1 2938 76 GENETIC AND EPIGENETIC ALTERATIONS IN BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA. ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPS FROM BARRETT'S ESOPHAGUS (BE), WHEREIN NORMAL SQUAMOUS EPITHELIA IS REPLACED BY SPECIALIZED INTESTINAL METAPLASIA IN RESPONSE TO CHRONIC GASTROESOPHAGEAL ACID REFLUX. BE CAN PROGRESS TO LOW- AND HIGH-GRADE DYSPLASIA, INTRAMUCOSAL, AND INVASIVE CARCINOMA. BOTH BE AND EAC ARE CHARACTERIZED BY LOSS OF HETEROZYGOSITY, ANEUPLOIDY, SPECIFIC GENETIC MUTATIONS, AND CLONAL DIVERSITY. GIVEN THE LIMITATIONS OF HISTOPATHOLOGY, GENOMIC AND EPIGENOMIC ANALYSES MAY IMPROVE THE PRECISION OF RISK STRATIFICATION. ASSAYS TO DETECT MOLECULAR ALTERATIONS ASSOCIATED WITH NEOPLASTIC PROGRESSION COULD BE USED TO IMPROVE THE PATHOLOGIC ASSESSMENT OF BE/EAC AND TO SELECT HIGH-RISK PATIENTS FOR MORE INTENSIVE SURVEILLANCE. 2015 2 5382 18 RECURRENT CHROMOSOMAL AND EPIGENETIC ALTERATIONS IN ORAL SQUAMOUS CELL CARCINOMA AND ITS PUTATIVE PREMALIGNANT CONDITION ORAL LICHEN PLANUS. HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AFFECTS ABOUT 700.000 INDIVIDUALS PER YEAR WORLDWIDE WITH ORAL SQUAMOUS CELL CARCINOMA (OSCC) AS A MAJOR SUBCATEGORY. DESPITE A COMPREHENSIVE TREATMENT CONCEPT INCLUDING SURGERY, RADIATION, AND CHEMOTHERAPY THE 5-YEAR SURVIVAL RATE IS STILL ONLY ABOUT 50 PERCENT. CHRONIC INFLAMMATION IS ONE OF THE HALLMARKS OF CARCINOGENESIS. UNTIL NOW, LITTLE IS KNOWN ABOUT THE PREMALIGNANT STATUS OF ORAL LICHEN PLANUS (OLP) AND MOLECULAR ALTERATIONS IN OLP ARE STILL POORLY CHARACTERIZED. OUR STUDY AIMS TO DELINEATE DIFFERENTIAL DNA METHYLATION PATTERNS IN OLP, OSCC, AND NORMAL ORAL MUCOSA. BY APPLYING A BEAD CHIP APPROACH, WE IDENTIFIED ALTERED CHROMOSOMAL PATTERNS CHARACTERISTIC FOR OSCC WHILE FINDING NO RECURRENT ALTERATIONS IN OLP. IN CONTRAST, WE IDENTIFIED NUMEROUS ALTERATIONS IN THE DNA METHYLATION PATTERN IN OLP, AS COMPARED TO NORMAL CONTROLS, THAT WERE ALSO PRESENT IN OSCC. OUR DATA SUPPORT THE HYPOTHESIS THAT OLP IS A PRECURSOR LESION OF OSCC SHARING MULTIPLE EPIGENETIC ALTERATIONS WITH OSCC. 2019 3 2996 14 GENETIC PROFILE AND MICROSATELLITE INSTABILITY IN A CASE OF SECONDARY ESOPHAGEAL SQUAMOUS CELL CARCINOMA 12 YEARS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR APLASTIC ANEMIA. WE REPORT ON A 16-YEAR-OLD JAPANESE BOY IN WHOM AN ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) DEVELOPED 12 YEARS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WAS PERFORMED FOR APLASTIC ANEMIA. A HIGH FREQUENCY OF MICROSATELLITE INSTABILITY WAS DETECTED IN SAMPLES OF ESCC. MOREOVER, THE DETECTION OF PATHOGENIC VARIANTS, INCLUDING SINGLE NUCLEOTIDE SUBSTITUTION OF TP53 (C.346C>T) AND BRCA2 (C.6952C>T) AND SPLICING OF KDM6A (C.1194+2T>G), SUGGEST THAT THE DEVELOPMENT OF ESCC IN THE PATIENT WAS TRIGGERED BY IMPAIRMENT OF CHECKPOINT AND REPAIR FOR DNA DAMAGE AND EPIGENETIC MODIFICATION THROUGH ACCUMULATION OF GENE MUTATIONS INDUCED BY CHRONIC GRAFT-VERSUS-HOST DISEASE AND PROLONGED ADMINISTRATION OF TACROLIMUS. 2020 4 563 42 BARRETT'S ESOPHAGUS: CAN BIOMARKERS PREDICT PROGRESSION TO MALIGNANCY? BARRETT'S ESOPHAGUS (BE) IS ONE OF THE MOST COMMON PREMALIGNANT LESIONS AND CAN PROGRESS TO ESOPHAGEAL ADENOCARCINOMA. IT IS CHARACTERIZED HISTOLOGICALLY BY A SPECIALIZED INTESTINAL METAPLASIA THAT REPLACES THE SQUAMOUS EPITHELIUM OF THE DISTAL ESOPHAGUS, AND IS ASSOCIATED WITH CHRONIC GASTROESOPHAGEAL REFLUX DISEASE AND OBESITY. SIMILAR TO THE ADENOMA-CARCINOMA SEQUENCE OF COLORECTAL CARCINOMAS, ESOPHAGEAL ADENOCARCINOMA DEVELOPS THROUGH PROGRESSION FROM BE TO LOW- AND HIGH-GRADE DYSPLASIA, THEN TO ADENOCARCINOMA WITH ACCUMULATION OF GENETIC AND EPIGENETIC ABNORMALITIES. THE EXACT MALIGNANCY POTENTIAL OF BE IS