1 4957 132 PATHOGENESIS OF ENDOMETRIOSIS: THE GENETIC/EPIGENETIC THEORY. OBJECTIVE: TO STUDY THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. DESIGN: OVERVIEW OF OBSERVATIONS ON ENDOMETRIOSIS. SETTING: NOT APPLICABLE. PATIENT(S): NONE. INTERVENTIONS(S): NONE. MAIN OUTCOME MEASURE(S): THE HYPOTHESIS IS COMPATIBLE WITH ALL OBSERVATIONS. RESULT(S): ENDOMETRIOSIS, ENDOMETRIUM-LIKE TISSUE OUTSIDE THE UTERUS, HAS A VARIABLE MACROSCOPIC APPEARANCE AND A POORLY UNDERSTOOD NATURAL HISTORY. IT IS A HEREDITARY AND HETEROGENEOUS DISEASE WITH MANY BIOCHEMICAL CHANGES IN THE LESIONS, WHICH ARE CLONAL IN ORIGIN. IT IS ASSOCIATED WITH PAIN, INFERTILITY, ADENOMYOSIS, AND CHANGES IN THE JUNCTIONAL ZONE, PLACENTATION, IMMUNOLOGY, PLASMA, PERITONEAL FLUID, AND CHRONIC INFLAMMATION OF THE PERITONEAL CAVITY. THE SAMPSON HYPOTHESIS OF IMPLANTED ENDOMETRIAL CELLS FOLLOWING RETROGRADE MENSTRUATION, ANGIOGENIC SPREAD, LYMPHOGENIC SPREAD, OR THE METAPLASIA THEORY CANNOT EXPLAIN ALL OBSERVATIONS IF METAPLASIA IS DEFINED AS CELLS WITH REVERSIBLE CHANGES AND AN ABNORMAL BEHAVIOR/MORPHOLOGY DUE TO THE ABNORMAL ENVIRONMENT. WE PROPOSE A POLYGENETIC/POLYEPIGENETIC MECHANISM. THE SET OF GENETIC AND EPIGENETIC INCIDENTS TRANSMITTED AT BIRTH COULD EXPLAIN THE HEREDITARY ASPECTS, THE PREDISPOSITION, AND THE ENDOMETRIOSIS-ASSOCIATED CHANGES IN THE ENDOMETRIUM, IMMUNOLOGY, AND PLACENTATION. TO DEVELOP TYPICAL, CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS, A VARIABLE SERIES OF ADDITIONAL TRANSMISSIBLE GENETIC AND EPIGENETIC INCIDENTS ARE REQUIRED TO OCCUR IN A CELL WHICH MAY VARY FROM ENDOMETRIAL TO STEM CELLS. SUBTLE LESIONS ARE VIEWED AS ENDOMETRIUM IN A DIFFERENT ENVIRONMENT UNTIL ADDITIONAL INCIDENTS OCCUR. TYPICAL CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS ARE HETEROGENEOUS AND REPRESENT THREE DIFFERENT DISEASES. CONCLUSION(S): THE GENETIC EPIGENETIC THEORY IS COMPATIBLE WITH ALL OBSERVATIONS ON ENDOMETRIOSIS. IMPLICATIONS FOR TREATMENT AND PREVENTION ARE DISCUSSED. 2019 2 1958 26 EPIGENETIC AGING AND COLORECTAL CANCER: STATE OF THE ART AND PERSPECTIVES FOR FUTURE RESEARCH. ALTHOUGH TRANSLATIONAL RESEARCH HAS IDENTIFIED A LARGE NUMBER OF POTENTIAL BIOMARKERS INVOLVED IN COLORECTAL CANCER (CRC) CARCINOGENESIS, A BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS ASSOCIATED WITH BIOLOGICAL AGING IN COLORECTAL CELLS AND TISSUES IS NEEDED. HERE, WE AIM TO SUMMARIZE THE STATE OF THE ART ABOUT THE ROLE OF AGE ACCELERATION, DEFINED AS THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IN THE DEVELOPMENT AND PROGRESSION OF CRC. SOME STUDIES HAVE SHOWN THAT ACCELERATED BIOLOGICAL AGING IS POSITIVELY ASSOCIATED WITH THE RISK OF CANCER AND DEATH IN GENERAL. IN LINE WITH THESE FINDINGS, OTHER STUDIES HAVE SHOWN HOW THE ASSESSMENT OF EPIGENETIC AGE IN PEOPLE AT RISK FOR CRC COULD BE HELPFUL FOR MONITORING THE MOLECULAR RESPONSE TO PREVENTIVE INTERVENTIONS. MOREOVER, IT WOULD BE INTERESTING TO INVESTIGATE WHETHER ABERRANT EPIGENETIC AGING COULD HELP IDENTIFY CRC PATIENTS WITH A HIGH RISK OF RECURRENCE AND A WORST PROGNOSIS, AS WELL AS THOSE WHO RESPOND POORLY TO TREATMENT. YET, THE APPLICATION OF THIS NOVEL CONCEPT IS STILL IN ITS INFANCY, AND FURTHER RESEARCH SHOULD BE ENCOURAGED IN ANTICIPATION OF FUTURE APPLICATIONS IN CLINICAL PRACTICE. 