALYSIS WAS ESTIMATED USING THE KAPLAN-MEIER METHOD. THE EXPRESSION OF MICRORNA-383 (MIR-383) IN TUMOR TISSUES AND CELL LINES WAS DETERMINED USING REVERSE TRANSCRIPTION QUANTITATIVE POLYMERASE CHAIN REACTION. FURTHERMORE, BIOINFORMATIC ANALYSES, LUCIFERASE REPORTER ASSAYS. AND WESTERN BLOT ANALYSIS IDENTIFIED ZINC FINGER E-BOX BINDING HOMEOBOX 2 (ZEB2) AS A DIRECT TARGET GENE OF MIR-383. AN MTT ASSAY WAS USED TO EXAMINE THE FUNCTION OF MIR-383 AND ZEB2 IN MALT LYMPHOMA. THE CLINICAL SYMPTOMS OF PATIENTS WITH GASTRIC MALT LYMPHOMA WERE NON-SPECIFIC AND INCLUDED EPIGASTRIC PAIN, ABDOMINAL DISCOMFORT AND BLEEDING. THE MAJORITY OF ENDOSCOPIC TYPES WERE CLASSIFIED AS ULCER, EROSION AND MUCOSA EDEMA. THE H. PYLORI INFECTION RATE WAS 79.5% (97/122) AND A TOTAL OF 47 PATIENTS UNDERWENT ERADICATION THERAPY. LYMPHOMA REMISSION WAS ACHIEVED IN 93.6% (44/47) OF PATIENTS AND COMPLETE REMISSION (CR) WAS ACHIEVED IN 74.4% (35/47). THE MEDIAN FOLLOW-UP TIME WAS 38 MONTHS (RANGE, 10-132 MONTHS) AND THE MEDIAN TIME TAKEN TO ACHIEVE CR WAS 4 MONTHS (RANGE, 3-7 MONTHS). THE ESTIMATED 3-YEAR SURVIVAL RATE WAS 90.3% AND THE 5-YEAR SURVIVAL RATE WAS 76.2%. THEREFORE, IT WAS DETERMINED THAT PATIENTS WITH STAGE I OR II GASTRIC MALT LYMPHOMA ARE ABLE TO UNDERGO H. PYLORI ERADICATION AS A FIRST-LINE TREATMENT AND THAT THE SURVIVAL RATE OF PATIENTS UNDERGOING THIS TREATMENT IS HIGH. FURTHERMORE, IT WAS DETERMINED THAT THE MECHANISM BY WHICH MIR-383 AND ZEB2 CONTRIBUTE TO MALT LYMPHOMA PROGRESSION IS BY THE TARGETING OF ZEB2 BY MIR-383, WHICH INHIBITS THE PROLIFERATION OF CANCER CELLS.	2018	

3  5245  35 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS.	2018	
                                                                                                                                                                                                                                                                                                                             
4  4922  28 PARENTAL AGE AND RISK OF LYMPHOID NEOPLASMS. HIGH PARENTAL AGE AT CHILDBIRTH HAS REPEATEDLY BEEN LINKED TO CHILDHOOD MALIGNANCIES, WHILE FEW STUDIES HAVE FOCUSED ON THE OFFSPRING'S RISK OF ADULT CANCER. IN THIS POPULATION-BASED CASE-CONTROL STUDY, WE IDENTIFIED 32,000 PATIENTS WITH LYMPHOID NEOPLASMS, DIAGNOSED AT AGES 0-79 YEARS DURING THE PERIOD 1987-2011, AND 160,000 MATCHED CONTROLS IN SWEDEN. USING PROSPECTIVELY REGISTERED DATA ON THEIR FIRST-DEGREE RELATIVES, WE EVALUATED THE IMPACT OF PARENTAL AGE ON THE RISK OF LYMPHOID NEOPLASMS BY SUBTYPE. OVERALL, EACH 5-YEAR INCREMENT IN MATERNAL AGE WAS ASSOCIATED WITH A 3% INCREASE IN INCIDENCE OF OFFSPRING LYMPHOID NEOPLASMS (HAZARD RATIO = 1.03, 95% CONFIDENCE INTERVAL: 1.02, 1.04). THE ASSOCIATION WAS SIMILAR FOR PATERNAL AGE AND PRESENT EVEN AMONG INDIVIDUALS OLDER THAN 70 YEARS OF AGE AT DIAGNOSIS. STRATIFIED ANALYSES FURTHER REVEALED THAT THE ASSOCIATION WAS LIMITED TO CERTAIN SUBTYPES, MOSTLY OF INDOLENT NATURE. RISKS OF CHRONIC LYMPHOCYTIC LEUKEMIA, FOLLICULAR LYMPHOMA, AND MANTLE CELL LYMPHOMA WERE 5%-10% HIGHER PER 5-YEAR INCREMENT IN MATERNAL AGE, BUT NO ASSOCIATIONS WERE