UNCERTAIN. DYSPLASIA IS THE MOST PREDICTIVE MARKER FOR RISK OF ESOPHAGEAL ADENOCARCINOMA, WHEREAS ENDOSCOPIC AND HISTOLOGICAL DIAGNOSES ARE STILL THE GOLD STANDARD FOR SURVEILLANCE OF PATIENTS WITH BE. HOWEVER, BOTH ARE LIMITED, EITHER BY SAMPLING ERRORS IN BIOPSIES OR BY DIFFERENCES IN HISTOLOGICAL INTERPRETATION. SEVERAL STUDIES HAVE IDENTIFIED CANDIDATE BIOMARKERS THAT MAY HAVE PREDICTIVE VALUE AND MAY SERVE AS ADDITIONAL FACTORS FOR THE RISK ASSESSMENT OF ESOPHAGEAL ADENOCARCINOMA. THIS REVIEW DISCUSSES THE ROLE OF BIOMARKERS IN THE PROGRESSION FROM BE TO ADENOCARCINOMA, FOCUSING ON CLINICAL AND MOLECULAR MARKERS. 2008 5 864 25 CHROMOSOMAL INSTABILITY IN ORAL SQUAMOUS CELL CARCINOMA. ORAL SQUAMOUS CELL CARCINOMA (OSCC) DEMONSTRATES AN INCREASING RATE DUE TO HIGH RISK HUMAN PAPILLOMA VIRUS (HR-HPV) PERSISTENT INFECTION, AND ALSO TO CHRONIC CIGARETTE AND ALCOHOL CONSUMPTION. GROSS CHROMOSOMAL ALTERATIONS (POLYSOMY, ANEUPLOIDY, INTRA-CHROMOSOME REARRANGEMENTS) AND SPECIFIC GENE ABERRATIONS SUCH AS AMPLIFICATIONS, DELETIONS, POINT MUTATIONS COMBINED OR NOT WITH EPIGENETIC ONES (PROMOTER METHYLATIONS AND MIRNA DEREGULATIONS) ARE RESPONSIBLE FOR THE PROGRESSIVE TRANSFORMATION OF NORMAL SQUAMOUS CELL EPITHELIA TO THE CORRESPONDING MALIGNANT. CHROMOSOMAL INSTABILITY (CI) -BASED ON STRUCTURAL OR NUMERICAL ABNORMALITIES- LEADS TO SPECIFIC ABNORMAL KARYOTYPES COMBINED OR NOT WITH FUNCTIONAL SUPPRESSOR GENE INACTIVATION AND ONCOGENE OVERACTIVATION IN SOLID MALIGNANCIES, INCLUDING OSCC. EXTENSIVE CYTOGENETIC ANALYSES HAVE SHOWN THAT GROSS ALTERATIONS (GAINS/LOSSES) IN CHROMOSOMES 3, 4, 7, 8, 9, 11, 14, 17, 18, 19 AND ALSO 20 FORM DIFFERENT CI PATTERNS IN OSCC, WHICH IN CONJUNCTION WITH AN AGGRESSIVE PHENOTYPE (PRESENCE OF LYMPH NODAL METASTASIS) NEGATIVELY AFFECT THE PROGNOSIS IN THE CORRESPONDING PATIENTS. IN THE MAJORITY OF OSCC CASES, LOSS OF CHROMOSOMAL BANDS ARE ALMOST EQUALLY DETECTED COMPARED WITH GAINS REGARDING THE CHROMOSOMES REFERRED ABOVE. IN THE CURRENT SPECIAL MOLECULAR PAPER WE EXPLORED THE ROLE OF CI IN THE PROGRESSION AND BIOLOGICAL BEHAVIOR OF OSCCS. 2018 6 1432 20 DIFFERENTIAL GENE HYPERMETHYLATION IN GENITAL LICHEN SCLEROSUS AND CANCER: A COMPARATIVE STUDY. AIMS: LICHEN SCLEROSUS (LS) IS A CHRONIC INFLAMMATORY DISEASE OF THE GENITAL SKIN OF UNKNOWN AETIOLOGY. THE ROLE OF LS IN PENILE SQUAMOUS CELL CARCINOGENESIS IS NOT WELL CHARACTERIZED. HPV HAS BEEN IMPLICATED IN BOTH, AS HAVE EPIGENETIC CHANGES. THE PRESENCE OF HPV AND HYPERMETHYLATION OF THE MGMT, P16, RASSF1, RASSF2, TSLC1 AND TSP1 GENES WERE STUDIED IN PENILE LS; MGMT, RASSF2 AND TSLC1 HYPERMETHYLATION IN PENILE CANCER AND TSLC1 HYPERMETHYLATION IN VULVAR LS AND CANCER EXTENDS PREVIOUS RESULTS REPORTED BY OUR GROUP. METHODS AND RESULTS: THIRTY-SEVEN HPV GENOTYPES AND HYPERMETHYLATION WERE EVALUATED BY PCR/REVERSE-LINE-BLOT AND METHYLATION-SPECIFIC PCR RESPECTIVELY, IN 27 PREPUTIAL LS, 24 PENILE SCC, 30 VULVAR SCC, 21 VULVAR LS AND 22 NORMAL SKIN CASES. HPV66 WAS PRESENT IN 3.7% OF PENILE LS CASES, AND P16 AND RASSF2 HYPERMETHYLATION WERE MORE FREQUENT IN PENILE CANCER THAN IN PENILE LS. P16, RASSF1, RASSF2 AND TSP1 HYPERMETHYLATION WERE SIMILAR IN PENILE AND VULVAR LS. CONCLUSIONS: GENE HYPERMETHYLATION IS A COMMON EVENT IN PENILE LS, AND OCCURS APPROXIMATELY AS FREQUENTLY AS IN VULVAR LS. CERTAIN GENES CAN BE HYPERMETHYLATED AS AN EARLY OR LATE EVENT IN LS OR CANCER, RESPECTIVELY. THIS SUGGESTS A POSSIBLE SEQUENTIAL ROLE FOR THESE ALTERATIONS IN THE TRANSITION FROM BENIGN TO MALIGNANT LESIONS. 