2020 3 3743 46 INSIGHTS FROM GENOMIC STUDIES ON THE ROLE OF SEX STEROIDS IN THE AETIOLOGY OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC NEURO-INFLAMMATORY DISORDER THE DEFINING FEATURE OF WHICH IS THE GROWTH OF TISSUE (LESIONS) THAT RESEMBLES THE ENDOMETRIUM OUTSIDE THE UTERUS. ESTIMATES OF PREVALENCE QUOTE RATES OF ~10% OF WOMEN OF REPRODUCTIVE AGE, EQUATING TO AT LEAST 190 MILLION WOMEN WORLD-WIDE. GENETIC, HORMONAL AND IMMUNOLOGICAL FACTORS HAVE ALL BEEN PROPOSED AS CONTRIBUTING TO RISK FACTORS ASSOCIATED WITH THE DEVELOPMENT OF LESIONS. TWIN STUDIES REPORT THE HERITABLE COMPONENT OF ENDOMETRIOSIS AS ~50%. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT APPEAR OVER-REPRESENTED IN PATIENTS WITH ENDOMETRIOSIS, PARTICULARLY THOSE WITH MORE EXTENSIVE DISEASE (STAGE III/IV). IN DIFFERENT SAMPLE POPULATIONS, THERE HAS BEEN REPLICATION OF SNPS NEAR GENES INVOLVED IN OESTROGEN AND OTHER STEROID REGULATED PATHWAYS INCLUDING ESR1 (OESTROGEN RECEPTOR ALPHA), GREB1, HOXA10, WNT4 AND MAPK KINASE SIGNALLING. COMPARISONS WITH GWAS CONDUCTED ON OTHER PATIENT COHORTS HAVE FOUND LINKS WITH REPRODUCTIVE TRAITS (AGE AT MENARCHE) AND DISORDERS (FIBROIDS, ENDOMETRIAL AND OVARIAN CANCER) AND COMMON CO-MORBIDITIES (MIGRAINE, DEPRESSION, ASTHMA). IN SUMMARY, GENETIC ANALYSES HAVE PROVIDED NEW INSIGHTS INTO THE HORMONE-REGULATED PATHWAYS THAT MAY CONTRIBUTE TO INCREASED RISK OF DEVELOPING ENDOMETRIOSIS SOME OF WHICH MAY ACT IN EARLY LIFE. NEW STUDIES ARE NEEDED TO CLARIFY THE RELATIONSHIP BETWEEN THE MANY SNPS IDENTIFIED, THE GENES THAT THEY REGULATE AND THEIR CONTRIBUTION(S) TO DEVELOPMENT OF DIFFERENT FORMS OF ENDOMETRIOSIS. WE HOPE THAT MORE ADVANCED METHODS ALLOWING INTEGRATION BETWEEN GWAS, EPIGENETIC AND TISSUE EXPRESSION DATA WILL IMPROVE RISK ANALYSIS AND REDUCE DIAGNOSITIC DELAY. LAY SUMMARY: ENDOMETRIOSIS IS A DEBILITATING REPRODUCTIVE DISORDER AFFECTING ~10% OF REPRODUCTIVE-AGE WOMEN, AND THOSE ASSIGNED FEMALE AT BIRTH, WHICH CAUSES A RANGE OF SYMPTOMS INCLUDING CHRONIC PAIN AND INFERTILITY. THE REASON WHY SOME, BUT NOT ALL THESE INDIVIDUALS, DEVELOP THE LESIONS THAT CHARACTERISE THE DISEASE ARE POORLY UNDERSTOOD, BUT RECENTLY ATTENTION HAS FOCUSED ON GENETIC RISK FACTORS TO EXPLAIN WHY THE INCIDENCE IS HIGHER IN SOME FAMILIES. STUDIES ON LARGE COHORTS OF PATIENTS WITH COMPARISON OF THEIR DNA TO WOMEN WITHOUT ENDOMETRIOSIS OR WITH OTHER DISORDERS HAVE DOCUMENTED CHANGES IN GENES ASSOCIATED WITH STEROID HORMONE PRODUCTION OR ACTION. THE RESULTS PROVIDE FURTHER EVIDENCE THAT ENDOMETRIOSIS SHARES GENETIC RISK FACTORS WITH OTHER DISORDERS OF THE REPRODUCTIVE SYSTEM AND A PLATFORM FOR NEW IDEAS RELATED TO RISK, BIOMARKERS AND THERAPIES. 