1 5557 139 ROLE OF GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENICITY. A REVIEW. EXPOSURE TO CHRONIC ARSENIC TOXICITY IS ASSOCIATED WITH CANCER. ALTHOUGH UNSTABLE GENOME IS A CHARACTERISTIC FEATURE OF CANCER CELLS, THE MECHANISMS LEADING TO GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD. WHILE THERE ARE EXCELLENT REVIEWS RELATING TO GENOMIC INSTABILITY IN GENERAL, THERE IS NO COMPREHENSIVE REVIEW PRESENTING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY. THIS REVIEW WAS UNDERTAKEN TO PRESENT THE CURRENT STATE OF RESEARCH IN THIS AREA AND TO HIGHLIGHT THE MAJOR MECHANISMS THAT MAY INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY LEADING TO CANCER. GENOMIC INSTABILITY IS BROADLY CLASSIFIED INTO CHROMOSOMAL INSTABILITY (CIN), PRIMARILY ASSOCIATED WITH MITOTIC ERRORS; AND MICROSATELLITE INSTABILITY (MIN), ASSOCIATED WITH DNA LEVEL INSTABILITY. ARSENIC-INDUCED GENOMIC INSTABILITY IS ESSENTIALLY MULTI-FACTORIAL IN NATURE AND INVOLVES MOLECULAR CROSS-TALK ACROSS SEVERAL CELLULAR PATHWAYS, AND IS MODULATED BY A NUMBER OF ENDOGENOUS AND EXOGENOUS FACTORS. ARSENIC AND ITS METABOLITES GENERATE OXIDATIVE STRESS, WHICH IN TURN INDUCES GENOMIC INSTABILITY THROUGH DNA DAMAGE, IRREVERSIBLE DNA REPAIR, TELOMERE DYSFUNCTION, MITOTIC ARREST AND APOPTOSIS. IN ADDITION TO GENETIC ALTERATION; EPIGENETIC REGULATION THROUGH PROMOTER METHYLATION AND MIRNA EXPRESSION ALTERS GENE EXPRESSION PROFILING LEADING TO GENOME MORE VULNERABLE AND UNSTABLE TOWARDS CANCER RISK. MOREOVER, MUTATIONS OR SILENCING OF PRO-APOPTOTIC GENES CAN LEAD TO GENOMIC INSTABILITY BY ALLOWING SURVIVAL OF DAMAGED CELLS THAT WOULD OTHERWISE DIE. ALTHOUGH A LARGE BODY OF INFORMATION IS NOW GENERATED REGARDING ARSENIC-INDUCED CARCINOGENESIS; FURTHER STUDIES EXPLORING GENOME-WIDE ASSOCIATION, ROLE OF ENVIRONMENT AND DIET ARE NEEDED FOR A BETTER UNDERSTANDING OF THE ARSENIC-INDUCED GENOMIC INSTABILITY. 2013 2 2689 19 EVOLUTION OF DNA METHYLATION IS LINKED TO GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ALTHOUGH CLONAL SELECTION BY GENETIC DRIVER ABERRATIONS IN CANCER IS WELL DOCUMENTED, THE ABILITY OF EPIGENETIC ALTERATIONS TO PROMOTE TUMOR EVOLUTION IS UNDEFINED. WE USED 450K ARRAYS AND NEXT-GENERATION SEQUENCING TO EVALUATE INTRATUMOR HETEROGENEITY AND EVOLUTION OF DNA METHYLATION AND GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). CLL CASES EXHIBIT VAST INTERPATIENT DIFFERENCES IN INTRATUMOR METHYLATION HETEROGENEITY, WITH GENETICALLY CLONAL CASES MAINTAINING LOW METHYLATION HETEROGENEITY AND UP TO 10% OF TOTAL CPGS IN A MONOALLELICALLY METHYLATED STATE. INCREASING METHYLATION HETEROGENEITY CORRELATES WITH ADVANCED GENETIC SUBCLONAL COMPLEXITY. SELECTION OF NOVEL DNA METHYLATION PATTERNS IS OBSERVED ONLY IN CASES THAT UNDERGO GENETIC EVOLUTION, AND INDEPENDENT GENETIC EVOLUTION IS UNCOMMON AND IS RESTRICTED TO LOW-RISK ALTERATIONS. THESE RESULTS REVEAL THAT ALTHOUGH EVOLUTION OF DNA METHYLATION OCCURS IN HIGH-RISK, CLINICALLY PROGRESSIVE