1 1071 103 CLONAL DYNAMICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA HAS A HIGHLY VARIABLE DISEASE COURSE ACROSS PATIENTS, THOUGHT TO BE DRIVEN BY THE VAST INTER- AND INTRAPATIENT MOLECULAR HETEROGENEITY DESCRIBED IN SEVERAL LARGE-SCALE DNA-SEQUENCING STUDIES CONDUCTED OVER THE PAST DECADE. ALTHOUGH THE LAST 5 YEARS HAVE SEEN A DRAMATIC SHIFT IN THE THERAPEUTIC LANDSCAPE FOR CHRONIC LYMPHOCYTIC LEUKEMIA, INCLUDING THE REGULATORY APPROVAL OF SEVERAL POTENT TARGETED AGENTS (IE, IDELALISIB, IBRUTINIB, VENETOCLAX), THE VAST MAJORITY OF PATIENTS STILL INEVITABLY EXPERIENCE DISEASE RECURRENCE OR PERSISTENCE. RECENT GENOME-WIDE SEQUENCING APPROACHES HAVE HELPED TO IDENTIFY SUBCLONAL POPULATIONS WITHIN TUMORS THAT DEMONSTRATE A BROAD SPECTRUM OF SOMATIC MUTATIONS, DIVERSE LEVELS OF RESPONSE TO THERAPY, PATTERNS OF REPOPULATION, AND GROWTH KINETICS. UNDERSTANDING THE IMPACT OF GENETIC, EPIGENETIC, AND TRANSCRIPTOMIC FEATURES ON CLONAL GROWTH DYNAMICS AND DRUG RESPONSE WILL BE AN IMPORTANT STEP TOWARD THE SELECTION AND TIMING OF THERAPY. 2019 2 4431 21 MOLECULAR CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA AND INTRAHEPATIC CHOLANGIOCARCINOMA: ONE STEP CLOSER TO PERSONALIZED MEDICINE? HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICC) ARE THE TWO MAJOR FORMS OF PRIMARY LIVER CANCERS (PLC), ACCOUNTING FOR APPROXIMATELY 90% AND 5% RESPECTIVELY. THE INCIDENCE OF EACH IS INCREASING RAPIDLY IN THE WESTERN WORLD, HOWEVER OUR KNOWLEDGE OF THE UNDERLYING MECHANISMS REMAINS LIMITED AND THE OUTCOME, DISMAL. THE ETIOLOGIES OF EACH VARY GEOGRAPHICALLY; NEVERTHELESS, CHRONIC INFLAMMATION HAS BEEN IDENTIFIED IN MORE THAN 80% OF THE CASES AND APPEARS TO BE A KEY MEDIATOR IN ALTERING THE LIVER MICROENVIRONMENT, INCREASING THE RISK OF CARCINOGENESIS. HOWEVER, SINCE NOT ALL HCC AND ESPECIALLY ICC CASES HAVE A RECOGNIZED RISK FACTOR, THERE ARE CURRENTLY TWO PROPOSED MODELS FOR LIVER CARCINOGENESIS. THE CLONAL EVOLUTION MODEL DEMONSTRATES A MULTI-STEP PROCESS OF TUMOR DEVELOPMENT FROM PRECANCEROUS LESIONS TO METASTATIC CARCINOMA, ARISING FROM THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES IN A CELL IN THE SETTING OF CHRONIC INFLAMMATION. WHILE THE MAJORITY OF CASES DO OCCUR AS A CONSEQUENCE OF CHRONIC INFLAMMATION, MOST INDIVIDUALS WITH CHRONIC INFECTION DO NOT DEVELOP PLC, SUGGESTING THE INVOLVEMENT OF INDIVIDUAL GENETIC AND ENVIRONMENTAL FACTORS. FURTHER, SINCE HEPATOCYTES AND CHOLANGIOCYTES BOTH HAVE REGENERATIVE POTENTIAL AND ARISE FROM THE SAME BI-POTENTIAL PROGENITOR CELL, THE MORE RECENTLY PROPOSED CANCER STEM CELL MODEL IS GAINING ITS DUE ATTENTION. THE INTEGRATION OF THESE MODELS AND THE CONSTANT IMPROVEMENT IN MOLECULAR PROFILING PLATFORMS IS ENABLING A BROADER UNDERSTANDING OF THE MECHANISMS UNDERLYING THESE TWO DEVASTATING MALIGNANCIES, PERHAPS MOVING US CLOSER TO A NEW WORLD OF MOLECULARLY-INFORMED PERSONALIZED MEDICINE. 