2022 4 1516 31 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL. 2018 5 6237 37 THE MAIN THEORIES ON THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A COMPLEX DISEASE, WHICH IS DEFINED BY ABNORMAL GROWTH OF ENDOMETRIAL TISSUE OUTSIDE THE UTERUS. IT AFFECTS ABOUT 10% OF WOMEN OF REPRODUCTIVE AGE ALL OVER THE WORLD. ENDOMETRIOSIS CAUSES SYMPTOMS THAT NOTABLY WORSEN PATIENT'S WELL-BEING-SUCH AS SEVERE PELVIC PAIN, DYSFUNCTION OF THE ORGANS OF PELVIC CAVITY, INFERTILITY AND SECONDARY MENTAL ISSUES. THE DIAGNOSIS OF ENDOMETRIOSIS IS QUITE OFTEN DELAYED BECAUSE OF NONSPECIFIC MANIFESTATIONS. SINCE THE DISEASE WAS DEFINED, SEVERAL DIFFERENT PATHOGENETIC PATHWAYS HAVE BEEN CONSIDERED, INCLUDING RETROGRADE MENSTRUATION, BENIGN METASTASIS, IMMUNE DYSREGULATION, COELOMIC METAPLASIA, HORMONAL DISBALANCE, INVOLVEMENT OF STEM CELLS AND ALTERATIONS IN EPIGENETIC REGULATION, BUT THE TRUE PATHOGENESIS OF ENDOMETRIOSIS REMAINS POORLY UNDERSTOOD. THE KNOWLEDGE OF THE EXACT MECHANISM OF THE ORIGIN AND PROGRESSION OF THIS DISEASE IS SIGNIFICANT FOR THE APPROPRIATE TREATMENT. THEREFORE, THIS REVIEW REPORTS THE MAIN PATHOGENETIC THEORIES OF ENDOMETRIOSIS BASED ON CURRENT STUDIES. 2023 6 6054 34 THE CURRENT STATE AND FUTURE OF T-CELL EXHAUSTION RESEARCH. 'EXHAUSTION' IS A TERM USED TO DESCRIBE A STATE OF NATIVE AND REDIRECTED T-CELL HYPO-RESPONSIVENESS RESULTING FROM PERSISTENT ANTIGEN EXPOSURE DURING CHRONIC VIRAL INFECTIONS OR CANCER. ALTHOUGH A WELL-ESTABLISHED PHENOTYPE ACROSS MICE AND HUMANS, EXHAUSTION AT THE MOLECULAR LEVEL REMAINS POORLY DEFINED AND INCONSISTENT ACROSS THE LITERATURE. THIS IS, IN PART, DUE TO AN OVERRELIANCE ON SURFACE RECEPTORS TO DEFINE THESE CELLS AND EXPLAIN EXHAUSTIVE BEHAVIOURS, AN INCOMPLETE UNDERSTANDING OF HOW EXHAUSTION ARISES, AND A LACK OF CLARITY OVER WHETHER EXHAUSTION IS THE SAME ACROSS CONTEXTS, E.G. CHRONIC VIRAL INFECTIONS VERSUS CANCER. WITH THE DEVELOPMENT OF SYSTEMS-BASED GENETIC APPROACHES SUCH AS SINGLE-CELL RNA-SEQ AND CRISPR SCREENS APPLIED TO IN VIVO DATA, WE ARE MOVING CLOSER TO A CONSENSUS VIEW OF EXHAUSTION, ALTHOUGH UNDERSTANDING HOW IT ARISES REMAINS CHALLENGING GIVEN THE DIFFICULTY IN MANIPULATING THE IN VIVO SETTING. ACCORDINGLY, PRODUCING AND STUDYING EXHAUSTED T-CELLS EX VIVO ARE BURGEONING, ALLOWING EXPERIMENTS TO BE CONDUCTED AT SCALE UP AND WITH HIGH THROUGHPUT. HERE, WE FIRST REVIEW WHAT IS CURRENTLY KNOWN ABOUT T-CELL EXHAUSTION AND HOW IT'S BEING STUDIED. WE THEN DISCUSS HOW IMPROVEMENTS IN THEIR METHOD OF ISOLATION/PRODUCTION AND EXAMINING THE IMPACT OF DIFFERENT MICROENVIRONMENTAL SIGNALS AND CELL INTERACTIONS HAVE NOW BECOME AN ACTIVE AREA OF RESEARCH. FINALLY, WE DISCUSS WHAT THE FUTURE HOLDS FOR THE ANALYSIS OF THIS PHYSIOLOGICAL CONDITION AND, GIVEN THE DIVERSITY OF WAYS IN WHICH EXHAUSTED CELLS ARE NOW BEING GENERATED, PROPOSE THE ADOPTION OF A UNIFIED APPROACH TO CLEARLY DEFINING EXHAUSTION USING A SET OF METABOLIC-, EPIGENETIC-, TRANSCRIPTIONAL-, AND ACTIVATION-BASED PHENOTYPIC MARKERS, THAT WE CALL 'M.E.T.A'. 