2013 7 4437 50 MOLECULAR EVOLUTION OF METAPLASIA TO ADENOCARCINOMA IN THE ESOPHAGUS. ESOPHAGEAL ADENOCARCINOMA (EAC) DEVELOPS FROM BARRETT'S ESOPHAGUS (BE), A CONDITION WHERE THE NORMAL SQUAMOUS EPITHELIA IS REPLACED BY SPECIALIZED INTESTINAL METAPLASIA IN RESPONSE TO CHRONIC GASTROESOPHAGEAL ACID REFLUX. IN A MINORITY OF INDIVIDUALS, BE CAN PROGRESS TO LOW- AND HIGH-GRADE DYSPLASIA AND EVENTUALLY TO INTRA-MUCOSAL AND THEN INVASIVE CARCINOMA. BE PROVIDES RESEARCHERS WITH A UNIQUE MODEL TO CHARACTERIZE THE PROCESS BY WHICH A CARCINOMA ARISES FROM ITS PRECURSOR LESION. MOLECULAR STUDIES OF BE HAVE DEMONSTRATED THAT IT IS NOT SIMPLY A METAPLASTIC TISSUE, BUT RATHER IT HARBORS FREQUENT ALTERATIONS THAT ARE ALSO PRESENT IN DYSPLASTIC BE AND IN EAC. BOTH BE AND EAC ARE CHARACTERIZED BY LOSS OF HETEROZYGOSITY, ANEUPLOIDY, SPECIFIC GENETIC MUTATIONS, AND CLONAL DIVERSITY. EPIGENETIC ABNORMALITIES, PRIMARY ALTERATIONS IN DNA METHYLATION, ARE ALSO FREQUENTLY SEEN IN BE AND EAC. CANDIDATE GENE AND ARRAY-BASED APPROACHES HAVE DEMONSTRATED THAT NUMEROUS TUMOR SUPPRESSOR GENES EXHIBIT ABERRANT PROMOTER METHYLATION, AND SOME OF THESE ALTERED GENES ARE ASSOCIATED WITH THE NEOPLASTIC PROGRESSION OF BE. IT HAS ALSO BEEN SHOWN THAT THE BE AND EAC EPIGENOMES ARE CHARACTERIZED BY HYPOMETHYLATION OF INTRAGENIC AND NON-CODING REGIONS RECENT STUDIES HAVE ALSO PROVIDED NEW INSIGHT INTO THE EVOLUTIONARY FORCES UNDERLYING THE MOLECULAR ALTERATIONS SEEN IN BE AND EAC AND INTO THE MOLECULAR PATHOGENESIS OF EAC. 2018 8 1975 27 EPIGENETIC ALTERATIONS FROM BARRETT'S ESOPHAGUS TO ESOPHAGEAL ADENOCARCINOMA. BARRETT'S ESOPHAGUS (BE) IS A DISEASE ENTITY THAT IS A SEQUELA OF CHRONIC GASTROESOPHAGEAL REFLUX DISEASE THAT MAY RESULT IN ESOPHAGEAL ADENOCARCINOMA (EAC) DUE TO COLUMNAR EPITHELIAL DYSPLASIA. THE HISTOLOGICAL DEGREE OF DYSPLASIA IS THE SOLE BIOMARKER FREQUENTLY UTILIZED BY CLINICIANS. HOWEVER, THE COST OF ENDOSCOPY AND THE FACT THAT THE DEGREE OF DYSPLASIA DOES NOT PROGRESS IN MANY PATIENTS WITH BE DIMINISH THE EFFECTIVENESS OF HISTOLOGICAL GRADING AS A PERFECT BIOMARKER. MULTIPLE OR MORE QUANTITATIVE BIOMARKERS ARE REQUIRED BY CLINICIANS SINCE EARLY DIAGNOSIS IS CRUCIAL IN ESOPHAGEAL ADENOCANCERS, WHICH HAVE A HIGH MORTALITY RATE. THE PRESENCE OF EPIGENETIC FACTORS IN THE EARLY STAGES OF THIS NEOPLASTIC TRANSFORMATION HOLDS PROMISE AS A PREDICTIVE BIOMARKER. IN THIS REVIEW, CURRENT STUDIES ON DNA METHYLATIONS, HISTONE MODIFICATIONS, AND NONCODING RNAS (MIRNAS) THAT HAVE BEEN DISCOVERED DURING THE PROGRESSION FROM BE DYSPLASIA TO EAC WERE COLLATED. 2023 9 2015 32 EPIGENETIC BIOMARKERS IN ESOPHAGEAL CANCER. THE ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES IS WELL DOCUMENTED IN ESOPHAGEAL CANCER, INCLUDING ADENOCARCINOMA (EAC) AND SQUAMOUS CELL CARCINOMA (ESCC) AS WELL AS IN BARRETT'S ESOPHAGUS (BE), A PRE-MALIGNANT CONDITION THAT IS ASSOCIATED WITH CHRONIC ACID REFLUX. BE IS A WELL-RECOGNIZED RISK FACTOR FOR THE DEVELOPMENT OF EAC, AND CONSEQUENTLY THE STANDARD OF CARE IS FOR INDIVIDUALS WITH BE TO BE PLACED IN ENDOSCOPIC SURVEILLANCE PROGRAMS AIMED AT DETECTING EARLY HISTOLOGIC CHANGES THAT ASSOCIATE WITH AN INCREASED RISK OF DEVELOPING EAC. YET BECAUSE THE ABSOLUTE RISK OF EAC IN INDIVIDUALS WITH BE IS MINIMAL, A CLINICAL NEED IN THE MANAGEMENT OF BE IS THE IDENTIFICATION OF ADDITIONAL RISK MARKERS THAT WILL INDICATE INDIVIDUALS WHO ARE AT A SIGNIFICANT ABSOLUTE RISK OF EAC SO THAT THEY MAY BE SUBJECTED TO MORE INTENSIVE SURVEILLANCE. THE BEST CURRENTLY AVAILABLE RISK MARKER IS THE DEGREE OF DYSPLASIA IN ENDOSCOPIC BIOPSIES FROM THE ESOPHAGUS; HOWEVER, THIS MARKER IS SUBOPTIMAL FOR A VARIETY OF REASONS. TO DATE, THERE ARE NO MOLECULAR BIOMARKERS THAT HAVE BEEN TRANSLATED TO WIDESPREAD CLINICAL PRACTICE. THE SEARCH FOR BIOMARKERS, INCLUDING HYPERMETHYLATED GENES, FOR EITHER THE DIAGNOSIS OF BE, EAC, OR ESCC OR FOR RISK STRATIFICATION FOR THE DEVELOPMENT OF EAC IN THOSE WITH BE IS CURRENTLY AN AREA OF ACTIVE RESEARCH. IN THIS REVIEW, WE SUMMARIZE THE STATUS OF IDENTIFIED CANDIDATE EPIGENETIC BIOMARKERS FOR BE, EAC, AND ESCC. MOST OF THESE ABERRANTLY METHYLATED GENES HAVE BEEN DESCRIBED IN THE CONTEXT OF EARLY DETECTION OR DIAGNOSTIC MARKERS; OTHERS MIGHT PROVE USEFUL FOR ESTIMATING PROGNOSIS OR PREDICTING RESPONSE TO TREATMENT. FINALLY, SPECIAL ATTENTION WILL BE PAID TO SOME OF THE CHALLENGES THAT MUST BE OVERCOME IN ORDER TO DEVELOP CLINICALLY USEFUL ESOPHAGEAL CANCER BIOMARKERS. 