CASES, POSITIVE SELECTION OF NOVEL METHYLATION PATTERNS ENTAILS COEVOLUTION OF GENETIC ALTERATION(S) IN CLL. 2014 3 945 31 CHRONIC LYMPHOCYTIC LEUKEMIA: MOLECULAR HETEROGENEITY REVEALED BY HIGH-THROUGHPUT GENOMICS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS BEEN CONSISTENTLY AT THE FOREFRONT OF GENETIC RESEARCH OWING TO ITS PREVALENCE AND THE ACCESSIBILITY OF SAMPLE MATERIAL. RECENTLY, GENOME-WIDE TECHNOLOGIES HAVE BEEN INTENSIVELY APPLIED TO CLL GENETICS, WITH REMARKABLE PROGRESS. SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS HAVE IDENTIFIED RECURRING CHROMOSOMAL ABERRATIONS, THEREBY FOCUSING FUNCTIONAL STUDIES ON DISCRETE GENOMIC LESIONS AND LEADING TO THE FIRST IMPLICATION OF SOMATIC MICRORNA DISRUPTION IN CANCER. NEXT-GENERATION SEQUENCING (NGS) HAS FURTHER TRANSFORMED OUR UNDERSTANDING OF CLL BY IDENTIFYING NOVEL RECURRENTLY MUTATED PUTATIVE DRIVERS, INCLUDING THE UNEXPECTED DISCOVERY OF SOMATIC MUTATIONS AFFECTING SPLICEOSOME FUNCTION. NGS HAS FURTHER ENABLED IN-DEPTH EXAMINATION OF THE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN CLL THAT ACCOMPANY GENETIC LESIONS, AND HAS SHED LIGHT ON HOW DIFFERENT DRIVER EVENTS APPEAR AT DIFFERENT STAGES OF DISEASE PROGRESSION AND CLONALLY EVOLVE WITH RELAPSED DISEASE. IN ADDITION TO PROVIDING IMPORTANT INSIGHTS INTO DISEASE BIOLOGY, THESE DISCOVERIES HAVE SIGNIFICANT TRANSLATIONAL POTENTIAL. THEY ENHANCE PROGNOSIS BY HIGHLIGHTING SPECIFIC LESIONS ASSOCIATED WITH POOR CLINICAL OUTCOMES (FOR EXAMPLE, DRIVER EVENTS SUCH AS MUTATIONS IN THE SPLICING FACTOR SUBUNIT GENE SF3B1) OR WITH INCREASED CLONAL HETEROGENEITY (FOR EXAMPLE, THE PRESENCE OF SUBCLONAL DRIVER MUTATIONS). HERE, WE REVIEW NEW GENOMIC DISCOVERIES IN CLL AND DISCUSS THEIR POSSIBLE IMPLICATIONS IN THE ERA OF PRECISION MEDICINE. 2013 4 4446 29 MOLECULAR MAP OF CHRONIC LYMPHOCYTIC LEUKEMIA AND ITS IMPACT ON OUTCOME. RECENT ADVANCES IN CANCER CHARACTERIZATION HAVE CONSISTENTLY REVEALED MARKED HETEROGENEITY, IMPEDING THE COMPLETION OF INTEGRATED MOLECULAR AND CLINICAL MAPS FOR EACH MALIGNANCY. HERE, WE FOCUS ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), A B CELL NEOPLASM WITH VARIABLE NATURAL HISTORY THAT IS CONVENTIONALLY CATEGORIZED INTO TWO SUBTYPES DISTINGUISHED BY EXTENT OF SOMATIC MUTATIONS IN THE HEAVY-CHAIN VARIABLE REGION OF IMMUNOGLOBULIN GENES (IGHV). TO BUILD THE 'CLL MAP,' WE INTEGRATED GENOMIC, TRANSCRIPTOMIC AND EPIGENOMIC DATA FROM 1,148 PATIENTS. WE IDENTIFIED 202 CANDIDATE GENETIC DRIVERS OF CLL (109 NEW) AND REFINED THE CHARACTERIZATION OF IGHV SUBTYPES, WHICH REVEALED DISTINCT GENOMIC LANDSCAPES AND LEUKEMOGENIC TRAJECTORIES. DISCOVERY OF NEW GENE EXPRESSION SUBTYPES FURTHER SUBCATEGORIZED THIS NEOPLASM AND PROVED TO BE INDEPENDENT PROGNOSTIC FACTORS. CLINICAL OUTCOMES WERE ASSOCIATED WITH A COMBINATION OF GENETIC, EPIGENETIC AND GENE EXPRESSION FEATURES, FURTHER ADVANCING OUR PROGNOSTIC PARADIGM. OVERALL, THIS WORK REVEALS FRESH INSIGHTS INTO CLL ONCOGENESIS AND PROGNOSTICATION. 