2023 7 2275 38 EPIGENETIC REGULATION AND T-CELL RESPONSES IN ENDOMETRIOSIS - SOMETHING OTHER THAN AUTOIMMUNITY. ENDOMETRIOSIS IS DEFINED AS THE PRESENCE OF ENDOMETRIAL-LIKE GLANDS AND STROMA LOCATED OUTSIDE THE UTERINE CAVITY. THIS COMMON, ESTROGEN DEPENDENT, INFLAMMATORY CONDITION AFFECTS UP TO 15% OF REPRODUCTIVE-AGED WOMEN AND IS A WELL-RECOGNIZED CAUSE OF CHRONIC PELVIC PAIN AND INFERTILITY. DESPITE THE STILL UNKNOWN ETIOLOGY OF ENDOMETRIOSIS, MUCH EVIDENCE SUGGESTS THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE DISEASE ETIOPATHOGENESIS. THE MAIN RATIONALE IS BASED ON THE FACT THAT HERITABLE PHENOTYPE CHANGES THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE ARE COMMON TRIGGERS FOR HORMONAL, IMMUNOLOGICAL, AND INFLAMMATORY DISORDERS, WHICH PLAY A KEY ROLE IN THE FORMATION OF ENDOMETRIOTIC FOCI. EPIGENETIC MECHANISMS REGULATING T-CELL RESPONSES, INCLUDING DNA METHYLATION AND POSTTRANSLATIONAL HISTONE MODIFICATIONS, DESERVE ATTENTION BECAUSE TISSUE-RESIDENT T LYMPHOCYTES WORK IN CONCERT WITH ORGAN STRUCTURAL CELLS TO GENERATE APPROPRIATE IMMUNE RESPONSES AND ARE FUNCTIONALLY SHAPED BY ORGAN-SPECIFIC ENVIRONMENTAL CONDITIONS. THUS, A FAILURE TO PRECISELY REGULATE IMMUNE CELL TRANSCRIPTION MAY RESULT IN COMPROMISED IMMUNOLOGICAL INTEGRITY OF THE ORGAN WITH AN INCREASED RISK OF INFLAMMATORY DISORDERS. THE COEXISTENCE OF ENDOMETRIOSIS AND AUTOIMMUNITY IS A WELL-KNOWN OCCURRENCE. RECENT RESEARCH RESULTS INDICATE REGULATORY T-CELL (TREG) ALTERATIONS IN ENDOMETRIOSIS, AND AN INCREASED NUMBER OF HIGHLY ACTIVE TREGS AND MACROPHAGES HAVE BEEN FOUND IN PERITONEAL FLUID FROM WOMEN WITH ENDOMETRIOSIS. ELIMINATION OF THE REGULATORY FUNCTION OF T CELLS AND AN IMBALANCE BETWEEN T HELPER CELLS OF THE TH1 AND TH2 TYPES HAVE BEEN REPORTED IN THE ENDOMETRIA OF WOMEN WITH ENDOMETRIOSIS-ASSOCIATED INFERTILITY. THIS REVIEW AIMS TO PRESENT THE STATE OF THE ART IN RECOGNITION EPIGENETIC REPROGRAMMING OF T CELLS AS THE KEY FACTOR IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS IN THE CONTEXT OF T-CELL-RELATED AUTOIMMUNITY. THE NEW POTENTIAL THERAPEUTIC APPROACHES BASED ON EPIGENETIC MODULATION AND/OR ADOPTIVE TRANSFER OF T CELLS WILL ALSO BE OUTLINED. 2022 8 6031 24 THE CANCER EPIGENOME: ITS ORIGINS, CONTRIBUTIONS TO TUMORIGENESIS, AND TRANSLATIONAL IMPLICATIONS. EPIGENETIC ABNORMALITIES IN LUNG AND OTHER CANCERS CONTINUE TO BE DEFINED AT A RAPID PACE. WE ARE COMING TO APPRECIATE THAT CANCERS HAVE AN "EPIGENETIC LANDSCAPE" WHEREIN GENES VULNERABLE TO ABNORMALITIES, SUCH AS PROMOTER DNA HYPERMETHYLATION AND ASSOCIATED GENE SILENCING, TEND TO RESIDE IN DEFINED NUCLEAR POSITIONS AND CHROMOSOME DOMAINS AND RELATIONSHIPS TO CHROMATIN REGULATION, WHICH FACILITATES STATES OF STEM CELL RENEWAL. THESE SAME GENES AND DOMAINS ARE ALSO VULNERABLE TO EPIGENETIC ABNORMALITIES INDUCED BY FACTORS TO WHICH CELLS ARE EXPOSED DURING CANCER RISK STATES, SUCH AS CHRONIC INFLAMMATION. WE CAN USE ALL OF THIS BASIC INFORMATION FOR TRANSLATIONAL PURPOSES IN TERMS OF DERIVING BIOMARKERS FOR CANCER RISK STATES AND DETECTION AND THERAPEUTIC STRATEGIES. 