OBSERVED FOR ACUTE LYMPHOBLASTIC LEUKEMIA, PLASMA CELL NEOPLASMS, OR DIFFUSE LARGE B-CELL LYMPHOMA. THESE FINDINGS INDICATED THAT PRENATAL GENETIC OR EPIGENETIC CHANGES INFLUENCE RISK OF ADULT LYMPHOID NEOPLASMS AND SUGGEST A DIFFERENCE IN THIS ASSOCIATION BETWEEN AGGRESSIVE AND INDOLENT LYMPHOMA SUBTYPES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  5462  19 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  1481  25 DIVERSITY OF GENOME PROFILES IN MALIGNANT LYMPHOMA. CHARACTERISTIC CHROMOSOME TRANSLOCATIONS ARE ASSOCIATED WITH SPECIFIC DISEASE ENTITIES, AND ARE KNOWN TO PLAY A PIVOTAL ROLE IN LYMPHOMA DEVELOPMENT. CHROMOSOME TRANSLOCATION ALONE, HOWEVER, IS NOT SUFFICIENT TO PRODUCE TUMORS. FACTORS INCLUDING THE MICROENVIRONMENT AND EPIGENETIC AND GENETIC ALTERATIONS OTHER THAN CHROMOSOME TRANSLOCATIONS HAVE BEEN SHOWN TO PLAY A ROLE IN LYMPHOMA DEVELOPMENT. FOLLICULAR LYMPHOMA CELLS PROLIFERATE IN CLOSE CONTACT WITH FOLLICULAR DENDRITIC CELLS. MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA CELLS PROLIFERATE AT THE MARGINAL ZONE AREA OF REACTIVE FOLLICLES WHICH ARE FORMED BY PRECEDING CHRONIC INFLAMMATION. THE IMPORTANCE OF GENETIC ALTERATIONS OTHER THAN CHROMOSOME TRANSLOCATION HAS BEEN RECOGNIZED SINCE THE INTRODUCTION OF ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ARRAY CGH). VARIATIONS IN THE GENOMIC PROFILE AMONG PATIENTS WITH THE SAME DISEASE ENTITY HAVE BEEN FOUND BY ARRAY CGH ANALYSES. THESE VARIATIONS INDICATE THAT MULTIPLE GENETIC PATHWAYS LEADING TO THE DEVELOPMENT OF LYMPHOMAS MAY EXIST AND HENCE RESULT IN THE VARIABLE CLINICOPATHOLOGICAL FEATURES OBSERVED.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  4925  33 PARENTAL MICRONUTRIENT DEFICIENCY DISTORTS LIVER DNA METHYLATION AND EXPRESSION OF LIPID GENES ASSOCIATED WITH A FATTY-LIVER-LIKE PHENOTYPE IN OFFSPRING. MICRONUTRIENT STATUS OF PARENTS CAN AFFECT LONG TERM HEALTH OF THEIR PROGENY. AROUND 2 BILLION HUMANS ARE AFFECTED BY CHRONIC MICRONUTRIENT DEFICIENCY. IN THIS STUDY WE USE ZEBRAFISH AS A MODEL SYSTEM TO EXAMINE MORPHOLOGICAL, MOLECULAR AND EPIGENETIC CHANGES IN MATURE OFFSPRING OF PARENTS THAT EXPERIENCED A ONE-CARBON (1-C) MICRONUTRIENT DEFICIENCY. ZEBRAFISH WERE FED A DIET SUFFICIENT, OR MARGINALLY DEFICIENT IN 1-C NUTRIENTS (FOLATE, VITAMIN B12, VITAMIN B6, METHIONINE, CHOLINE), AND THEN MATED. OFFSPRING LIVERS UNDERWENT HISTOLOGICAL EXAMINATION, RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS. PARENTAL 1-C MICRONUTRIENT DEFICIENCY RESULTED IN INCREASED LIPID INCLUSION AND WE IDENTIFIED 686 DIFFERENTIALLY EXPRESSED GENES IN OFFSPRING LIVER, THE MAJORITY OF WHICH WERE DOWNREGULATED. DOWNREGULATED GENES WERE ENRICHED FOR FUNCTIONAL CATEGORIES RELATED TO STEROL, STEROID AND LIPID BIOSYNTHESIS, AS WELL AS MITOCHONDRIAL PROTEIN SYNTHESIS. DIFFERENTIAL DNA METHYLATION WAS FOUND AT 2869 CPG SITES, ENRICHED IN PROMOTER REGIONS AND PERMUTATION ANALYSES CONFIRMED THE ASSOCIATION WITH PARENTAL FEED. OUR DATA INDICATE THAT PARENTAL 1-C NUTRIENT STATUS CAN PERSIST AS LOCUS SPECIFIC DNA METHYLATION MARKS IN DESCENDANTS AND SUGGEST AN EFFECT ON LIPID UTILIZATION AND MITOCHONDRIAL PROTEIN