2022 5 2944 34 GENETIC AND EPIGENETIC BASIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. PURPOSE OF REVIEW: NEXT-GENERATION SEQUENCING OF WHOLE GENOMES, EXOMES AND DNA METHYLOMES IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS PROVIDED THE FIRST COMPREHENSIVE VIEW OF SOMATIC MUTATIONS AND METHYLATION CHANGES IN THIS DISEASE. THIS REVIEW SUMMARIZES THE RECENT FINDINGS IN THIS FIELD AND THEIR IMPACT ON OUR CURRENT UNDERSTANDING OF THIS NEOPLASM. RECENT FINDINGS: GENOMIC STUDIES HAVE REVEALED A REMARKABLE MOLECULAR HETEROGENEITY OF THE DISEASE, WITH ONLY FEW GENES MUTATED IN UP TO 10-15% OF THE PATIENTS AND A RELATIVELY LARGE NUMBER OF GENES RECURRENTLY MUTATED AT LOW FREQUENCY. THE MUTATED GENES TEND TO CLUSTER IN DIFFERENT PATHWAYS THAT INCLUDE NOTCH1 SIGNALING, RNA SPLICING, PROCESSING AND TRANSPORT MACHINERY, INNATE INFLAMMATORY RESPONSE, AND DNA DAMAGE AND CELL CYCLE CONTROL, AMONG OTHERS. NOTCH1 AND SF3B1 MUTATIONS ARE EMERGING AS NEW DRIVERS OF AGGRESSIVE FORMS OF THE DISEASE. GENOME-WIDE METHYLATION STUDIES HAVE SHOWN THAT CLL TRANSFORMATION IS ASSOCIATED WITH A MASSIVE HYPOMETHYLATION PHENOMENON FREQUENTLY AFFECTING THE ENHANCER REGIONS. THIS EPIGENETIC REPROGRAMMING MAINTAINS AN IMPRINT OF THE PUTATIVE CELL OF ORIGIN FROM NAIVE AND MEMORY B-CELLS. SUMMARY: GENOMIC AND EPIGENOMIC STUDIES OF CLL ARE RESHAPING OUR UNDERSTANDING OF THE DISEASE AND PROVIDE NEW PERSPECTIVE FOR A MORE INDIVIDUALIZED DIAGNOSIS AND NEW POTENTIAL THERAPEUTIC TARGETS. 2013 6 1582 35 DNA METHYLATION PROFILES IN PRECANCEROUS TISSUE AND CANCERS: CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION BASED ON DNA METHYLATION STATUS. ALTERATIONS IN DNA METHYLATION, WHICH ARE ASSOCIATED WITH DNA METHYLTRANSFERASE ABNORMALITIES AND RESULT IN SILENCING OF TUMOR-RELATED GENES AND CHROMOSOMAL INSTABILITY, ARE INVOLVED EVEN IN PRECANCEROUS CHANGES IN VARIOUS ORGANS. DNA METHYLATION ALTERATIONS ALSO ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. THEREFORE, WE HAVE ANALYZED DNA METHYLATION ON A GENOME-WIDE SCALE IN CLINICAL TISSUE SAMPLES. OUR APPROACH USING THE BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION METHOD HAS REVEALED THAT DNA METHYLATION ALTERATIONS CORRELATED WITH THE FUTURE DEVELOPMENT OF MORE MALIGNANT CANCERS ARE ALREADY ACCUMULATED AT THE PRECANCEROUS STAGE IN THE KIDNEY, LIVER AND URINARY TRACT. DNA METHYLATION PROFILES AT PRECANCEROUS STAGES ARE BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. SUCH DNA METHYLATION ALTERATIONS MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. ON THE BASIS OF BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION DATA, INDICATORS FOR CARCINOGENETIC RISK ESTIMATION HAVE BEEN ESTABLISHED USING LIVER TISSUE SPECIMENS FROM PATIENTS WITH HEPATITIS VIRUS INFECTION, CHRONIC HEPATITIS AND LIVER CIRRHOSIS OR HISTOLOGICALLY NORMAL UROTHELIA, AND FOR PROGNOSTICATION USING BIOPSY OR SURGICALLY RESECTED SPECIMENS FROM PATIENTS WITH RENAL CELL CARCINOMA, HEPATOCELLULAR CARCINOMA AND UROTHELIAL CARCINOMA. SUCH GENOME-WIDE DNA METHYLATION PROFILING HAS NOW FIRMLY ESTABLISHED THE CLINICAL RELEVANCE OF TRANSLATIONAL EPIGENETICS. 