2014 10 6415 22 THE STUDY OF P16 AND P15 GENE METHYLATION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA AND THEIR QUANTITATIVE EVALUATION IN PLASMA BY REAL-TIME PCR. EPIGENETIC SILENCING OF THE P16 AND P15 GENES BY PROMOTER METHYLATION ARE COMMONLY OBSERVED IN HUMAN EPITHELIAL MALIGNANCIES, INCLUDING HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC). IN THIS STUDY, A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) WAS USED TO EVALUATE THE METHYLATION STATUS OF THE P16 AND P15 GENES IN 73 HNSCC SURGICAL SPECIMENS. P16 AND P15 GENE METHYLATION WAS ALSO EXAMINED IN 29 PAIRED METASTATIC LYMPH NODES AND 29 PAIRED HISTOLOGICALLY, NORMAL RESECTION MARGIN MUCOSAE. THE QUANTITY OF CELL-FREE METHYLATED P16 AND P15 DNA IN THE PLASMA SAMPLES OF 20 HNSCC PATIENTS AND 24 HEALTHY CONTROLS WAS ALSO EXAMINED USING A FLUORESCENCE-BASED REAL-TIME PCR ASSAY. THE FREQUENCIES OF P16 AND P15 METHYLATION IN THE PRIMARY TUMOUR WERE 49% AND 60%, RESPECTIVELY. CONCORDANT METHYLATION OF P16 AND P15 IN TUMOUR SAMPLES AND METASTATIC LYMPH NODES WAS FOUND IN 59 AND 38% OF CASES, RESPECTIVELY. A SIGNIFICANTLY HIGHER PREVALENCE OF P15 METHYLATION WAS FOUND IN HISTOLOGICALLY-NORMAL SURGICAL MARGIN EPITHELIA OF HNSCC PATIENTS WITH CHRONIC SMOKING AND DRINKING HABITS COMPARED WITH NON-SMOKERS AND NON-DRINKERS. IN ADDITION, METHYLATED P16 AND P15 DNA LEVELS WERE SIGNIFICANTLY HIGHER IN THE PLASMA OF HNSCC PATIENTS (MEAN 56 COPIES/ML PLASMA AND 65 COPIES/ML PLASMA, RESPECTIVELY) COMPARED WITH NORMAL CONTROLS (MEAN 6 COPIES/ML PLASMA AND 16 COPIES/ML PLASMA, RESPECTIVELY). IN CONCLUSION, PROMOTER METHYLATION OF THE P16 AND P15 GENES IS INVOLVED IN THE PATHOGENESIS OF HNSCC AND MAY BE RELATED TO CHRONIC SMOKING AND DRINKING. THE DIFFERENTIAL LEVELS OF METHYLATED P16 AND P15 DNA IN PLASMA MIGHT BE POTENTIAL USEFUL MARKERS IN SCREENING HIGH-RISK POPULATIONS FOR EARLY HNSCC AND MONITORING THEIR TREATMENT RESPONSE. 2003 11 5673 18 SHARED EPIGENETIC ALTERATIONS BETWEEN ORAL CANCER AND PERIODONTITIS: A PRELIMINARY STUDY. INTRODUCTION: WE RECENTLY DEVELOPED A NON-INVASIVE SAMPLING PROCEDURE FOR ORAL SQUAMOUS CELL CARCINOMA (OSCC) DETECTION BASED ON DNA METHYLATION ANALYSIS OF A PANEL OF 13 GENES. ORAL CANCER, AS WELL AS ACUTE AND CHRONIC INFLAMMATORY DISEASES, MAY INFLUENCE THE METHYLATION LEVEL OF SEVERAL GENES IN THE ORAL CAVITY. IN THE PRESENT STUDY, WE EVALUATED THE PRESENCE OF PERIODONTAL DISEASE (PD) AND THE METHYLATION STATUS USING OUR 13-GENE PANEL. METHODS: ORAL BRUSHING SPECIMENS WERE COLLECTED FROM THREE DIFFERENT PATIENT GROUPS: 23 GINGIVAL OSCC PATIENTS, 15 PATIENTS AFFECTED BY PD, AND 15 HEALTHY VOLUNTEERS LACKING EVIDENCE OF PD. DNA METHYLATION ANALYSIS WAS PERFORMED AND EACH SAMPLE WAS DETERMINED TO BE POSITIVE OR NEGATIVE BASED ON A PREDEFINED CUT-OFF VALUE. RESULTS: POSITIVE RESULTS WERE FOUND FOR 23/23 OSCC PATIENTS, 3/15 PD PATIENTS, AND 0/15 SAMPLES FROM HEALTHY VOLUNTEERS. THE GP1BB AND MIR193 GENES IN THE PD GROUP EXHIBITED MEAN METHYLATION LEVELS SIMILAR TO OSCC PATIENTS. ZAP70 SHOWED DIFFERENT METHYLATION LEVELS AMONG THREE GROUPS. CONCLUSION: PRELIMINARY DATA IDENTIFIED SHARED EPIGENETIC ALTERATIONS BETWEEN PD AND OSCC PATIENTS IN TWO INFLAMMATORY GENES (GP1BB AND MIR193). THIS STUDY MAY HELP TO IDENTIFY POTENTIAL LINKS BETWEEN THE TWO DISEASES AND SERVE AS A STARTING POINT FOR THE FUTURE RESEARCH FOCUSED ON PATHOGENESIS. 