TRANSLATION IN F(1) LIVERS. THIS POINTS TOWARD PARENTAL MICRONUTRIENTS STATUS AS AN IMPORTANT FACTOR FOR OFFSPRING HEALTH AND WELFARE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  5243  30 PROGNOSTIC IMPACT OF EPIGENETIC CLASSIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: THE CASE OF SUBSET #2. BASED ON THE METHYLATION STATUS OF 5 SINGLE CPG SITES, A NOVEL EPIGENETIC CLASSIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WAS RECENTLY PROPOSED, CLASSIFYING CLL PATIENTS INTO 3 CLINICO-BIOLOGICAL SUBGROUPS WITH DIFFERENT OUTCOME, TERMED MEMORY LIKE CLL (M-CLL), NAIVE LIKE CLL (N-CLL), AND A THIRD INTERMEDIATE CLL SUBGROUP (I-CLL). WHILE M-CLL AND N-CLL PATIENTS AT LARGE CORRESPONDED TO PATIENTS CARRYING MUTATED AND UNMUTATED IGHV GENES, RESPECTIVELY, LIMITED INFORMATION EXISTS REGARDING THE LESS DEFINED I-CLL GROUP. USING PYROSEQUENCING, WE INVESTIGATED THE PROGNOSTIC IMPACT OF THE PROPOSED 5 CPG SIGNATURE IN A WELL-CHARACTERIZED CLL COHORT (135 CASES), INCLUDING IGHV-MUTATED AND UNMUTATED PATIENTS AS WELL AS CLINICALLY AGGRESSIVE STEREOTYPED SUBSET #2 PATIENTS. OVERALL, WE CONFIRMED THE SIGNATURE'S ASSOCIATION WITH ESTABLISHED PROGNOSTIC MARKERS. MOREOVER, IN THE PRESENCE OF THE IGHV MUTATIONAL STATUS, THE EPIGENETIC SIGNATURE REMAINED INDEPENDENTLY ASSOCIATED WITH BOTH TIME-TO-FIRST-TREATMENT AND OVERALL SURVIVAL IN MULTIVARIATE ANALYSES. AS A PRIME FINDING, WE OBSERVED THAT SUBSET #2 PATIENTS WERE PREDOMINANTLY CLASSIFIED AS I-CLL, PROBABLY REFLECTING THEIR BORDERLINE IGHV MUTATIONAL STATUS (97-99% GERMLINE IDENTITY), THOUGH HAVING A SIMILARLY POOR PROGNOSIS AS N-CLL PATIENTS. IN SUMMARY, WE VALIDATED THE EPIGENETIC CLASSIFIER AS AN INDEPENDENT FACTOR IN CLL PROGNOSTICATION AND PROVIDE FURTHER EVIDENCE THAT SUBSET #2 IS A MEMBER OF THE I-CLL GROUP, HENCE SUPPORTING THE EXISTENCE OF A THIRD, INTERMEDIATE EPIGENETIC SUBGROUP.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  3560  21 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  1692  23 DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA AT DELIVERY, DNA METHYLATION IN UMBILICAL CORD BLOOD AND THEIR ASSOCIATION WITH OFFSPRING ASTHMA IN NON-HISPANIC BLACK WOMEN. EPIDURAL ANESTHESIA IS AN EFFECTIVE PAIN RELIEF MODALITY, WIDELY USED FOR LABOR ANALGESIA. CHILDHOOD ASTHMA IS ONE OF THE COMMONEST CHRONIC MEDICAL ILLNESSES IN THE USA WHICH PLACES A SIGNIFICANT BURDEN ON THE HEALTH-CARE SYSTEM. WE RECENTLY DEMONSTRATED A NEGATIVE ASSOCIATION BETWEEN THE DURATION OF EPIDURAL ANESTHESIA AND THE DEVELOPMENT OF CHILDHOOD ASTHMA; HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS STILL REMAIN UNCLEAR. IN THIS STUDY OF 127 MOTHER-CHILD PAIRS COMPRISED OF 75 NON-HISPANIC BLACK (NHB) AND 52 NON-HISPANIC WHITE (NHW) FROM THE NEWBORN EPIGENETIC STUDY, WE TESTED THE HYPOTHESIS THAT UMBILICAL CORD BLOOD DNA METHYLATION MEDIATES THE ASSOCIATION BETWEEN THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA AT DELIVERY AND THE DEVELOPMENT OF CHILDHOOD ASTHMA AND WHETHER THIS DIFFERED BY RACE/ETHNICITY. IN THE MOTHER-CHILD PAIRS OF NHB ANCESTRY, THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA WAS ASSOCIATED