2010 7 3067 37 GENOME-WIDE DNA METHYLATION PROFILES IN PRECANCEROUS CONDITIONS AND CANCERS. ALTERATIONS OF DNA METHYLATION, WHICH RESULT IN CHROMOSOMAL INSTABILITY AND SILENCING OF TUMOR-RELATED GENES, ARE AMONG THE MOST CONSISTENT EPIGENETIC CHANGES OBSERVED IN HUMAN CANCERS. ANALYSIS OF TISSUE SPECIMENS HAS REVEALED THAT DNA METHYLATION ALTERATIONS PARTICIPATE IN MULTISTAGE CARCINOGENESIS, EVEN FROM THE EARLY AND PRECANCEROUS STAGES, ESPECIALLY IN ASSOCIATION WITH CHRONIC INFLAMMATION AND/OR PERSISTENT VIRAL INFECTION, SUCH AS CHRONIC HEPATITIS OR LIVER CIRRHOSIS RESULTING FROM INFECTION WITH HEPATITIS B OR C VIRUS. DNA METHYLATION ALTERATIONS CAN ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY, BUT IS SIGNIFICANTLY CORRELATED WITH ACCUMULATION OF DNA HYPERMETHYLATION IN CPG ISLANDS OF TUMOR-RELATED GENES. ALTERATION OF DNA METHYLTRANSFERASE 3B SPLICING MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION IN PERICENTROMERIC SATELLITE REGIONS. GENOME-WIDE ANALYSIS OF DNA METHYLATION STATUS HAS REVEALED THAT THE DNA METHYLATION PROFILE AT THE PRECANCEROUS STAGE IS BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. DNA METHYLATION STATUS IS NOT SIMPLY ALTERED AT THE PRECANCEROUS STAGE; RATHER, DNA METHYLATION ALTERATIONS AT THE PRECANCEROUS STAGE MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. THEREFORE, GENOME-WIDE DNA METHYLATION PROFILING MAY PROVIDE OPTIMAL INDICATORS FOR CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION, AND THUS PROVIDE AN AVENUE FOR CANCER PREVENTION AND THERAPY ON AN INDIVIDUAL BASIS. 2010 8 2106 24 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY. 2019 9 3768 29 INTEGRATIVE EPIGENOMICS IN CHRONIC LYMPHOCYTIC LEUKAEMIA: BIOLOGICAL INSIGHTS AND CLINICAL APPLICATIONS. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS NOT ONLY CHARACTERISED BY DRIVER GENETIC ALTERATIONS BUT BY EXTENSIVE EPIGENETIC CHANGES. OVER THE LAST DECADE, EPIGENOMIC STUDIES HAVE DESCRIBED THE DNA METHYLOME, CHROMATIN ACCESSIBILITY, HISTONE MODIFICATIONS AND THE THREE-DIMENSIONAL (3D) GENOME ARCHITECTURE OF CLL. BEYOND ITS REGULATORY ROLE, THE DNA METHYLOME CONTAINS IMPRINTS OF THE CELLULAR ORIGIN AND PROLIFERATIVE HISTORY OF CLL CELLS. THESE TWO ASPECTS ARE STRONG INDEPENDENT PROGNOSTIC FACTORS. INTEGRATIVE ANALYSES OF CHROMATIN MARKS HAVE UNCOVERED NOVEL REGULATORY ELEMENTS AND ALTERED TRANSCRIPTION FACTOR NETWORKS AS NON-GENETIC MEANS MEDIATING GENE DEREGULATION IN CLL. ADDITIONALLY, CLL CELLS DISPLAY A DISEASE-SPECIFIC PATTERN OF 3D GENOME INTERACTIONS. FROM THE TECHNOLOGICAL PERSPECTIVE, WE ARE CURRENTLY WITNESSING A TRANSITION FROM BULK OMICS TO SINGLE-CELL ANALYSES. THIS REVIEW AIMS AT SUMMARISING THE MAJOR FINDINGS FROM THE EPIGENOMICS FIELD AS WELL AS PROVIDING A PROSPECT OF THE PRESENT AND FUTURE OF SINGLE-CELL ANALYSES IN CLL. 2023 10 1577 32 DNA METHYLATION PROFILE IN CHRONIC MYELOMONOCYTIC LEUKEMIA ASSOCIATES WITH DISTINCT CLINICAL, BIOLOGICAL AND GENETIC FEATURES. CHROMOSOMAL ABNORMALITIES ARE DETECTED IN 20-30% OF PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND CORRELATE WITH PROGNOSIS. ON THE MUTATION LEVEL, DISRUPTIVE ALTERATIONS ARE PARTICULARLY FREQUENT IN CHROMATIN REGULATORY GENES. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENTIAL ALTERATIONS IN THE EPIGENETIC MARKING OF THE GENOME. HERE, WE REPORT THE ANALYSIS OF GENOMIC DNA METHYLATION PATTERNS OF 64 CMML PATIENTS AND 10 HEALTHY CONTROLS, USING A DNA METHYLATION MICROARRAY FOCUSED ON PROMOTER REGIONS. DIFFERENTIAL METHYLATION ANALYSIS BETWEEN PATIENTS AND CONTROLS ALLOWED US TO IDENTIFY ABNORMALITIES IN DNA METHYLATION, INCLUDING HYPERMETHYLATION OF SPECIFIC GENES AND LARGE GENOME REGIONS WITH ABERRANT DNA METHYLATION. UNSUPERVISED HIERARCHICAL CLUSTER ANALYSIS IDENTIFIED TWO MAIN CLUSTERS THAT ASSOCIATED WITH THE CLINICAL, BIOLOGICAL, AND GENETIC FEATURES OF PATIENTS. GROUP 1 WAS ENRICHED IN PATIENTS WITH ADVERSE CLINICAL AND BIOLOGICAL CHARACTERISTICS AND POORER OVERALL AND PROGRESSION-FREE SURVIVAL. IN ADDITION, SIGNIFICANT DIFFERENCES IN DNA METHYLATION WERE OBSERVED BETWEEN PATIENTS WITH LOW RISK AND INTERMEDIATE/HIGH RISK KARYOTYPES AND BETWEEN TET2 MUTANT AND WILD TYPE PATIENTS. TAKEN TOGETHER, OUR RESULTS DEMONSTRATE THAT ALTERED DNA METHYLATION PATTERNS REFLECT THE CMML DISEASE STATE AND ALLOW TO IDENTIFY PATIENT GROUPS WITH DISTINCT CLINICAL FEATURES. 2018 11 5210 26 PRENEOPLASTIC ALTERATIONS DEFINE CLL DNA METHYLOME AND PERSIST THROUGH DISEASE PROGRESSION AND THERAPY. MOST HUMAN CANCERS CONVERGE TO A DEREGULATED METHYLOME WITH REDUCED GLOBAL LEVELS AND ELEVATED METHYLATION AT SELECT CPG ISLANDS. TO INVESTIGATE THE EMERGENCE AND DYNAMICS OF THE CANCER METHYLOME, WE CHARACTERIZED GENOME-WIDE DNA METHYLATION IN PRE-NEOPLASTIC MONOCLONAL B CELL LYMPHOCYTOSIS (MBL) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), INCLUDING SERIAL SAMPLES COLLECTED ACROSS DISEASE COURSE. WE DETECTED THE ABERRANT TUMOR-ASSOCIATED METHYLATION LANDSCAPE AT CLL DIAGNOSIS AND FOUND NO SIGNIFICANTLY DIFFERENTIALLY METHYLATED REGIONS IN THE HIGH-COUNT MBL-TO-CLL TRANSITION. PATIENT METHYLOMES SHOWED REMARKABLE STABILITY WITH NATURAL DISEASE AND POST-THERAPY PROGRESSION. SINGLE CLL CELLS WERE CONSISTENTLY ABERRANTLY METHYLATED, INDICATING A HOMOGENEOUS TRANSITION TO THE ALTERED EPIGENETIC STATE, AND A DISTINCT EXPRESSION PROFILE TOGETHER WITH MBL CELLS COMPARED TO NORMAL B CELLS. OUR LONGITUDINAL ANALYSIS REVEALS THE CANCER METHYLOME TO EMERGE EARLY, WHICH MAY PROVIDE A PLATFORM FOR SUBSEQUENT GENETICALLY-DRIVEN GROWTH DYNAMICS AND TOGETHER WITH ITS PERSISTENT PRESENCE SUGGESTS A CENTRAL ROLE IN THE NORMAL-TO-CANCER TRANSITION. 