2012 9 728 34 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 10 605 32 BEYOND ENDOMETRIOSIS GENOME-WIDE ASSOCIATION STUDY: FROM GENOMICS TO PHENOMICS TO THE PATIENT. ENDOMETRIOSIS IS A HERITABLE, COMPLEX CHRONIC INFLAMMATORY DISEASE, FOR WHICH MUCH OF THE CAUSAL PATHOGENIC MECHANISM REMAINS UNKNOWN. GENOME-WIDE ASSOCIATION STUDIES (GWAS) TO DATE HAVE IDENTIFIED 12 SINGLE NUCLEOTIDE POLYMORPHISMS AT 10 INDEPENDENT GENETIC LOCI ASSOCIATED WITH ENDOMETRIOSIS. MOST OF THESE WERE MORE STRONGLY ASSOCIATED WITH REVISED AMERICAN FERTILITY SOCIETY STAGE III/IV, RATHER THAN STAGE I/II. THE LOCI ARE ALMOST ALL LOCATED IN INTERGENIC REGIONS THAT ARE KNOWN TO PLAY A ROLE IN THE REGULATION OF EXPRESSION OF TARGET GENES YET TO BE IDENTIFIED. TO IDENTIFY THE TARGET GENES AND PATHWAYS PERTURBED BY THE IMPLICATED VARIANTS, STUDIES ARE REQUIRED INVOLVING FUNCTIONAL GENOMIC ANNOTATION OF THE SURROUNDING CHROMOSOMAL REGIONS, IN TERMS OF TRANSCRIPTION FACTOR BINDING, EPIGENETIC MODIFICATION (E.G., DNA METHYLATION AND HISTONE MODIFICATION) SITES, AS WELL AS THEIR CORRELATION WITH RNA TRANSCRIPTION. THESE STUDIES NEED TO BE CONDUCTED IN TISSUE TYPES RELEVANT TO ENDOMETRIOSIS-IN PARTICULAR, ENDOMETRIUM. IN ADDITION, TO ALLOW BIOLOGICALLY AND CLINICALLY RELEVANT INTERPRETATION OF MOLECULAR PROFILING DATA, THEY NEED TO BE COMBINED AND CORRELATED WITH DETAILED, SYSTEMATICALLY COLLECTED PHENOTYPIC INFORMATION (SURGICAL AND CLINICAL). THE WERF ENDOMETRIOSIS PHENOME AND BIOBANKING HARMONISATION PROJECT IS A GLOBAL STANDARDIZATION INITIATIVE THAT HAS PRODUCED CONSENSUS DATA AND SAMPLE COLLECTION PROTOCOLS FOR ENDOMETRIOSIS RESEARCH. THESE NOW PAVE THE WAY FOR COLLABORATIVE STUDIES INTEGRATING PHENOMIC WITH GENOMIC DATA, TO IDENTIFY INFORMATIVE SUBTYPES OF ENDOMETRIOSIS THAT WILL ENHANCE UNDERSTANDING OF THE PATHOGENIC MECHANISMS OF THE DISEASE AND DISCOVERY OF NOVEL, TARGETED TREATMENTS. 2016 11 6116 24 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS. 2022 12 1206 21 COUNTERACTING AGED DNA METHYLATION STATES TO COMBAT AGEING AND AGE-RELATED DISEASES. DNA METHYLATION (DNAM) OVERWRITES INFORMATION ABOUT MULTIPLE EXTRINSIC FACTORS ON THE GENOME. AGE IS ONE OF THESE FACTORS. AGE CAUSES CHARACTERISTIC DNAM CHANGES THAT ARE THOUGHT TO BE NOT ONLY MAJOR DRIVERS OF NORMAL AGEING BUT ALSO PRECURSORS TO DISEASES, CANCER BEING ONE OF THESE. ALTHOUGH THERE IS STILL MUCH TO LEARN ABOUT THE RELATIONSHIP BETWEEN AGEING, AGE-RELATED DISEASES AND DNAM, WE NOW KNOW HOW TO INTERPRET SOME OF THE EFFECTS CAUSED BY AGE IN THE FORM OF CHANGES IN METHYLATION MARKS AT SPECIFIC LOCI. IN FACT, THESE CHANGES FORM THE BASIS OF THE SO CALLED "EPIGENETIC CLOCKS", WHICH TRANSLATE THE GENOMIC METHYLATION PROFILE INTO AN "EPIGENETIC AGE". EPIGENETIC AGE DOES NOT ONLY ESTIMATE CHRONOLOGICAL AGE BUT CAN ALSO PREDICT THE RISK OF CHRONIC DISEASES AND MORTALITY. EPIGENETIC AGE IS BELIEVED TO BE ONE OF THE MOST ACCURATE METRICS OF BIOLOGICAL AGE. INITIAL EVIDENCE HAS RECENTLY BEEN GATHERED POINTING TO THE POSSIBILITY THAT THE RATE OF EPIGENETIC AGEING CAN BE SLOWED DOWN OR EVEN REVERSED. IN THIS REVIEW, WE DISCUSS SOME OF THE MOST RELEVANT ADVANCES IN THIS FIELD. EXPECTED OUTCOME IS THAT THIS APPROACH CAN PROVIDE INSIGHTS INTO HOW TO PRESERVE HEALTH AND REDUCE THE IMPACT OF AGEING DISEASES IN HUMANS. 2022 13 3003 42 GENETIC, EPIGENETIC AND STEM CELL ALTERATIONS IN ENDOMETRIOSIS: NEW INSIGHTS AND POTENTIAL THERAPEUTIC PERSPECTIVES. HUMAN ENDOMETRIUM IS A HIGHLY DYNAMIC TISSUE, UNDERGOING PERIODIC GROWTH AND REGRESSION AT EACH MENSTRUAL CYCLE. ENDOMETRIOSIS IS A FREQUENT CHRONIC PATHOLOGICAL STATUS CHARACTERIZED BY ENDOMETRIAL TISSUE WITH AN ECTOPIC LOCALIZATION, CAUSING PELVIC PAIN AND INFERTILITY AND A VARIABLE CLINICAL PRESENTATION. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION IN APPROXIMATELY 1.0% OF AFFECTED WOMEN, WITH THE INVOLVEMENT OF MULTIPLE PATHWAYS OF DEVELOPMENT. INCREASING EVIDENCE SUPPORTS A KEY CONTRIBUTION OF DIFFERENT STEM/PROGENITOR CELL POPULATIONS NOT ONLY IN THE CYCLIC REGENERATION OF EUTOPIC ENDOMETRIUM, BUT ALSO IN THE PATHOGENESIS OF AT LEAST SOME TYPES OF ENDOMETRIOSIS. EVIDENCE HAS ARISEN FROM EXPERIMENTS IN ANIMAL MODELS OF DISEASE THROUGH DIFFERENT KINDS OF ASSAYS (INCLUDING CLONOGENICITY, THE LABEL-RETAINING CELL APPROACH, THE ANALYSIS OF UNDIFFERENTIATION MARKERS), AS WELL AS FROM DESCRIPTIVE STUDIES ON ECTOPIC AND EUTOPIC TISSUE SAMPLES HARVESTED FROM AFFECTED WOMEN. CHANGES IN STEM CELL POPULATIONS IN ENDOMETRIOTIC LESIONS ARE ASSOCIATED WITH GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING IMBALANCE OF MIRNA EXPRESSION, HISTONE AND DNA MODIFICATIONS AND CHROMOSOMAL ABERRATIONS. THE PRESENT SHORT REVIEW MAINLY SUMMARIZES THE LATEST OBSERVATIONS CONTRIBUTING TO THE CURRENT KNOWLEDGE REGARDING THE PRESENCE AND THE POTENTIAL CONTRIBUTION OF STEM/PROGENITOR CELLS IN EUTOPIC ENDOMETRIUM AND THE AETIOLOGY OF ENDOMETRIOSIS, TOGETHER WITH A REPORT OF THE MOST RECENTLY IDENTIFIED GENETIC AND EPIGENETIC ALTERATIONS IN ENDOMETRIOSIS. WE ALSO DESCRIBE THE POTENTIAL ADVANTAGES OF SINGLE CELL MOLECULAR PROFILING IN ENDOMETRIUM AND IN ENDOMETRIOTIC LESIONS. ALL THESE DATA CAN HAVE CLINICAL IMPLICATIONS AND PROVIDE A BASIS FOR NEW POTENTIAL THERAPEUTIC APPLICATIONS. 2014 14 1028 37 CIRCULATING MIRNAS RELATED TO EPITHELIAL-MESENCHYMAL TRANSITIONS (EMT) AS THE NEW MOLECULAR MARKERS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC GYNECOLOGICAL DISEASE DEFINED BY THE PRESENCE OF ENDOMETRIAL-LIKE TISSUE FOUND OUTSIDE THE UTERUS, MOST COMMONLY IN THE PERITONEAL CAVITY. ENDOMETRIOSIS LESIONS ARE HETEROGENOUS BUT USUALLY CONTAIN ENDOMETRIAL STROMAL CELLS AND EPITHELIAL GLANDS, IMMUNE CELL INFILTRATES AND ARE VASCULARIZED AND INNERVATED BY NERVES. THE COMPLEX ETIOPATHOGENESIS AND HETEROGENITY OF THE CLINICAL SYMPTOMS, AS WELL AS THE LACK OF A SPECIFIC NON-INVASIVE DIAGNOSTIC BIOMARKERS, UNDERLINE THE NEED FOR MORE ADVANCED DIAGNOSTIC TOOLS. UNFORTUNATELY, THE CONTRIBUTION OF ENVIRONMENTAL, HORMONAL AND IMMUNOLOGICAL FACTORS IN THE DISEASE ETIOLOGY IS INSUFFICIENT, AND THE CONTRIBUTION OF GENETIC/EPIGENETIC FACTORS IS STILL FRAGMENTARY. THEREFORE, THERE IS A NEED FOR MORE FOCUSED STUDY ON THE MOLECULAR MECHANISMS OF ENDOMETRIOSIS AND NON-INVASIVE DIAGNOSTIC MONITORING SYSTEMS. MICRORNAS (MIRNAS) DEMONSTRATE HIGH STABILITY AND TISSUE SPECIFICITY AND PLAY A SIGNIFICANT ROLE IN MODULATING A RANGE OF MOLECULAR PATHWAYS, AND HENCE MAY BE SUITABLE DIAGNOSTIC BIOMARKERS FOR THE ORIGIN AND DEVELOPMENT OF ENDOMETRIOSIS. OF THESE, THE MOST FREQUENTLY STUDIED ARE THOSE RELATED TO ENDOMETRIOSIS, INCLUDING THOSE INVOLVED IN EPITHELIAL-MESENCHYMAL TRANSITION (EMT), WHOSE EXPRESSION IS ALTERED IN PLASMA OR ENDOMETRIOTIC LESION BIOPSIES; HOWEVER, THE RESULTS ARE AMBIGUOUS. SPECIFIC MIRNAS EXPRESSED IN ENDOMETRIOSIS MAY SERVE AS DIAGNOSTICS MARKERS WITH PROGNOSTIC VALUE, AND THEY HAVE BEEN PROPOSED AS MOLECULAR TARGETS FOR TREATMENT. THE AIM OF THIS REVIEW IS TO PRESENT SELECTED MIRNAS ASSOCIATED WITH EMT KNOWN TO HAVE EXPERIMENTALLY CONFIRMED SIGNIFICANCE, AND DISCUSS THEIR UTILITY AS BIOMARKERS IN ENDOMETRIOSIS. 