WITH A MARGINALLY LOWER RISK OF ASTHMA (ODDS RATIO = 0.88, 95% CONFIDENCE INTERVAL = 0.76-1.01) FOR EACH 1-H INCREASE IN EXPOSURE TO EPIDURAL ANESTHESIA. OF THE 20 CPGS IN THE NHB POPULATION SHOWING THE STRONGEST MEDIATION EFFECT, 50% DEMONSTRATED AN AVERAGE MEDIATION PROPORTION OF 52%, WITH DIRECTIONAL CONSISTENCY OF DIRECT AND INDIRECT EFFECTS. THESE TOP 20 CPGS MAPPED TO 21 GENES ENRICHED FOR PATHWAYS ENGAGED IN ANTIGEN PROCESSING, ANTIGEN PRESENTATION, PROTEIN UBIQUITINATION AND REGULATORY NETWORKS RELATED TO THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I COMPLEX AND NUCLEAR FACTOR KAPPA-B (NFKB) COMPLEX. OUR FINDINGS SUGGEST THAT DNA METHYLATION IN IMMUNE-RELATED PATHWAYS CONTRIBUTES TO THE EFFECTS OF THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA ON CHILDHOOD ASTHMA RISK IN NHB OFFSPRING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  5435  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12   817  42 CHARACTERISTIC PATTERNS OF ALTERED DNA METHYLATION PREDICT EMERGENCE OF HUMAN HEPATOCELLULAR CARCINOMA. WE AIMED TO IDENTIFY THE SPECIFIC SUBSET OF TUMOR SUPPRESSOR GENES (TSGS) THAT ARE METHYLATION-SILENCED DURING THE EARLIEST STEPS OF HEPATOCARCINOGENESIS, AND TO FURTHER EVALUATE WHETHER THESE GENES CAN SERVE AS PREDICTIVE BIOMARKERS OF HEPATOCELLULAR CARCINOMA (HCC) EMERGENCE. A TOTAL OF 482 LIVER TISSUES INCLUDING 177 PAIRS OF HCCS AND MATCHED NONTUMOR LIVERS AND 128 LIVER BIOPSIES FROM CHRONIC HEPATITIS C (CHC) PATIENTS WERE ANALYZED FOR QUANTITATIVE METHYLATION ANALYSIS IN 24 TSG PROMOTERS AND THREE MINT LOCI. THE TUMORS WERE CLASSIFIED AS EARLY, LESS-PROGRESSED, AND HIGHLY PROGRESSED HCCS USING HISTOLOGY AND RADIOLOGICAL APPROACHES. A SUBSET OF TSGS THAT HARBORED DISTINCTLY HIGH LEVELS OF METHYLATION IN EARLY HCCS WERE SELECTED. BASED ON THE METHYLATION PROFILES OF THESE GENES, KAPLAN-MEIER ANALYSES WERE PERFORMED TO DETERMINE TIME-TO-HCC OCCURRENCE IN CHC PATIENTS. SUBSEQUENTLY, MULTIVARIATE ANALYSIS WAS PERFORMED USING AGE, GENDER, FIBROSIS STAGE, AND NUMBER OF METHYLATED TSGS AS COVARIATES. AMONG TSGS ANALYZED, A SUBSET OF EIGHT TSGS (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3, AND PRDM2) DEMONSTRATED A DISTINCT CLUSTER BY HIERARCHICAL CLUSTERING AND RECEIVER OPERATING CHARACTERISTIC ANALYSES. THIS SUBSET OF TSGS SHOWED SIGNIFICANTLY HIGHER METHYLATION LEVELS IN THE EARLY HCCS (P < 0.0001). IN THE CHC PATIENTS, METHYLATION FREQUENCIES IN THESE TSGS WERE ASSOCIATED WITH SHORTER TIME-TO-HCC OCCURRENCE (P < 0.0001), AND NUMBER OF METHYLATED GENES WAS AN INDEPENDENT RISK FACTOR FOR HCC (HAZARD RATIO = 5.21, 95% CONFIDENCE INTERVAL = 2.25-11.76, P = 0.0002). CONCLUSION: EPIGENETIC INACTIVATION OF A SUBSET OF TSGS PLAYS A CRITICAL ROLE IN THE EARLIEST STEPS OF HEPATOCARCINOGENESIS. FURTHERMORE, EPIGENETIC INACTIVATION OF THESE GENES IN CHC PROVIDES A PROGNOSTIC VALUE FOR DETERMINING THE RISK FOR DEVELOPING HCC LATER IN LIFE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                             