2021 12 1481 29 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 13 349 29 ALTERED DNA METHYLATION PROFILES IN SF3B1 MUTATED CLL PATIENTS. MUTATIONS IN SPLICING FACTOR GENES HAVE A SEVERE IMPACT ON THE SURVIVAL OF CANCER PATIENTS. SPLICING FACTOR 3B SUBUNIT 1 (SF3B1) IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL); PATIENTS CARRYING THESE MUTATIONS HAVE A POOR PROGNOSIS. SINCE THE SPLICING MACHINERY AND THE EPIGENOME ARE CLOSELY INTERCONNECTED, WE INVESTIGATED WHETHER THESE ALTERATIONS MAY AFFECT THE EPIGENOMES OF CLL PATIENTS. WHILE AN OVERALL HYPOMETHYLATION DURING CLL CARCINOGENESIS HAS BEEN OBSERVED, THE INTERPLAY BETWEEN THE EPIGENETIC STAGE OF THE ORIGINATING B CELLS AND SF3B1 MUTATIONS, AND THE SUBSEQUENT EFFECT OF THE MUTATIONS ON METHYLATION ALTERATIONS IN CLL, HAVE NOT BEEN INVESTIGATED. WE PROFILED THE GENOME-WIDE DNA METHYLATION PATTERNS OF 27 CLL PATIENTS WITH AND WITHOUT SF3B1 MUTATIONS AND IDENTIFIED LOCAL DECREASES IN METHYLATION LEVELS IN SF3B1(MUT) CLL PATIENTS AT 67 GENOMIC REGIONS, MOSTLY IN PROXIMITY TO TELOMERIC REGIONS. THESE DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE ENRICHED IN GENE BODIES OF CANCER-RELATED SIGNALING GENES, E.G., NOTCH1, HTRA3, AND BCL9L. IN OUR STUDY, SF3B1 MUTATIONS EXCLUSIVELY EMERGED IN TWO OUT OF THREE EPIGENETIC STAGES OF THE ORIGINATING B CELLS. HOWEVER, NOT ALL THE DMRS COULD BE ASSOCIATED WITH THE METHYLATION PROGRAMMING OF B CELLS DURING DEVELOPMENT, SUGGESTING THAT MUTATIONS IN SF3B1 CAUSE ADDITIONAL EPIGENETIC ABERRATIONS DURING CARCINOGENESIS. 2021 14 2639 27 EPIGENOMIC ANALYSIS DETECTS WIDESPREAD GENE-BODY DNA HYPOMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. WE HAVE EXTENSIVELY CHARACTERIZED THE DNA METHYLOMES OF 139 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH MUTATED OR UNMUTATED IGHV AND OF SEVERAL MATURE B-CELL SUBPOPULATIONS THROUGH THE USE OF WHOLE-GENOME BISULFITE SEQUENCING AND HIGH-DENSITY MICROARRAYS. THE TWO MOLECULAR SUBTYPES OF CLL HAVE DIFFERING DNA METHYLOMES THAT SEEM TO REPRESENT EPIGENETIC IMPRINTS FROM DISTINCT NORMAL B-CELL SUBPOPULATIONS. DNA HYPOMETHYLATION IN THE GENE BODY, TARGETING MOSTLY ENHANCER SITES, WAS THE MOST FREQUENT DIFFERENCE BETWEEN NAIVE AND MEMORY B CELLS AND BETWEEN THE TWO MOLECULAR SUBTYPES OF CLL AND NORMAL B CELLS. ALTHOUGH DNA METHYLATION AND GENE EXPRESSION WERE POORLY CORRELATED, WE IDENTIFIED GENE-BODY CPG DINUCLEOTIDES WHOSE METHYLATION WAS POSITIVELY OR NEGATIVELY ASSOCIATED WITH EXPRESSION. WE HAVE ALSO RECOGNIZED A DNA METHYLATION SIGNATURE THAT DISTINGUISHES NEW CLINICO-BIOLOGICAL SUBTYPES OF CLL. WE PROPOSE AN EPIGENOMIC SCENARIO IN WHICH DIFFERENTIAL METHYLATION IN THE GENE BODY MAY HAVE FUNCTIONAL AND CLINICAL IMPLICATIONS IN LEUKEMOGENESIS. 2012 15 3015 27 GENETICS AND EPIGENETICS OF CLL. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS A HETEROGENEOUS BIOLOGICAL BEHAVIOR, WHICH IS HIGHLY INFLUENCED BY ITS IMMUNOGENETIC, EPIGENETIC, AND GENOMIC PROPERTIES. THE REMARKABLY VARIABLE CLINICAL COURSE OF THE DISEASE HAS BEEN ASSOCIATED WITH GENETIC FEATURES SUCH AS CHROMOSOMAL ABNORMALITIES, THE PRESENCE OF EITHER HIGH OR LOW NUMBERS OF SOMATIC HYPERMUTATIONS (SHM) IN THE VARIABLE REGION OF THE IMMUNOGLOBULIN HEAVY CHAIN LOCUS (IGHV), AND SOMATIC MUTATIONS OF SEVERAL SPECIFIC DRIVER GENES. NEXT-GENERATION SEQUENCING (NGS) TECHNOLOGIES HAVE PROVIDED A COMPREHENSIVE CHARACTERIZATION OF THE GENOMIC AND EPIGENOMIC LANDSCAPE IN CLL, ELUCIDATING IMPORTANT UNDERLYING MECHANISMS OF THE DISEASE'S BIOLOGY. THE SCOPE OF THIS REVIEW IS TO SUMMARIZE THE MOST RECENT DISCOVERIES ABOUT NOVEL GENETIC AND EPIGENETIC ALTERATIONS, DISCUSSING THEIR IMPACT ON CLINICAL OUTCOMES AND RESPONSE TO CURRENTLY AVAILABLE THERAPY. 2023 16 3089 32 GENOMIC AND EPIGENOMIC ALTERATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA IS A COMMON DISEASE IN WESTERN COUNTRIES AND HAS HETEROGENEOUS CLINICAL BEHAVIOR. THE RELEVANCE OF THE GENETIC BASIS OF THE DISEASE HAS COME TO THE FOREFRONT RECENTLY, WITH GENOME-WIDE STUDIES THAT HAVE PROVIDED A COMPREHENSIVE VIEW OF STRUCTURAL VARIANTS, SOMATIC MUTATIONS, AND DIFFERENT LAYERS OF EPIGENETIC CHANGES. THE MUTATIONAL LANDSCAPE IS CHARACTERIZED BY RELATIVELY COMMON COPY NUMBER ALTERATIONS, A FEW MUTATED GENES OCCURRING IN 10-15% OF CASES, AND A LARGE NUMBER OF GENES MUTATED IN A SMALL NUMBER OF CASES. THE EPIGENOMIC PROFILE HAS REVEALED A MARKED REPROGRAMMING OF REGULATORY REGIONS IN TUMOR CELLS COMPARED WITH NORMAL B CELLS. ALL OF THESE ALTERATIONS ARE DIFFERENTIALLY DISTRIBUTED IN CLINICAL AND BIOLOGICAL SUBSETS OF THE DISEASE, INDICATING THAT THEY MAY UNDERLIE THE HETEROGENEOUS EVOLUTION OF THE DISEASE. THESE GLOBAL STUDIES ARE REVEALING THE MOLECULAR COMPLEXITY OF CHRONIC LYMPHOCYTIC LEUKEMIA AND PROVIDE NEW PERSPECTIVES THAT HAVE HELPED TO UNDERSTAND ITS PATHOGENIC MECHANISMS AND IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS. 2020 17 2074 39 EPIGENETIC DEREGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: CLINICAL AND BIOLOGICAL IMPACT. DEREGULATED TRANSCRIPTIONAL CONTROL CAUSED BY ABERRANT DNA METHYLATION AND/OR HISTONE MODIFICATIONS IS A HALLMARK OF CANCER CELLS. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST COMMON ADULT LEUKEMIA, THE EPIGENETIC 'LANDSCAPE' HAS ADDED A NEW LAYER OF COMPLEXITY TO OUR UNDERSTANDING OF THIS CLINICALLY AND BIOLOGICALLY HETEROGENEOUS DISEASE. EARLY STUDIES IDENTIFIED ABERRANT DNA METHYLATION, OFTEN BASED ON SINGLE GENE PROMOTER ANALYSIS WITH BOTH BIOLOGICAL AND CLINICAL IMPACT. SUBSEQUENT GENOME-WIDE PROFILING STUDIES REVEALED DIFFERENTIAL DNA METHYLATION BETWEEN CLLS AND CONTROLS AND IN PROGNOSTICS SUBGROUPS OF THE DISEASE. FROM THESE STUDIES, IT BECAME APPARENT THAT DNA METHYLATION IN REGIONS OUTSIDE OF PROMOTERS, SUCH AS ENHANCERS, IS IMPORTANT FOR THE REGULATION OF CODING GENES AS WELL AS FOR THE REGULATION OF NON-CODING RNAS. ALTHOUGH DNA METHYLATION PROFILES ARE REPORTEDLY STABLE OVER TIME AND IN RELATION TO THERAPY, A HIGHER EPIGENETIC HETEROGENEITY OR 'BURDEN' IS SEEN IN MORE AGGRESSIVE CLL SUBGROUPS, ALBEIT AS NON-RECURRENT 'PASSENGER' EVENTS. MORE RECENTLY, DNA METHYLATION PROFILES IN CLL ANALYZED IN