2023 12 1284 27 DECIPHERING THE MOLECULAR LANDSCAPE OF CUTANEOUS SQUAMOUS CELL CARCINOMA FOR BETTER DIAGNOSIS AND TREATMENT. CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) IS A COMMON TYPE OF NEOPLASIA, REPRESENTING A TERRIBLE BURDEN ON PATIENTS' LIFE AND CLINICAL MANAGEMENT. ALTHOUGH IT SELDOM METASTASIZES, AND MOST CASES CAN BE EFFECTIVELY TREATED WITH SURGICAL INTERVENTION, ONCE METASTATIC CSCC DISPLAYS CONSIDERABLE AGGRESSIVENESS LEADING TO THE DEATH OF AFFECTED INDIVIDUALS. NO CONSENSUS HAS BEEN REACHED AS TO WHICH FEATURES BETTER CHARACTERIZE THE AGGRESSIVE BEHAVIOR OF CSCC, AN ACHIEVEMENT HINDERED BY THE HIGH MUTATIONAL BURDEN CAUSED BY CHRONIC ULTRAVIOLET LIGHT EXPOSURE. EVEN THOUGH SOME SUBTYPES HAVE BEEN RECOGNIZED AS HIGH RISK VARIANTS, DEPENDING ON CERTAIN TUMOR FEATURES, CSCC THAT ARE NORMALLY THOUGHT OF AS LOW RISK COULD POSE AN INCREASED DANGER TO THE PATIENTS. IN LIGHT OF THIS, SPECIFIC GENETIC AND EPIGENETIC MARKERS FOR CUTANEOUS SCC, WHICH COULD SERVE AS RELIABLE DIAGNOSTIC MARKERS AND POSSIBLE TARGETS FOR NOVEL TREATMENT DEVELOPMENT, HAVE BEEN SEARCHED FOR. THIS REVIEW AIMS TO GIVE AN OVERVIEW OF THE MUTATIONAL LANDSCAPE OF CSCC, POINTING OUT ESTABLISHED BIOMARKERS, AS WELL AS NOVEL CANDIDATES, AND FUTURE POSSIBLE MOLECULAR THERAPIES FOR CSCC. 2020 13 5181 26 PREMALIGNANT LESIONS IN GASTRIC CANCER. DESPITE A PLATEAU IN INCIDENCE, GASTRIC CANCER IS ONE OF THE MOST COMMON CANCERS WORLDWIDE AND CAUSES CONSIDERABLE MORBIDITY AND MORTALITY. PREMALIGNANT GASTRIC LESIONS ARE WELL KNOWN RISK FACTORS FOR THE DEVELOPMENT OF INTESTINAL-TYPE GASTRIC ADENOCARCINOMAS. IN THIS MULTISTEP MODEL OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI CAUSES CHRONIC ACTIVE INFLAMMATION OF THE GASTRIC MUCOSA, WHICH SLOWLY PROGRESSES THROUGH THE PREMALIGNANT STAGES OF ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND ADENOMA/DYSPLASIA TO GASTRIC CARCINOMA. THIS PROGRESSION IS PARALLELED BY A STEPWISE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. DETECTION, TREATMENT, AND MOLECULAR ANALYSES OF PREMALIGNANT LESIONS MAY THUS PROVIDE A BASIS FOR GASTRIC CANCER PREVENTION. THIS REVIEW DESCRIBES AN OVERVIEW OF CURRENT KNOWLEDGE ON PREMALIGNANT GASTRIC LESIONS. IT ALSO REVIEWS THE ISSUE OF SURVEILLANCE OF PATIENTS WITH PREMALIGNANT LESIONS IN ORDER TO IMPROVE THE SURVIVAL OF PATIENTS WITH GASTRIC CANCER. 2010 14 562 28 BARRETT ESOPHAGUS: HISTORY, DEFINITION AND ETIOPATHOGENY. THE INJURY OF THE ESOPHAGEAL EPITHELIUM MAY BE DETERMINED BY THE REFLUX OF THE GASTRIC ACID IN THE ESOPHAGUS. BARRETT'S ESOPHAGUS (BE) IS CHARACTERIZED BY THE REPLACEMENT OF THE NORMAL SQUAMOUS EPITHELIUM WITH THE COLUMNAR EPITHELIUM, WHEN THE HEALING OF THE LESION OCCURS. ACCORDING TO SOME STUDIES, THE INCIDENCE OF THE ESOPHAGEAL ADENOCARCINOMA IN PATIENTS WITH BE IS OF ABOUT 0,5% PER YEAR. THE TERM BARRETT'S ESOPHAGUS IS SUBJECTED TO INTERPRETATION NOWADAYS, SO IT LACKS THE CLARITY NEEDED FOR THE CLINICAL AND SCIENTIFIC COMMUNICATION ON THE SUBJECT OF COLUMNAR METAPLASIA OF THE ESOPHAGEAL MUCOSA. THE MAJOR PATHOGENETIC FACTOR IN THE DEVELOPMENT OF BE IS REPRESENTED BY THE REFLUX DISEASE. THE CELLULAR ORIGIN OF BE IS CONTROVERSIAL AND IT REPRESENTS AN ISSUE THAT NEEDS TO BE RESOLVED BECAUSE IT WILL HAVE IMPLICATIONS IN THE PUTATIVE MOLECULAR MECHANISMS UNDERLYING THE METAPLASTIC PROCESS. THE EPIGENETIC OR GENETIC CHANGES, WHICH ALTER PROTEIN EXPRESSION, FUNCTION, AND/ OR ACTIVITY, IN POST-MITOTIC CELLS TO DRIVE TRANSDIFFERENTIATION OR IN STEM/ PROGENITOR CELLS SUCH THAT THEY ARE