13  2439  41 EPIGENETIC SILENCING OF THE MLH1 PROMOTER IN RELATION TO THE DEVELOPMENT OF GASTRIC CANCER AND ITS USE AS A BIOMARKER FOR PATIENTS WITH MICROSATELLITE INSTABILITY: A SYSTEMATIC ANALYSIS. BACKGROUND/AIMS: HUMAN MUTL HOMOLOG 1 (MLH1) PROMOTER METHYLATION WAS REPORTED IN GASTRIC CANCER (GC). THIS STUDY DETERMINED THE CLINICOPATHOLOGICAL, PROGNOSTIC, AND DIAGNOSTIC EFFECTS OF MLH1 PROMOTER METHYLATION IN GC. METHODS: THE COMBINED ODDS RATIO (OR) OR HAZARD RATIO (HR) AND THEIR CORRESPONDING 95% CONFIDENCE INTERVALS (95% CI) WERE CALCULATED. THE POOLED SENSITIVITY, SPECIFICITY, AND AREA UNDER THE CURVE (AUC) WERE ANALYZED. RESULTS: A TOTAL OF 4654 GC PATIENTS AND 3669 NON-MALIGNANT CONTROLS WERE IDENTIFIED IN THIS SYSTEMATIC ANALYSIS. MLH1 PROMOTER METHYLATION WAS SIGNIFICANTLY HIGHER IN GC SAMPLES THAN IN GASTRIC ADENOMAS, CHRONIC GASTRITIS, ADJACENT TISSUES, NORMAL GASTRIC MUCOSA, AND NORMAL HEALTHY BLOOD SAMPLES, BUT IT EXHIBITED A SIMILAR FREQUENCY IN GC VS. INTESTINAL METAPLASIA AND DYSPLASIA SAMPLES. MLH1 PROMOTER METHYLATION CORRELATED WITH AGE AND MICROSATELLITE INSTABILITY (MSI), BUT IT WAS NOT ASSOCIATED WITH GENDER, H. PYLORI INFECTION, SMOKING, DRINKING BEHAVIORS, PATHOLOGICAL HISTOLOGY, TUMOR DIFFERENTIATION, CLINICAL STAGE, LYMPH NODE STATUS, DISTANT METASTASIS, OR OVERALL SURVIVAL OF GC. MLH1 PROMOTER METHYLATION EXHIBITED A POOR SENSITIVITY VALUE (< 0.5) IN PATIENTS WITH GC COMPARED WITH ADJACENT TISSUES, GASTRIC ADENOMAS, CHRONIC GASTRITIS, NORMAL GASTRIC MUCOSA, AND NORMAL HEALTHY BLOOD SAMPLES. THE POOLED SENSITIVITY, SPECIFICITY, AND AUC OF MLH1 PROMOTER METHYLATION IN GC WITH MSI VS. GC WITH MICROSATELLITE STABILITY (MSS) SAMPLES WERE 0.64, 0.96, AND 0.90, RESPECTIVELY. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE DETECTION OF MLH1 PROMOTER METHYLATION MAY BE A POTENTIAL PROGNOSTIC BIOMARKER FOR GC PATIENTS WITH MSI.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14   672  31 BRAF, KRAS AND HELICOBACTER PYLORI EPIGENETIC CHANGES-ASSOCIATED CHRONIC GASTRITIS IN EGYPTIAN PATIENTS WITH AND WITHOUT GASTRIC CANCER. WE AIMED TO STUDY MLH1 AND MGMT METHYLATION STATUS IN HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS IN EGYPTIAN PATIENTS WITH AND WITHOUT GASTRIC CANCER. 39 PATIENTS WERE INCLUDED IN OUR STUDY. THEY WERE DIVIDED INTO 2 GROUPS; PATIENTS WITHOUT (GROUP I) AND WITH GASTRIC ADENOCARCINOMA (GROUP II). PATIENTS WERE SUBJECTED TO CLINICAL EXAMINATION, ABDOMINAL ULTRASOUND AND UPPER ENDOSCOPY FOR GASTRIC BIOPSY. BIOPSIES WERE SUBJECTED TO UREASE TEST, HISTOLOGICAL EXAMINATION, AND DNA PURIFICATION. H. PYLORI, BRAF, KRAS, MLH1 AND MGMT METHYLATION WERE ASSESSED BY QUANTITATIVE PCR. DNA SEQUENCING WAS PERFORMED TO ASSESS BRAF AND KRAS GENES MUTATION. QPCR OF H. PYLORI WAS SIGNIFICANTLY HIGHER IN PATIENTS WITH ADENOCARCINOMA (GROUP II) THAN THOSE WITHOUT ADENOCARCINOMA (GROUP I); WITH A P < 0.001 AS WELL AS IN PATIENTS WITH AGE ABOVE 50 YEARS WITH A P VALUE = 0.008. BY APPLYING LOGISTIC REGRESSION ANALYSIS IT WAS REPORTED THAT THE H. PYLORI QPCR IS A SIGNIFICANT PREDICTOR TO THE ADENOCARCINOMA WITH OR = 1.025 (95 % CI: 1. 