2011 3 3575 30 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 4 945 33 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 5 940 30 CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: CROSSROADS OF GENETIC AND MICROENVIRONMENT INTERACTIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL) ARE 2 WELL-DEFINED ENTITIES THAT DIVERGE IN THEIR BASIC PATHOGENIC MECHANISMS AND CLINICAL EVOLUTION BUT THEY SHARE EPIDEMIOLOGICAL CHARACTERISTICS, CELLS OF ORIGIN, MOLECULAR ALTERATIONS, AND CLINICAL FEATURES THAT DIFFER FROM OTHER LYMPHOID NEOPLASMS. CLL AND MCL ARE CLASSICALLY CONSIDERED INDOLENT AND AGGRESSIVE NEOPLASMS, RESPECTIVELY. HOWEVER, THE CLINICAL EVOLUTION OF BOTH TUMORS IS VERY HETEROGENEOUS, WITH SUBSETS OF PATIENTS HAVING STABLE DISEASE FOR A LONG TIME WHEREAS OTHERS REQUIRE IMMEDIATE INTERVENTION. BOTH CLL AND MCL INCLUDE 2 MAJOR MOLECULAR SUBTYPES THAT SEEM TO DERIVE FROM ANTIGEN-EXPERIENCED CD5(+) B CELLS THAT RETAIN A NAIVE OR MEMORY-LIKE EPIGENETIC SIGNATURE AND CARRY A VARIABLE LOAD OF IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION SOMATIC MUTATIONS FROM TRULY UNMUTATED TO HIGHLY MUTATED, RESPECTIVELY. THESE 2 SUBTYPES OF TUMORS DIFFER IN THEIR MOLECULAR PATHWAYS, GENOMIC ALTERATIONS, AND CLINICAL BEHAVIOR, BEING MORE AGGRESSIVE IN NAIVE-LIKE THAN MEMORY-LIKE-DERIVED TUMORS IN BOTH CLL AND MCL. THE PATHOGENESIS OF THE 2 ENTITIES INTEGRATES THE RELEVANT INFLUENCE OF B-CELL RECEPTOR SIGNALING, TUMOR CELL MICROENVIRONMENT INTERACTIONS, GENOMIC ALTERATIONS, AND EPIGENOME MODIFICATIONS THAT CONFIGURE THE EVOLUTION OF THE TUMORS AND OFFER NEW POSSIBILITIES FOR THERAPEUTIC INTERVENTION. THIS REVIEW WILL FOCUS ON THE SIMILARITIES AND DIFFERENCES OF THESE 2 TUMORS BASED ON RECENT STUDIES THAT ARE ENHANCING THE UNDERSTANDING OF THEIR PATHOGENESIS AND CREATING SOLID BASES FOR NEW MANAGEMENT STRATEGIES. 2018 6 4552 32 MUTATIONAL LANDSCAPE OF CHRONIC MYELOID LEUKEMIA: MORE THAN A SINGLE ONCOGENE LEUKEMIA. THE BCR-ABL1 FUSION GENE, WHICH CAUSES ABERRANT KINASE ACTIVITY AND UNCONTROLLED CELL PROLIFERATION, IS THE HALLMARK OF CHRONIC MYELOID LEUKEMIA (CML). THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKI) THAT TARGET THE BCR-ABL ONCOPROTEIN HAS LED TO DRAMATIC IMPROVEMENT IN CML MANAGEMENT. HOWEVER, SOME CHALLENGES REMAIN TO BE ADDRESSED IN THE TKI ERA, INCLUDING PATIENT STRATIFICATION AND THE SELECTION OF FRONTLINE