REPROGRAMMED TO DIFFERENTIATE INTO COLUMNAR RATHER THAN SQUAMOUS CELLS, ARE DRIVEN BY THE INFLAMMATORY ENVIRONMENT CREATED BY CHRONIC REFLUX. IN ORDER TO BE ABLE TO DEVELOP BETTER THERAPEUTIC STRATEGIES FOR THE PATIENTS WITH THIS DISEASE, AN INCREASING INTEREST IN UNDERSTANDING THE PATHOGENESIS OF BE AT THE CELLULAR AND MOLECULAR LEVEL PRESENTS THESE DAYS. 2014 15 5674 18 SHARED GENETIC AND EPIGENETIC MECHANISMS BETWEEN CHRONIC PERIODONTITIS AND ORAL SQUAMOUS CELL CARCINOMA. OBJECTIVES: TO ANALYZE BIOINFORMATIC DATASETS FOR DETECTING GENETIC AND EPIGENETIC MECHANISMS SHARED BY CHRONIC PERIODONTITIS (CP) AND ORAL SQUAMOUS CELL CARCINOMA (OSCC). MATERIALS AND METHODS: DATASETS FROM GEO AND TCGA DATABASES REPORTING MRNAS, MIRNAS OR METHYLATION EXPRESSION IN HUMAN CP AND OSCC TISSUES WERE ANALYZED. DIFFERENTIAL EXPRESSION, FUNCTIONAL ENRICHMENT AND PROTEIN-PROTEIN INTERACTION (PPI) NETWORK ANALYSES WERE PERFORMED. DIFFERENTIALLY EXPRESSED MIRNAS (DEMIRNAS) AND GENES (DEG) IN CP AND OSCC WERE DETERMINED. DEMIRNA-TARGET AND DEMIRNA-DEG NETWORKS WERE CONSTRUCTED. DIRECTLY AND INDIRECTLY INTERACTING CROSS-TALK GENES WERE SCREENED, AND THEIR PREDICTION ACCURACY AND ASSOCIATION WITH OSCC PROGNOSIS WAS DETERMINED. RESULTS: 3 DE-MIRNAS (MIR-375, MIR-3609 AND MIR-3652) EXPRESSED IN BOTH CP AND OSCC CRITICALLY REGULATED MOST DEGS. AMONG 12 DIRECTLY INTERACTING CROSS-TALK GENES, NCAPH WAS SIGNIFICANTLY RELATED WITH THE PROGNOSIS OF OSCC. NR2F2 HAD HIGHEST DIFFERENTIAL EXPRESSION IN CP AND OSCC. AMONG 4 CROSS-TALK GENES (FN1, MPPED1, NDEL1, AND NR2F2) DIFFERENTIALLY EXPRESSED IN CP, 3 (FN1, MPPED1, NDEL1) WERE ALSO EXPRESSED IN OSCC. AMONG 12 INDIRECTLY INTERACTING CROSS-TALK GENES DIFFERENTIALLY EXPRESSED IN OSCC, 3 GENES (CDCA8, HIST1H3J, AND RAD51) WERE SIGNIFICANTLY RELATED TO ITS PROGNOSIS. SIGNIFICANT PATHWAYS INVOLVED IN CP AND OSCC INCLUDED: CHEMOKINE RECEPTORS, CLASS I PI3K SIGNALING EVENTS, EPITHELIAL-TO-MESENCHYMAL TRANSITION AND SIGNALING EVENTS BY VEGFR1 AND VEGFR2, EGF RECEPTOR (ERBB1). CONCLUSION: BIOINFORMATIC ANALYSIS OF AVAILABLE DATASETS IMPLICATED 1 DIRECTLY INTERACTING CROSS-TALK GENE (NCAPH), 4 INDIRECTLY INTERACTING CROSS-TALK GENES (NCAPH, NR2F2, FN1, AND MPPED1) AND 3 DE-MIRNAS (HSA-MIR-375, MIR-3609 AND MIR-3652) AS SHARED GENETIC AND EPIGENETIC EXPRESSION PATTERNS BETWEEN CP AND OSCC. 2018 16 5182 24 PREMALIGNANT LESIONS OF SQUAMOUS CELL CARCINOMA OF THE LUNG: THE MOLECULAR MAKE-UP AND FACTORS AFFECTING THEIR PROGRESSION. SQUAMOUS CELL CARCINOMA (SCC), ONE OF THE MOST COMMON FORMS OF LUNG CANCER, SHOWS ACCELERATED PROGRESSION AND AGGRESSIVE GROWTH AND USUALLY IS OBSERVED AT ADVANCED STAGES. SCC ORIGINATES FROM MORPHOLOGICAL CHANGES IN THE BRONCHIAL EPITHELIUM THAT OCCUR DURING CHRONIC INFLAMMATION: BASAL CELL HYPERPLASIA, SQUAMOUS METAPLASIA, AND DYSPLASIA I-III. HOWEVER, THE PROCESS IS NOT INEVITABLE; IT CAN BE STOPPED AT ANY STAGE, REMAIN IN THE STABLE STATE INDEFINITELY AND EITHER PROGRESS OR REGRESS. THE REASONS AND MECHANISMS OF DIFFERENT SCENARIOS OF THE EVOLUTION OF PREMALIGNANT LESIONS IN THE RESPIRATORY EPITHELIUM ARE NOT FULLY UNDERSTOOD. IN THIS REVIEW, WE SUMMARIZED THE LITERATURE DATA (INCLUDING OUR OWN DATA) REGARDING GENETIC, EPIGENETIC, TRANSCRIPTOMIC AND PROTEOMIC PROFILES OF THE PREMALIGNANT LESIONS AND HIGHLIGHTED FACTORS (ENVIRONMENTAL CAUSES, INFLAMMATION, AND GENE POLYMORPHISM) THAT MAY GOVERN THEIR PROGRESSION OR REGRESSION. IN CONCLUSION, WE REVIEWED STRATEGIES FOR LUNG CANCER PREVENTION AND PROPOSED NEW MODELS AND RESEARCH DIRECTIONS FOR STUDYING PREMALIGNANT LESIONS AND DEVELOPING NEW TOOLS TO PREDICT THE RISK OF THEIR MALIGNANT TRANSFORMATION. 