002-1.048), WITH SENSITIVITY OF 90 % AND SPECIFICITY OF 100 %. ADENOCARCINOMA PATIENTS HAD A SIGNIFICANTLY HIGHER MEAN AGE AND LEVELS OF H. PYLORI, BRAF, K-RAS, METHYLATED MGMT AND METHYLATED MLH1 THAN THOSE OF GASTRITIS PATIENTS. DNA SEQUENCE ANALYSIS OF BRAF (CODON 12) AND KRAS (CODON 600) HAD GENES MUTATION IN GASTRIC ADENOCARCINOMA VERSUS CHRONIC GASTRITIS. CONCLUSION: H. PYLORI MAY CAUSE EPIGENETIC CHANGES PREDISPOSING THE PATIENTS TO CANCER STOMACH. ESTIMATION OF H. PYLORI BY QPCR CAN BE A GOOD PREDICTOR TO ADENOCARCINOMA. BRAF AND KRAS GENES MUTATION WERE REVELED IN GASTRITIS AND ADENOCARCINOMA PATIENTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  3897  42 LARGE-SCALE ANALYSIS OF THE GENETIC AND EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA FROM SOUTHEAST CHINA. OUR KNOWLEDGE ABOUT MOLECULAR ALTERATIONS DURING HEPATOCARCINOGENESIS IS STILL FRAGMENTARY, DUE TO LACK OF COMPREHENSIVE GENETIC AND EPIGENETIC ANALYSES IN THE SAME SET OF HEPATOCELLULAR CARCINOMAS (HCCS). IN THIS STUDY, WE CONDUCTED A LARGE-SCALE ANALYSIS, INCLUDING MUTATION SCREENING IN 50 GENES AND METHYLATION ASSAYS IN THREE GENES IN 54 PAIRS OF HCCS AND THEIR NEIGHBORING NON-CANCEROUS TISSUES. ALL SAMPLES WERE COLLECTED FROM THE RESIDENTS IN SOUTHEAST CHINA. WE FOUND HBV INFECTION AND CHRONIC HEPATITIS/CIRRHOSIS IN 83.3% AND 98.1% OF THE CASES, RESPECTIVELY. MUTATIONS WERE IDENTIFIED IN 18 OUT OF 54 (33.3%) SAMPLES, WITH P53 ALTERATIONS IN 14 CASES AND BETA-CATENIN MUTATIONS IN FOUR TUMORS. NO MUTATIONS WERE IDENTIFIED IN THE NEIGHBORING TISSUES. INTERESTINGLY, 9 OUT OF 14 (64.3%) TUMORS CARRYING P53 MUTATIONS DISPLAYED SUBSTITUTION OF SERINE BY ARGININE AT CODON 249, A CHARACTERISTIC CHANGE BELIEVED TO BE INDUCED BY AFLATOXIN-B1. FURTHERMORE, P53 MUTATION WAS SIGNIFICANTLY ASSOCIATED WITH SHORTER RECURRENCE-FREE SURVIVAL (P=0.004). THE RESULTS ALSO REVEALED ABERRANT METHYLATION IN TWO OR MORE GENES IN AS HIGH AS 90% OF TUMORS AND 40% OF ADJACENT TISSUES. THE FREQUENCY OF RASSF1A HYPERMETHYLATION WAS MUCH HIGHER THAN THAT OF P16INK4A AND HAI2 IN BOTH HCC AND NEIGHBORING TISSUES, INDICATING THAT DEREGULATION OF RASSF1A MAY PRECEDE THE OTHER TWO GENES. THESE DATA SUGGEST THAT ABERRANT METHYLATION OCCURS BEFORE MUTATION AND IS AN EARLY EVENT IN THE DEVELOPMENT OF THIS SET OF HCC. OUR FINDINGS HIGHLIGHT P53 AS A PROGNOSTIC FACTOR OF HCC AND RASSF1A AS A POTENTIAL TARGET IN PREVENTING MALIGNANT TRANSFORMATION OF HEPATOCYTES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  6373  20 THE ROLE OF MIRNAS AND EPIGENETIC MECHANISMS IN PRIMARY GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA. GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA IS A RARE LOW-GRADE B-CELL NON-HODGKIN LYMPHOMA ASSOCIATED WITH HELICOBACTER PYLORI INFECTION AND THE SUBSEQUENT CHRONIC INFLAMMATION. SIGNIFICANT PROGRESS IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE HAS ALREADY BEEN MADE. HOWEVER, THE EXACT MOLECULAR PATHWAYS OF LYMPHOMAGENESIS REMAIN UNCLEAR. FURTHERMORE, DIFFICULTIES REGARDING ACCURATE DIAGNOSIS OF GASTRIC MALT LYMPHOMA AND ITS DISCRIMINATION FROM GASTRITIS OR OTHER LYMPHOMA SUBTYPES ARISE. RECENT STUDIES EVALUATE THE ROLE OF MIRNAS AND EPIGENETIC ALTERATIONS ON MALT LYMPHOMA PATHOGENESIS AND PROGNOSIS. THIS REVIEW CRITICALLY SUMMARIZES THE MOST IMPORTANT DATA ON THE ROLE OF MIRNAS AND EPIGENETICS IN MALT LYMPHOMAS PATHOGENESIS, PROGNOSIS AND TREATMENT.