TKIS AND CML PROGRESSION. ADDITIONALLY, WITH THE EMERGING GOAL OF TREATMENT-FREE REMISSION (TFR) IN CML MANAGEMENT, BIOMARKERS THAT PREDICT THE OUTCOMES OF STOPPING TKI REMAIN TO BE IDENTIFIED. NOTABLY, RECENT REPORTS HAVE REVEALED THE POWER OF GENOME SCREENING IN UNDERSTANDING THE ROLE OF GENOME ABERRATIONS OTHER THAN BCR-ABL1 IN CML PATHOGENESIS. THESE STUDIES HAVE DISCOVERED THE PRESENCE OF DISEASE-PHASE SPECIFIC MUTATIONS AND LINKED CERTAIN MUTATIONS TO INFERIOR RESPONSES TO TKI TREATMENT AND CML PROGRESSION. A PERSONALIZED APPROACH THAT INCORPORATES GENETIC DATA IN TAILORING TREATMENT STRATEGIES HAS BEEN SUCCESSFULLY IMPLEMENTED IN ACUTE LEUKEMIA, AND IT REPRESENTS A PROMISING APPROACH FOR THE MANAGEMENT OF HIGH-RISK CML PATIENTS. IN THIS ARTICLE, WE WILL REVIEW CURRENT KNOWLEDGE ABOUT THE MUTATIONAL PROFILE IN DIFFERENT PHASES OF CML AS WELL AS PATTERNS OF MUTATIONAL DYNAMICS IN PATIENTS HAVING DIFFERENT OUTCOMES. WE HIGHLIGHT THE EFFECTS OF SOMATIC MUTATIONS INVOLVING CERTAIN GENES (E.G. EPIGENETIC MODIFIERS) ON THE OUTCOMES OF TKI TREATMENT. WE ALSO DISCUSS THE POTENTIAL VALUE OF INCORPORATING GENETIC DATA IN TREATMENT DECISIONS AND THE ROUTINE CARE OF CML PATIENTS AS A FUTURE DIRECTION FOR OPTIMIZING CML MANAGEMENT. 2021 7 6653 26 UPDATE ON PANCREATIC CANCER AND ALCOHOL-ASSOCIATED RISK. DUCTAL ADENOCARCINOMA OF THE PANCREAS IS CHARACTERIZED BY EXTREMELY AGGRESSIVE BEHAVIOR, WITH AN OVERALL 5-YEAR SURVIVAL OF <4%. BECAUSE CONVENTIONAL AND SPECIFICALLY TAILORED THERAPEUTIC REGIMENS HAVE LITTLE IMPACT ON PATIENT SURVIVAL, EPIDEMIOLOGICAL AND MOLECULAR RESEARCH AIMS AT IDENTIFYING AND REDUCING RISK FACTORS. CIGARETTE SMOKING, OBESITY, DIABETES MELLITUS, AND CHRONIC PANCREATITIS ARE AMENABLE TO MEDICAL PREVENTION OR THERAPY. HEAVY ALCOHOL CONSUMPTION IS AN INCONSISTENT SINGLE RISK FACTOR FOR PANCREATIC CANCER BUT MAY PROMOTE CARCINOGENESIS BY INCREASING THE RISK OF DIABETES MELLITUS OR CHRONIC PANCREATITIS. FOR VARIOUS AGENTS, THE KEY CARCINOGENIC EFFECT IS PROBABLY AN INFLAMMATORY RESPONSE IN THE PANCREATIC TISSUE. ON THE MOLECULAR LEVEL, MUTATIONS OF ONCOGENES AND TUMOR SUPPRESSOR GENES, AS WELL AS VARIOUS EPIGENETIC ALTERATIONS, SUCH AS OVEREXPRESSION OF GROWTH FACTORS AND THEIR RECEPTORS, ARE IMPORTANT IN TUMORIGENESIS. COMPLETE AND SAFE SURGICAL RESECTION, TOGETHER WITH ADJUVANT THERAPY, OFFERS PROLONGED SURVIVAL, WITH 5-YEAR SURVIVAL RATES OF APPROXIMATELY 25%. HOWEVER, FOR UNRESECTABLE OR DISSEMINATED DISEASE, WHICH CONSTITUTES THE VAST MAJORITY OF CASES, TREATMENT IS PALLIATIVE. DESPITE INCREASING KNOWLEDGE ABOUT THE MOLECULAR PATHOLOGY OF PANCREATIC CANCER AND DESPITE ADVANCES IN TREATMENT, THE OVERALL COURSE OF THE DISEASE IS DISMAL, AND REINFORCED EFFORTS TO REDUCE INCIDENCE AND IMPROVE OUTCOME ARE NEEDED DESPERATELY. 