2021 15 2651 26 EPIGENOMICS AND TRANSCRIPTOMICS IN THE PREDICTION AND DIAGNOSIS OF CHILDHOOD ASTHMA: ARE WE THERE YET? ASTHMA IS THE MOST COMMON NON-COMMUNICABLE CHRONIC DISEASE OF CHILDHOOD. DESPITE ITS HIGH PREVALENCE, TO DATE WE LACK METHODS THAT ARE BOTH EFFICIENT AND ACCURATE IN DIAGNOSING ASTHMA. MOST TRADITIONAL APPROACHES HAVE BEEN BASED ON GARNERING CLINICAL EVIDENCE, SUCH AS RISK FACTORS AND EXPOSURES. GIVEN THE HIGH HERITABILITY OF ASTHMA, MORE RECENT APPROACHES HAVE LOOKED AT GENETIC POLYMORPHISMS AS POTENTIAL "RISK FACTORS." HOWEVER, GENETIC VARIANTS EXPLAIN ONLY A SMALL PROPORTION OF ASTHMA RISK, AND HAVE BEEN LESS THAN OPTIMAL AT PREDICTING RISK FOR INDIVIDUAL SUBJECTS. EPIGENOMIC STUDIES OFFER SIGNIFICANT ADVANTAGES OVER PREVIOUS APPROACHES. EPIGENETIC REGULATION IS HIGHLY TISSUE-SPECIFIC, AND CAN INDUCE BOTH SHORT- AND LONG-TERM CHANGES IN GENE EXPRESSION. SUCH CHANGES CAN START IN UTERO, CAN VARY THROUGHOUT THE LIFE SPAN, AND IN SOME INSTANCES CAN BE PASSED ON FROM ONE GENERATION TO ANOTHER. MOST IMPORTANTLY, THE EPIGENOME CAN BE MODIFIED BY ENVIRONMENTAL FACTORS AND EXPOSURES, AND THUS EPIGENETIC AND TRANSCRIPTOMIC PROFILING MAY YIELD THE MOST ACCURATE RISK ESTIMATES FOR A GIVEN PATIENT BY INCORPORATING ENVIRONMENTAL (AND TREATMENT) EFFECTS THROUGHOUT THE LIFESPAN. HERE WE WILL REVIEW THE MOST RECENT ADVANCES IN THE USE OF EPIGENETIC AND TRANSCRIPTOMIC ANALYSIS FOR THE EARLY DIAGNOSIS OF ASTHMA AND ATOPY, AS WELL AS CHALLENGES AND FUTURE DIRECTIONS IN THE FIELD AS IT MOVES FORWARD. WE WILL PARTICULARLY FOCUS ON DNA METHYLATION, THE MOST STUDIED MECHANISM OF EPIGENETIC REGULATION. 2019 16 5378 26 RECENT INSIGHTS ON THE GENETICS AND EPIGENETICS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A GYNECOLOGIC DISEASE AFFECTING UP TO 10% OF THE WOMEN AND A MAJOR CAUSE OF PAIN AND INFERTILITY. IT IS CHARACTERIZED BY THE IMPLANTATION OF FUNCTIONAL ENDOMETRIAL TISSUE AT ECTOPIC POSITIONS GENERALLY WITHIN THE PERITONEUM. THIS COMPLEX DISEASE HAS AN IMPORTANT GENETIC COMPONENT WITH A HERITABILITY ESTIMATED AT AROUND 50%. THIS REVIEW AIMS AT PROVIDING RECENT INSIGHTS INTO THE GENETIC BASES OF ENDOMETRIOSIS, AND PRESENTS A DETAILED OVERVIEW OF EVIDENCE OF EPIGENETIC ALTERATIONS SPECIFIC TO THIS DISEASE. IN THE FUTURE, THESE ALTERATIONS MAY CONSTITUTE THERAPEUTIC TARGETS FOR PHARMACOLOGICAL COMPOUNDS ABLE TO MODIFY THE EPIGENETIC CODE. 2017 17 3653 19 INDIVIDUAL EPIGENETIC VARIATION: WHEN, WHY, AND SO WHAT? EPIGENETICS PROVIDES A POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL FACTORS MODIFY THE RISK FOR COMMON DISEASES AMONG INDIVIDUALS. INTERINDIVIDUAL VARIATION IN DNA METHYLATION AND EPIGENETIC REGULATION HAS BEEN REPORTED AT SPECIFIC GENOMIC REGIONS INCLUDING TRANSPOSABLE ELEMENTS, GENOMICALLY IMPRINTED