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  3873  29 K-RAS AND P16(INK4A)ALTERATIONS IN SPUTUM OF NSCLC PATIENTS AND IN HEAVY ASYMPTOMATIC CHRONIC SMOKERS. NSCLC RATES AMONG THE MOST FREQUENT AND LETHAL NEOPLASM WORLD-WIDE AND A SIGNIFICANT DECREASE IN MORBIDITY AND MORTALITY RELIES ONLY UPON EFFECTIVE EARLY DIAGNOSTIC STRATEGIES. WE INVESTIGATED K-RAS MUTATIONS AND P16(INK4A) HYPERMETHYLATION IN TUMOR TISSUE AND SPUTUM OF 50 PATIENTS WITH NSCLC AND CORRELATED THEM WITH SPUTUM CYTOLOGY AND WITH TUMOR STAGING, GRADING AND LOCATION, TO ASCERTAIN, IN SPUTUM, THEIR POTENTIAL DIAGNOSTIC IMPACT. THE SAME GENETIC/EPIGENETIC ABNORMALITIES AND CYTOLOGICAL FEATURES WERE ALSO EVALUATED IN SPUTUM FROM 100 CHRONIC HEAVY SMOKERS. GENETIC ANALYSIS IDENTIFIED MOLECULAR ABNORMALITIES IN 64% TUMORS (14/50 K-RAS MUTATIONS AND 24/50 P16(INK4A) HYPERMETHYLATION) AND IN 48% SPUTUM (11/50 K-RAS MUTATIONS AND 16/50 P16(INK4A) HYPERMETHYLATION). IN TUMORS K-RAS MUTATIONS AND P16(INK4A) HYPERMETHYLATION WERE MOSTLY MUTUALLY EXCLUSIVE, BEING FOUND IN THE SAME PATIENTS IN 3 CASES ONLY. GENETIC ABNORMALITIES IN SPUTUM WERE DETECTED ONLY IN MOLECULAR ABNORMAL TUMORS. MOLECULAR CHANGES IN SPUTUM HAD RATES OF DETECTION SIMILAR TO CYTOLOGY (42%) BUT THE CYTO-MOLECULAR COMBINATION INCREASED THE DIAGNOSTIC YIELD UP TO 60%. INTERESTINGLY, THE RATE OF DETECTION OF GENETIC CHANGES IN SPUTUM OF TUMORS AT EARLY STAGE (T1) WAS NOT SIGNIFICANTLY DIFFERENT FROM THAT OF TUMORS AT MORE ADVANCED STAGE (T2-T4). IN FACT K-RAS POINT MUTATIONS WERE FREQUENTLY RECOGNISED IN TUMORS AT EARLY STAGE WHILE P16(INK4A) INACTIVATION PREVAILED IN TUMORS AT ADVANCED STAGE ( P=0.0063). AS EXPECTED, DIAGNOSTIC CYTOLOGICAL FINDINGS WERE MORE FREQUENTLY FOUND IN TUMORS AT ADVANCED STAGE (P=0.004). NO CORRELATION WAS FOUND BETWEEN TUMOR GRADING AND LOCATION (CENTRAL VERSUS PERIPHERAL) AND MOLECULAR CHANGES. P16(INK4A) HYPERMETHYLATION, BUT NOT K-RAS MUTATIONS, WAS DOCUMENTED IN SPORADIC CASES OF ASYMPTOMATIC HEAVY SMOKERS (4%) WHERE IT WAS UNCOUPLED FROM CYTOLOGICAL ABNORMALITIES. IN CONCLUSION THE CYTO-MOLECULAR DIAGNOSTIC STRATEGY ADOPTED IN THIS STUDY WAS ABLE TO DETECT THE MAJORITY OF TUMORS BUT IN ORDER TO BE PROPOSED AS EFFECTIVE AND EARLY DIAGNOSTIC TOOL, THIS MOLECULAR PANEL NEEDS TO BE TESTED IN PROSPECTIVE STUDIES WITH ADEQUATE FOLLOW-UP.	2004	
                                                                                            
18   185  36 ACCUMULATION OF ABERRANT CPG HYPERMETHYLATION BY HELICOBACTER PYLORI INFECTION PROMOTES DEVELOPMENT AND PROGRESSION OF GASTRIC MALT LYMPHOMA. ABERRANT DNA HYPERMETHYLATION IS AN IMPORTANT MECHANISM FOR THE INACTIVATION OF TUMOR-RELATED GENES IN HUMAN TUMORS. GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMAS ARISE FROM HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS; MOST PATIENTS ARE H. PYLORI-POSITIVE AND ERADICATION THERAPY IS HIGHLY EFFECTIVE. IN THE PRESENT STUDY, WE USED METHYLATION-SPECIFIC PCR TO ANALYZE THE DNA METHYLATION STATUS OF 11 TUMOR-RELATED GENES (KIP2, P16, HMLH-1, P15, P73, MGMT, DAPK, MINT1, MINT2, MINT31 AND HCAD) IN 21 SPECIMENS OF MALT LYMPHOMA, 5 SPECIMENS OF MALT LYMPHOMA WITH LARGE CELL COMPONENT (HIGH-GRADE MALT LYMPHOMA), 15 SPECIMENS OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL), 8 SPECIMENS OF COMPLETE REMISSION OF MALT LYMPHOMA AFTER ERADICATION THERAPY, 5 SPECIMENS WITH NO EVIDENCE OF MALIGNANCY AND PBMCS FROM 10 HEALTHY DONORS. THE AVERAGE NUMBER OF METHYLATED GENES WAS SIGNIFICANTLY GREATER IN GASTRIC LYMPHOMAS AS COMPARED TO NORMAL CONTROLS (P<0.001). THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WAS OBSERVED IN 93.3% (14/15) OF DLBCLS, 100% (5/5) OF HIGH-GRADE MALT LYMPHOMAS AND 61.9% (13/21) OF MALT LYMPHOMAS; IN CONTRAST, CIMP WAS NOT FOUND IN THE CONTROL GROUP (0%). THE AVERAGE NUMBER OF METHYLATED GENES AND THE CIMP INCIDENCE SIGNIFICANTLY INCREASED WITH H. PYLORI INFECTION. FURTHERMORE, ABERRANT CPG METHYLATION OF SPECIFIC GENES, SUCH AS P16, MGMT AND MINT31, WAS CONSISTENTLY ASSOCIATED WITH H. PYLORI INFECTION. THESE FINDINGS STRONGLY SUGGEST THAT H. PYLORI INFECTION CAUSES THE ABERRANT DNA HYPERMETHYLATION OF SPECIFIC GENES AND INDUCES CIMP, WHICH IS AN IMPORTANT EPIGENETIC MECHANISM FOR THE DEVELOPMENT AND PROGRESSION OF GASTRIC MALT LYMPHOMA; ADDITIONALLY, OUR FINDINGS PROVIDE NEW EPIGENETIC MARKERS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  2678  36 EVALUATION OF A PROGNOSTIC EPIGENETIC CLASSIFICATION SYSTEM IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. BACKGROUND: METHYLATION AT 5 CPG SITES WAS PREVIOUSLY SHOWN TO CLASSIFY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO 3 PROGNOSTIC SUBGROUPS. HERE, WE AIMED TO VALIDATE THE MARKER SET IN AN ADDITIONAL COHORT AND TO EVALUATE ITS CLINICAL UTILITY FOR CLL PATIENT STRATIFICATION. METHODS: WE EVALUATED THIS EPIGENETIC MARKER SET IN 79 GERMAN PATIENTS USING BISULFITE TREATMENT FOLLOWED BY PYROSEQUENCING AND CLASSIFICATION USING A SUPPORT VECTOR MACHINE-LEARNING TOOL. RESULTS: THE N-CLL, I-CLL, AND M-CLL CLASSIFICATION WAS DETECTED IN 28 (35%), 10 (13%), AND 41 (51%) PATIENTS, RESPECTIVELY. EPIGENETIC GROUPING WAS ASSOCIATED WITH IGHV MUTATIONAL STATUS (P = 2 X 10(-12)), ISOLATED DEL13Q (P = 9 X 10(-6)), DEL17P (P = .015), COMPLEX KARYOTYPE (P = .005), VH-USAGE, AND CLINICAL OUTCOME AS TIME TO FIRST TREATMENT (P = 1.4 X 10(-12)) AND OVERALL SURVIVAL (P = .003). MULTIVARIATE COX REGRESSION ANALYSIS IDENTIFIED N-CLL AS A FACTOR FOR EARLIER TREATMENT HAZARD RATIO (HR), 6.3 (95% CONFIDENCE INTERVAL [CI] 2.4-16.4; P = .0002) COMPARED TO IGHV MUTATIONAL STATUS (HR 4.6, 95% CI 1.9-11.3, P = .0008). IN ADDITION, WHEN COMPARING THE PROGNOSTIC VALUE OF THE EPIGENETIC CLASSIFICATION SYSTEM WITH THE IGHV CLASSIFICATION, EPIGENETIC GROUPING PERFORMED BETTER COMPARED TO IGHV MUTATIONAL STATUS USING KAPLAN-MEIER ESTIMATION AND ALLOWED THE IDENTIFICATION OF A THIRD, INTERMEDIATE (I-CLL) GROUP. THUS, OUR STUDY CONFIRMED THE PROGNOSTIC VALUE OF THE EPIGENETIC MARKER SET FOR PATIENT STRATIFICATION IN ROUTINE CLINICAL DIAGNOSTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20  1431  27 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