2006 8 6857 27 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS. 2011 9 5969 26 TERT PROMOTER MUTATIONS IN PRIMARY LIVER TUMORS. NEXT-GENERATION SEQUENCING HAS DRAWN THE GENETIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA AND SEVERAL SIGNALING PATHWAYS ARE ALTERED AT THE DNA LEVEL IN TUMORS: WNT/BETA-CATENIN, CELL CYCLE REGULATOR, EPIGENETIC MODIFIER, HISTONE METHYLTRANSFERASE, OXIDATIVE STRESS, RAS/RAF/MAP KINASE AND AKT/MTOR PATHWAYS. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS STARTING WITH THE EXPOSURE TO DIFFERENT RISK FACTORS, FOLLOWED BY THE DEVELOPMENT OF A CHRONIC LIVER DISEASE AND CIRRHOSIS PRECEDE IN THE VAST MAJORITY OF THE CASES THE DEVELOPMENT OF HCC. SEVERAL LINES OF EVIDENCE HAVE UNDERLINED THE PIVOTAL ROLE OF TELOMERE MAINTENANCE IN BOTH CIRRHOSIS AND HCC PATHOGENESIS. TERT PROMOTER MUTATIONS WERE IDENTIFIED AS THE MOST FREQUENT GENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH AN OVERALL FREQUENCY AROUND 60%. MOREOVER, IN CIRRHOSIS, TERT PROMOTER MUTATIONS ARE OBSERVED AT THE EARLY STEPS OF HEPATOCARCINOGENESIS SINCE THEY ARE RECURRENTLY IDENTIFIED IN LOW-GRADE AND HIGH-GRADE DYSPLASTIC NODULES. IN CONTRAST, ACQUISITION OF GENOMIC DIVERSITY THROUGH MUTATIONS OF CLASSICAL ONCOGENES AND TUMOR SUPPRESSOR GENES (TP53, CTNNB1, ARID1A...) OCCURRED ONLY IN PROGRESSED HCC. IN NORMAL LIVER, A SUBSET OF HCC CAN DERIVED FROM THE MALIGNANT TRANSFORMATION OF HEPATOCELLULAR ADENOMA (HCA). IN HCA, CTNNB1 MUTATIONS PREDISPOSE TO TRANSFORMATION OF HCA IN HCC AND TERT PROMOTER MUTATIONS ARE REQUIRED IN MOST OF THE CASES AS A SECOND HIT FOR A FULL MALIGNANT TRANSFORMATION. ALL THESE FINDINGS HAVE REFINED OUR KNOWLEDGE OF HCC PATHOGENESIS AND HAVE POINTED TELOMERASE AS A TARGET FOR TAILORED THERAPY IN THE FUTURE. 2016 10 4473 28 MOLECULAR PATHOGENESIS OF CLL AND ITS EVOLUTION. IN SPITE OF BEING THE MOST PREVALENT ADULT LEUKEMIA IN WESTERN COUNTRIES, THE MOLECULAR MECHANISMS DRIVING THE ESTABLISHMENT AND PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) REMAIN LARGELY UNKNOWN. IN RECENT YEARS, THE USE OF NEXT-GENERATION SEQUENCING TECHNIQUES HAS UNCOVERED NEW AND, IN SOME CASES, UNEXPECTED DRIVER GENES WITH PROGNOSTIC AND THERAPEUTIC VALUE. THE MUTATIONAL LANDSCAPE OF CLL IS CHARACTERIZED BY HIGH-GENETIC AND EPIGENETIC HETEROGENEITY, LOW MUTATION RECURRENCE AND A LONG TAIL OF CASES WITH UNDEFINED DRIVER GENES. ON THE OTHER HAND, THE USE OF DEEP SEQUENCING HAS ALSO REVEALED HIGH INTRA-TUMOR HETEROGENEITY AND PROVIDED A DETAILED