2019 17 6381 24 THE ROLE OF ONCOGENIC DNA VIRUSES IN PENILE CANCER DEVELOPMENT. PENILE CANCER IS A RELATIVELY RARE NEOPLASIA IN DEVELOPED COUNTRIES, WITH SIGNIFICANT MORBIDITY AND MORTALITY IN DEVELOPING COUNTRIES. PENILE CANCER CAN BE SUBDIVIDED INTO HUMAN PAPILLOMAVIRUS (HPV)-POSITIVE AND HPV-NEGATIVE CASES. WORLDWIDE, THE HPV PREVALENCE IN PENILE CANCER SAMPLES IS AROUND 50%, AND HPV16 IS THE MOST PREVALENT GENOTYPE. ALTHOUGH HPV IS AN IMPORTANT FACTOR FOR CANCER DEVELOPMENT, OTHER ONCOGENIC FACTORS MAY BE ASSOCIATED WITH CARCINOGENESIS. SOME OF THESE FACTORS CAN BE INFECTIOUS, SUCH AS THE EPSTEIN-BARR VIRUS (EBV), AS WELL AS THE MERKEL CELL POLYOMAVIRUS (MCPYV). THE PREVALENCE RATES OF NEARLY 50% FOR BOTH HPV AND EBV INFECTIONS INDICATE AN IMPORTANT ROLE OF THESE VIRUSES IN PENILE TISSUE MALIGNANCY, REINFORCING THE IDEA OF A MULTIFACTORIAL ETIOLOGY OF THE DISEASE. ALTHOUGH THE HPV ROLE IS BETTER UNDERSTOOD, EBV IS THOUGHT TO FACILITATE PERSISTENCE, INTEGRATION, AND MUTATIONS. RECENT STUDIES ON THE MERKEL CELL POLYOMAVIRUS HAVE NOT SHOWN A RELEVANT PREVALENCE IN PENILE CANCER SAMPLES, BUT ITS PRESENCE INDICATES THE OPPORTUNISTIC INFECTIOUS POTENTIAL OF THIS VIRUS. REGARDING HPV-NEGATIVE CASES, THE LITERATURE SUGGESTS A LINK WITH YOUNGER AGE AND EPIGENETIC ALTERATIONS, MAINLY THROUGH THE P16INK4A PATHWAY. RECENTLY, SEVERAL BIOMARKERS THAT MIGHT ACT AS PROGNOSTIC TOOLS (E.G., KI-67, SQUAMOUS CELL CARCINOMA ANTIGEN, AMONG OTHERS) HAVE BEEN PROPOSED, BUT THE RESULTS REMAIN CONTROVERSIAL. IN ADDITION, OTHER RISK FACTORS HAVE ALSO BEEN ASSOCIATED WITH PENILE CARCINOGENESIS, SUCH AS THE PRESENCE OF PHIMOSIS, NONCIRCUMCISION, CHRONIC INFLAMMATION, AND NUMBER OF SEXUAL PARTNERS. FURTHER STUDIES ARE NEEDED TO DEVELOP TOOLS FOR EARLY DETECTION AND EPIDEMIOLOGICAL SURVEILLANCE OF PENILE CANCER. 2019 18 4232 22 METHYLATION OF RUNX3 IN VARIOUS TYPES OF HUMAN CANCERS AND PREMALIGNANT STAGES OF GASTRIC CARCINOMA. ACCUMULATING EVIDENCE HAS IDENTIFIED A MECHANISM POTENTIALLY RESPONSIBLE FOR THE INACTIVATION OF TUMOR SUPPRESSOR GENES, NAMELY TRANSCRIPTIONAL SILENCING BY ABERRANT METHYLATION OF CPG ISLANDS. A PREVIOUS STUDY HAS SHOWN THE LOSS OF RUNX3 EXPRESSION, DUE TO ABERRANT METHYLATION OF ITS CPG ISLAND, IN GASTRIC CANCER CELL LINES, SUGGESTING THAT RUNX3 IS A TARGET FOR EPIGENETIC GENE SILENCING IN GASTRIC CARCINOGENESIS. HOWEVER, THERE ARE LIMITED DATA ON THE METHYLATION STATUS OF RUNX3 IN THE NEOPLASTIC AND NON-NEOPLASTIC TISSUES IN VARIOUS TYPES OF HUMAN CANCERS, INCLUDING GASTRIC CANCER. HERE, WE REPORT THAT 60% OF GASTRIC CANCER CELL LINES AND 64% OF PRIMARY GASTRIC CARCINOMAS (N=75) WERE METHYLATED AT THE RUNX3 CPG ISLAND. RUNX3 METHYLATION WAS ALSO DETECTED IN HEPATOCELLULAR CARCINOMAS (73%, N=48), LARYNX CANCERS (62%, N=37), LUNG CANCERS (46%, N=24), BREAST CANCERS (25%, N=25), PROSTATE CANCERS (23%, N=44), ENDOMETRIAL CANCERS (12.5%, N=24), COLON CANCERS (4.9%, N=61) AND UTERINE CERVICAL CANCERS (2.5%, N=40), SHOWING THAT RUNX3 METHYLATION IS NOT RESTRICTED TO GASTRIC CANCER. INTERESTINGLY, THE RUNX3 METHYLATION WAS ESPECIALLY FREQUENT IN TUMORS FROM TISSUES OF A FOREGUT DERIVATIVE, THAT IS, THE STOMACH, LIVER, LARYNX AND LUNG. NEXT, THE METHYLATION STATUS OF RUNX3 IN VARIOUS NON-NEOPLASTIC TISSUES WAS EXAMINED, INCLUDING THE PREMALIGNANT LESIONS OF GASTRIC CARCINOMAS. THE RUNX3 METHYLATION WAS FOUND IN 8.1% OF CHRONIC GASTRITIS (N=99), 28.1% OF INTESTINAL METAPLASIA (N=32), 27.3% OF GASTRIC ADENOMAS (N=77) AND 64% OF GASTRIC CARCINOMAS (N=75), BUT NOT IN CHRONIC HEPATITIS B, NORMAL PROSTATE AND COLON MUCOSA, EVEN THOUGH IN CASES OF CHRONIC HEPATITIS, THE METHYLATION FREQUENCY OF ITS NEOPLASTIC TISSUES WAS VERY HIGH. IN CONCLUSION, RUNX3 METHYLATION IS FREQUENTLY FOUND IN HUMAN CANCERS, INCLUDING GASTRIC CANCER, AND IS MOSTLY CANCER SPECIFIC, WITH THE EXCEPTION OF THE STOMACH, AND THUS, MIGHT BE USEFUL AS A POTENTIAL DIAGNOSTIC BIOMARKER OF CANCER. 