GENES AND THE 'INACTIVE' X CHROMOSOMES IN FEMALES. WE CURRENTLY HAVE A VERY POOR UNDERSTANDING OF THE FACTORS THAT CONTRIBUTE TO INTERINDIVIDUAL EPIGENETIC VARIATION. IN PARTICULAR, IT IS IMPORTANT TO UNDERSTAND WHEN DURING THE LIFE CYCLE EPIGENETIC VARIATION ARISES, WHY EPIGENETIC REGULATION VARIES AMONG INDIVIDUALS, AND WHETHER EPIGENETIC INTERINDIVIDUALITY AFFECTS SUSCEPTIBILITY TO DIET-RELATED CHRONIC DISEASE. IN THIS REVIEW WE WILL SUMMARIZE CURRENT PROGRESS TOWARD ANSWERING THESE QUESTIONS. 2008 18 186 24 ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL CELLS AND CANCER RISK. CANCERS DEVELOP DUE TO THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. GENETIC ALTERATIONS ARE INDUCED BY AGING, MUTAGENIC CHEMICALS, ULTRAVIOLET LIGHT, AND OTHER FACTORS; WHEREAS, EPIGENETIC ALTERATIONS ARE MAINLY BY AGING AND CHRONIC INFLAMMATION. THE ACCUMULATION AND PATTERNS OF ALTERATIONS IN NORMAL CELLS REFLECT OUR PAST EXPOSURE LEVELS AND LIFE HISTORY. MOST ACCUMULATED ALTERATIONS ARE CONSIDERED AS PASSENGERS, BUT THEIR ACCUMULATION IS CORRELATED WITH CANCER DRIVERS. THIS HAS BEEN SHOWN FOR ABERRANT DNA METHYLATION BUT HAS ONLY BEEN SPECULATED FOR GENETIC ALTERATIONS. HOWEVER, RECENT TECHNOLOGICAL ADVANCEMENTS HAVE ENABLED MEASUREMENT OF RARE POINT MUTATIONS, AND STUDIES HAVE SHOWN THAT THEIR ACCUMULATION LEVELS ARE INDEED CORRELATED WITH CANCER RISK. WHEN THE ACCUMULATION LEVELS OF ABERRANT DNA METHYLATION AND POINT MUTATIONS ARE COMBINED, RISK PREDICTION BECOMES EVEN MORE ACCURATE. WHEN HIGH LEVELS OF ALTERATIONS ACCUMULATE, THE TISSUE HAS A HIGH RISK OF DEVELOPING CANCER OR EVEN MULTIPLE CANCERS AND IS CONSIDERED AS A "CANCERIZATION FIELD", WITH OR WITHOUT EXPANSION OF PHYSIOLOGICAL PATCHES OF CLONAL CELLS. IN THIS REVIEW, WE DESCRIBE THE FORMATION OF A CANCERIZATION FIELD AND HOW WE CAN APPLY ITS DETECTION IN PRECISION CANCER RISK DIAGNOSIS. 2019 19 777 26 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 20 1546 24 DNA METHYLATION IN NASAL EPITHELIUM: STRENGTHS AND LIMITATIONS OF AN EMERGENT BIOMARKER FOR CHILDHOOD ASTHMA. ASTHMA IS ONE OF THE MOST WIDESPREAD CHRONIC RESPIRATORY CONDITIONS. THIS DISEASE PRIMARILY DEVELOPS IN CHILDHOOD AND IS INFLUENCED BY DIFFERENT FACTORS, MAINLY GENETICS AND ENVIRONMENTAL FACTORS. DNA METHYLATION IS AN EPIGENETIC MECHANISM WHICH MAY REPRESENT A BRIDGE BETWEEN THESE TWO FACTORS, PROVIDING A TOOL TO COMPREHEND THE INTERACTION BETWEEN GENETICS AND ENVIRONMENT. MOST EPIDEMIOLOGICAL STUDIES IN THIS FIELD HAVE BEEN CONDUCTED USING BLOOD SAMPLES, ALTHOUGH DNA METHYLATION MARKS IN BLOOD MAY NOT BE RELIABLE FOR DRAWING EXHAUSTIVE CONCLUSIONS ABOUT DNA METHYLATION IN THE AIRWAYS. BECAUSE OF THE ROLE OF NASAL EPITHELIUM IN ASTHMA AND THE TISSUE SPECIFICITY OF DNA METHYLATION, STUDYING THE RELATIONSHIP BETWEEN DNA METHYLATION AND CHILDHOOD ASTHMA MIGHT REVEAL CRUCIAL INFORMATION ABOUT THIS WIDESPREAD RESPIRATORY DISEASE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE CURRENT FINDINGS IN THIS FIELD OF RESEARCH. WE WILL PRESENT A VIEWPOINT OF SELECTED STUDIES, CONSIDER STRENGTHS AND LIMITATIONS, AND PROPOSE FUTURE RESEARCH IN THIS AREA. 2020