PICTURE OF CLONAL EVOLUTION PROCESSES. THIS PHENOMENON, IN WHICH ABERRANT DNA METHYLATION CAN ALSO PARTICIPATE, APPEARS TO BE TIGHTLY ASSOCIATED TO POOR OUTCOMES AND CHEMO-REFRACTORINESS, THUS PROVIDING A NEW SUBJECT FOR THERAPEUTIC INTERVENTION. HENCE, AND HAVING IN MIND THE LIMITATIONS DERIVED FROM THE CLL COMPLEXITY THUS DESCRIBED, THE APPLICATION OF MASSIVELY PARALLEL SEQUENCING STUDIES HAS UNVEILED A WEALTH OF INFORMATION THAT IS EXPECTED TO SUBSTANTIALLY IMPROVE PATIENT STAGING SCHEMES AND CLL CLINICAL MANAGEMENT. 2015 11 3928 20 LIVER CELL CIRCUITS AND THERAPEUTIC DISCOVERY FOR ADVANCED LIVER DISEASE AND CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR GLOBAL HEALTH CHALLENGE WITH RISING INCIDENCE. DESPITE THE PREVIOUS APPROVAL OF SEVERAL NOVEL THERAPEUTIC APPROACHES, HCC REMAINS THE SECOND COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE VAST MAJORITY OF HCCS ARISES IN THE CONTEXT OF CHRONIC FIBROTIC LIVER DISEASES CAUSED BY VIRAL OR METABOLIC ETIOLOGIES. IN PATIENTS WITH ADVANCED LIVER DISEASE THE RISK OF HCC PERSISTS EVEN AFTER VIRAL CURE OR CONTROL OF INFECTION. MOREOVER, GIVEN THE CHANGE IN THE LIFESTYLE AND INCREASE OF OBESITY AND METABOLIC DISORDERS, HCC INCIDENCE IS PREDICTED TO DRASTICALLY AUGMENT IN THE NEXT DECADE. EARLY DETECTION, IMPROVEMENT OF THE SCREENING METHOD IN PATIENT AT-RISK AND DEVELOPMENT OF CHEMOPREVENTIVE STRATEGIES ARE THEREFORE URGENTLY NEEDED TO REDUCE HCC RISK. THIS REVIEW SUMMARIZES THE MAJOR CHALLENGES IN THE IDENTIFICATION OF PATIENT AT RISK FOR HCC AND THE EMERGENT STRATEGIES FOR HCC PREVENTION TO IMPROVE PATIENTS' OUTCOME. 2021 12 3089 27 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 13 3015 32 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 14 1481 21 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 15 467 26 ARE WE FINALLY GETTING PERSONAL? MOVING TOWARDS A PERSONALIZED APPROACH IN CHRONIC LYMPHOCYTIC LEUKEMIA. WITH ITS HETEROGENEOUS BIOLOGICAL FEATURES AND CLINICAL COURSE, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST FREQUENT ADULT LEUKEMIA IN THE WESTERN WORLD, IS A PARADIGMATIC CONDITION REQUIRING A TAILORED APPROACH AND A PRECISE KNOWLEDGE OF THE BIOLOGY BEHIND EACH INDIVIDUAL PATIENT. THIS PERSONALIZED MANAGEMENT IS BECOMING EVEN MORE CRUCIAL, SINCE, AFTER DECADES OF PRECLINICAL WORK UNRAVELLING THE KEY ROLE OF THE B-CELL RECEPTOR (BCR) SIGNALLING PATHWAYS AND THE ANTI-APOPTOTIC MECHANISMS IN CLL CELL SURVIVAL AND PROLIFERATION, WE HAVE NOW BCR AND BCL2 INHIBITORS AVAILABLE IN CLINICAL PRACTICE. THANKS TO THIS, WE ARE NOW ABLE TO EXPLOIT SPECIFIC BIOMARKERS TO TAILOR OUR TREATMENT STRATEGIES AND