RELATION TO DIFFERENTIATING NORMAL B-CELL POPULATIONS REVEALED THAT THE MAJORITY OF THE CLL EPIGENOME REFLECTS THE EPIGENOMES PRESENT IN THE CELL OF ORIGIN AND THAT ONLY A SMALL FRACTION OF THE EPIGENETIC ALTERATIONS REPRESENTS TRULY CLL-SPECIFIC CHANGES. FURTHERMORE, CLL PATIENTS CAN BE GROUPED INTO AT LEAST THREE CLINICALLY RELEVANT EPIGENETIC SUBGROUPS, POTENTIALLY ORIGINATING FROM DIFFERENT CELLS AT VARIOUS STAGES OF DIFFERENTIATION AND ASSOCIATED WITH DISTINCT OUTCOMES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE DNA METHYLOME IN CLL, THE ROLE OF HISTONE MODIFYING ENZYMES, HIGHLIGHT INSIGHTS DERIVED FROM ANIMAL MODELS AND ATTEMPTS MADE TO TARGET EPIGENETIC REGULATORS IN CLL ALONG WITH THE FUTURE DIRECTIONS OF THIS RAPIDLY ADVANCING FIELD. 2018 18 937 18 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017 19 342 32 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS. 2007 20 6616 43 UNCOVERING THE DNA METHYLOME IN CHRONIC LYMPHOCYTIC LEUKEMIA. OVER THE PAST TWO DECADES, ABERRANT DNA METHYLATION HAS EMERGED AS A KEY PLAYER IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AND KNOWLEDGE REGARDING ITS BIOLOGICAL AND CLINICAL CONSEQUENCES IN THIS DISEASE HAS EVOLVED RAPIDLY. SINCE THE INITIAL STUDIES RELATING DNA HYPOMETHYLATION TO GENOMIC INSTABILITY IN CLL, A PLETHORA OF REPORTS HAVE FOLLOWED SHOWING THE IMPACT OF DNA HYPERMETHYLATION IN SILENCING VITAL SINGLE GENE PROMOTERS AND THE REVERSIBLE NATURE OF DNA METHYLATION THROUGH INHIBITOR DRUGS. WITH THE RECOGNITION THAT DNA HYPERMETHYLATION EVENTS COULD POTENTIALLY ACT AS NOVEL PROGNOSTIC AND TREATMENT TARGETS IN CLL, THE SEARCH FOR ABERRANTLY METHYLATED GENES, GENE FAMILIES AND PATHWAYS HAS ENSUED. SUBSEQUENTLY, THE ADVENT OF MICROARRAY AND NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS SUPPORTED THE HUNT FOR SUCH TARGETS, ALLOWING EXPLORATION OF THE METHYLATION LANDSCAPE IN CLL AT AN UNPRECEDENTED SCALE. IN LIGHT OF THESE ANALYSES, WE NOW UNDERSTAND THAT DIFFERENT CLL PROGNOSTIC SUBGROUPS ARE CHARACTERIZED BY DIFFERENTIAL METHYLATION PROFILES; WE RECOGNIZE DNA METHYLATION OF A NUMBER OF SIGNALING PATHWAYS GENES TO BE ALTERED IN CLL, AND ACKNOWLEDGE THE ROLE OF DNA METHYLATION OUTSIDE OF TRADITIONAL CPG ISLAND PROMOTERS AS FUNDAMENTAL PLAYERS IN THE REGULATION OF GENE EXPRESSION. TODAY, THE SIGNIFICANCE AND TIMING OF ALTERED DNA METHYLATION WITHIN THE COMPLEX EPIGENETIC NETWORK OF CONCOMITANT EPIGENETIC MESSENGERS SUCH AS HISTONES AND MIRNAS IS AN INTENSIVE AREA OF RESEARCH. IN CLL, IT APPEARS THAT DNA METHYLATION IS A RATHER STABLE EPIGENETIC MARK OCCURRING RATHER EARLY IN THE DISEASE PATHOGENESIS. HOWEVER, OTHER CONSEQUENCES, SUCH AS HOW AND WHY ABERRANT METHYLATION MARKS OCCUR, ARE LESS EXPLORED. IN THIS REVIEW, WE WILL NOT ONLY PROVIDE A COMPREHENSIVE SUMMARY OF THE CURRENT LITERATURE WITHIN THE EPIGENETICS FIELD OF CLL, BUT ALSO HIGHLIGHT SOME OF THE NOVEL FINDINGS RELATING TO WHEN, WHERE, WHY AND HOW ALTERED DNA METHYLATION MATERIALIZES IN CLL. 2013