IMPROVE LONG-TERM DISEASE CONTROL, PATIENT OUTCOME AND QUALITY OF LIFE. THAT NOTWITHSTANDING, AS THE DISEASE ITSELF REMAINS INCURABLE, NOVEL CHALLENGES AND UNMET CLINICAL NEEDS HAVE RISEN FROM THE INTRODUCTION OF NOVEL TARGETED AGENTS, INCLUDING MECHANISMS OF RESISTANCE AT BOTH GENETIC AND EPIGENETIC LEVELS. IN THIS REVIEW, WE SUMMARIZE THE CURRENTLY ESTABLISHED PREDICTIVE BIOMARKERS (I.E. IGHV MUTATION STATUS AND TP53 GENE DISRUPTION) THAT SHOULD BE APPLIED IN CLINICAL PRACTICE TO INFORM TREATMENT DECISION IN 2021 BUT ALSO DISCUSS THE MOST PROMISING PROGNOSTIC BIOMARKERS (B-CELL RECEPTOR STEREOTYPY, COMPLEX KARYOTYPE, SOMATIC GENE MUTATIONS, MEASURABLE RESIDUAL DISEASE - MRD) THAT MIGHT BECOME KEY TO DEFINE THE MANAGEMENT OF OUR PATIENTS IN A NEAR FUTURE. 2022 16 6573 32 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES. 2020 17 1507 28 DNA METHYLATION AND INTRA-CLONAL HETEROGENEITY: THE CHRONIC MYELOID LEUKEMIA MODEL. CHRONIC MYELOID LEUKEMIA (CML) IS A MODEL TO INVESTIGATE THE IMPACT OF TUMOR INTRA-CLONAL HETEROGENEITY IN PERSONALIZED MEDICINE. INDEED, TYROSINE KINASE INHIBITORS (TKIS) TARGET THE BCR-ABL FUSION PROTEIN, WHICH IS CONSIDERED THE MAJOR CML DRIVER. TKI USE HAS HIGHLIGHTED THE EXISTENCE OF INTRA-CLONAL HETEROGENEITY, AS INDICATED BY THE PERSISTENCE OF A MINORITY SUBCLONE FOR SEVERAL YEARS DESPITE THE PRESENCE OF THE TARGET FUSION PROTEIN IN ALL CELLS. EPIGENETIC MODIFICATIONS COULD PARTLY EXPLAIN THIS HETEROGENEITY. THIS REVIEW SUMMARIZES THE RESULTS OF DNA METHYLATION STUDIES IN CML. NEXT-GENERATION SEQUENCING TECHNOLOGIES ALLOWED FOR MOVING FROM SINGLE-GENE TO GENOME-WIDE ANALYSES SHOWING THAT METHYLATION ABNORMALITIES ARE MUCH MORE WIDESPREAD IN CML CELLS. THESE DATA SHOWED THAT GLOBAL HYPOMETHYLATION IS ASSOCIATED WITH HYPERMETHYLATION OF SPECIFIC SITES ALREADY AT DIAGNOSIS IN THE EARLY PHASE OF CML. THE BCR-ABL-INDEPENDENCE OF SOME METHYLATION PROFILE ALTERATIONS AND THE RECENT DEMONSTRATION OF THE INITIAL INTRA-CLONAL DNA METHYLATION HETEROGENEITY SUGGESTS THAT SOME DNA METHYLATION ALTERATIONS MAY BE BIOMARKERS OF TKI SENSITIVITY/RESISTANCE AND OF DISEASE PROGRESSION RISK. THESE RESULTS ALSO OPEN PERSPECTIVES FOR UNDERSTANDING THE EPIGENETIC/GENETIC BACKGROUND OF CML PREDISPOSITION AND FOR DEVELOPING NEW THERAPEUTIC STRATEGIES. 2021 18 4142 30 MECHANISMS OF RESISTANCE TO TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA AND RECENT THERAPEUTIC STRATEGIES TO OVERCOME RESISTANCE. GIVEN ITS RELATIVE RARITY, IT MAY AT FIRST SEEM SURPRISING THAT CHRONIC MYELOID LEUKEMIA (CML) HAS GARNERED SO MUCH ATTENTION OVER THE LAST DECADE. YET, THE ADVANCES IN MOLECULAR PATHOGENESIS THAT HAVE BEEN DERIVED FROM STUDYING THIS LEUKEMIA HAVE CLEARLY BENEFITED ALL OF ONCOLOGY. MOREOVER, THE STRIDES IN DRUG DESIGN AND DEVELOPMENT THAT HAVE ALSO ENSUED AROUND CML HAVE GIVEN RISE TO WHAT OTHERS HAVE CALLED A MOLECULAR REVOLUTION IN CANCER THERAPY. WHILE A MAJORITY OF PATIENTS WITH CHRONIC PHASE CML (CP-CML) HAVE AN EXCELLENT DURABLE RESPONSE TO IMATINIB (GLEEVEC, NOVARTIS, BASEL, SWITZERLAND), A CLEAR MINORITY WILL UNFORTUNATELY HAVE SIGNS OF PRIMARY OR SECONDARY RESISTANCE TO THERAPY. SIGNIFICANT EFFORTS GEARED TOWARD UNDERSTANDING THE MOLECULAR MECHANISMS OF IMATINIB RESISTANCE HAVE YIELDED VALUABLE INSIGHTS INTO THE BIOLOGY OF DRUG TRAFFICKING INTO AND OUT OF CELLS, EPIGENETIC CONTROL OF CELLULAR PROCESSES, ALTERATIONS IN ENZYMATIC STRUCTURES, AND THE RATIONAL STRUCTURAL-BASED DESIGN OF SMALL MOLECULE ENZYME INHIBITORS. THIS REVIEW WILL DESCRIBE THE EFFORTS AT UNDERSTANDING THE PATHOGENESIS OF IMATINIB RESISTANCE AND THE MOLECULAR RATIONALE FOR THE DEVELOPMENT OF SECOND- AND NOW THIRD-GENERATION THERAPIES FOR PATIENTS WITH CML. 2009 19 2074 35 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 20 777 21 CELL-FREE CIRCULATING EPIGENOMIC SIGNATURES: NON-INVASIVE BIOMARKER FOR CARDIOVASCULAR AND OTHER AGE-RELATED CHRONIC DISEASES. THE BURDEN OF CARDIO-VASCULAR AND OTHER AGE-RELATED NON-COMMUNICABLE DISEASES ARE RAPIDLY INCREASING WORLDWIDE. MAJORITY OF THESE CHRONIC AILMENTS ARE CURABLE, IF DIAGNOSED AT EARLY STAGES. CANDIDATE BIOMARKERS OF EARLY DETECTION ARE THEREFORE ESSENTIAL FOR IDENTIFICATION OF HIGH-RISK INDIVIDUALS, PROMPT AND ACCURATE DISEASE DIAGNOSIS, AND TO MONITOR THERAPEUTIC RESPONSE. THE FUNCTIONAL SIGNIFICANCE OF CIRCULATING NUCLEIC ACIDS THAT RECAPITULATE SPECIFIC DISEASE PROFILES IS NOW WELL ESTABLISHED. BUT SUBTLE CHANGES IN DNA SEQUENCE MAY NOT SOLELY REFLECT THE DIFFERENTIATION OF GENE EXPRESSION PATTERNS OBSERVED IN DIVERSE SET OF DISEASES AS EPIGENETIC PHENOMENA PLAY A LARGER ROLE IN AETIOLOGY AND PATHO-PHYSIOLOGY. UNLIKE GENETIC MARKERS, KNOWLEDGE ABOUT THE DIAGNOSTIC UTILITY OF CIRCULATING EPIGENETIC SIGNATURES: METHYLATED DNA; MICRO RNA AND MODIFIED HISTONES ARE DEFICIENT. CHARACTERIZATION OF THESE NOVEL ENTITIES THROUGH OMICS-BASED MOLECULAR TECHNOLOGIES MIGHT PROMPT DEVELOPMENT OF A RANGE OF LABORATORY-BASED STRATEGIES, THEREBY ACCELERATING THEIR BROADER TRANSLATIONAL PURPOSE FOR EARLY DISEASE DIAGNOSIS, MONITORING THERAPEUTIC RESPONSE AND DRUG RESISTANCE. HOWEVER, LARGEST OPPORTUNITY FOR INNOVATION LIES IN DEVELOPING POINT-OF-CARE TESTS WITH ACCURATE DIAGNOSTIC AND HIGHER PROGNOSTIC SCORE THAT IS APPLICABLE FOR SCREENING OF HIGH-RISK POPULATIONS. 2017