2004 19 2843 24 FREQUENT CPG ISLAND METHYLATION IN PRECURSOR LESIONS AND EARLY GASTRIC ADENOCARCINOMAS. GASTRIC CARCINOGENESIS INVOLVES MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC SILENCING OF TUMOR-RELATED GENES DUE TO CPG ISLAND METHYLATION (CIM) HAS BEEN RECENTLY REPORTED IN GASTRIC CANCER, BUT THE ROLE IN PRECURSOR LESIONS IS NOT WELL UNDERSTOOD. WE ANALYSED THE METHYLATION STATUS OF THE TUMOR SUPPRESSOR GENE P16, THE DNA MISMATCH REPAIR GENE HMLH1, AND FOUR CPG ISLANDS (MINT1, MINT2, MINT25, AND MINT31) USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION IN 35 POLYPOID ADENOMAS AND 46 FLAT DYSPLASIAS UNASSOCIATED WITH CARCINOMA, 34 EARLY ADENOCARCINOMAS (T1N0M0) AND ASSOCIATED ADENOMAS/DYSPLASIAS, AND CORRESPONDING ADJACENT NON-NEOPLASTIC MUCOSA. THE EXTENT OF CIM WAS DEFINED BY THE FRACTION OF METHYLATED LOCI (METHYLATION INDEX), AND COMPARED WITH PREVIOUSLY CHARACTERIZED GENETIC ALTERATIONS (MICROSATELLITE INSTABILITY (MSI) AND APC GENE MUTATION). WE FOUND THAT METHYLATION OF P16 WAS MORE FREQUENT IN ADENOCARCINOMA-ASSOCIATED DYSPLASIAS/ADENOMAS (29%) AND ADENOCARCINOMAS (44%) AS COMPARED TO FLAT DYSPLASIAS (4%) AND ADENOMAS (18%) UNASSOCIATED WITH ADENOCARCINOMA (P=0.001). THE MEAN METHYLATION INDEX INCREASED FROM NORMAL/CHRONIC GASTRITIS (CG) MUCOSA (0.09) TO INTESTINAL METAPLASIA (IM) (0.16), FLAT DYSPLASIAS (0.40) OR POLYPOID ADENOMAS (0.41) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH CARCINOMA (0.44), AND ADENOCARCINOMAS (0.44). THERE WAS NO DIFFERENCE IN FREQUENCIES OF HIGH-LEVEL CPG ISLAND METHYLATION (CIM-H, METHYLATION INDEX > OR =0.5) AMONG FLAT DYSPLASIAS (50%) AND POLYPOID ADENOMAS (51%) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH ADENOCARCINOMA (47%), AND ADENOCARCINOMA (47%). CIM-H WAS PRESENT IN 15% OF IM, BUT NOT IN NORMAL/CG MUCOSA. THERE WAS A SIGNIFICANT CORRELATION BETWEEN METHYLATION OF HMLH1 AND HIGH-LEVEL OF MICROSATELLITE INSTABILITY (MSI-H): METHYLATION OF HMLH1 WAS PRESENT IN 71% OF MSI-H TUMORS, BUT ONLY 8% OF MSI-LOW TUMORS AND 13% OF MICROSATELLITE-STABLE TUMORS (P=0.0001). THERE WAS NO STATISTICAL DIFFERENCE BETWEEN METHYLATION INDEX AND APC MUTATION. OUR RESULTS INDICATE THAT CONCURRENT PROMOTER METHYLATION IS AN EARLY AND FREQUENT EVENT IN GASTRIC TUMORIGENESIS, INCLUDING BOTH MSI-H AND MICROSATELLITE-STABLE NEOPLASMS. METHYLATION OF THE P16 GENE MAY CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF GASTRIC PRECURSOR LESIONS. 2004 20 1624 19 DNA-METHYLOME-BASED TUMOR HYPOXIA CLASSIFIER IDENTIFIES HPV-NEGATIVE HEAD AND NECK CANCER PATIENTS AT RISK FOR LOCOREGIONAL RECURRENCE AFTER PRIMARY RADIOCHEMOTHERAPY. PURPOSE: TUMOR HYPOXIA IS A PARADIGMATIC NEGATIVE PROGNOSTICATOR OF TREATMENT RESISTANCE IN HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC). THE LACK OF ROBUST AND RELIABLE HYPOXIA CLASSIFIERS LIMITS THE ADAPTATION OF STRATIFIED THERAPIES. WE HYPOTHESIZED THAT THE TUMOR DNA METHYLATION LANDSCAPE MIGHT INDICATE EPIGENETIC REPROGRAMMING INDUCED BY CHRONIC INTRATUMORAL HYPOXIA. EXPERIMENTAL DESIGN: A DNA-METHYLOME-BASED TUMOR HYPOXIA CLASSIFIER (HYPOXIA-M) WAS TRAINED IN THE TCGA (THE CANCER GENOME ATLAS)-HNSCC COHORT BASED ON MATCHED ASSIGNMENTS USING GENE EXPRESSION-BASED SIGNATURES OF HYPOXIA (HYPOXIA-GES). HYPOXIA-M WAS VALIDATED IN A MULTICENTER DKTK-ROG TRIAL CONSISTING OF HUMAN PAPILLOMAVIRUS (HPV)-NEGATIVE PATIENTS WITH HNSCC TREATED WITH PRIMARY RADIOCHEMOTHERAPY (RCHT). RESULTS: ALTHOUGH HYPOXIA-GES FAILED TO STRATIFY PATIENTS IN THE DKTK-ROG, HYPOXIA-M WAS INDEPENDENTLY PROGNOSTIC FOR LOCAL RECURRENCE (HR, 4.3; P = 0.001) AND OVERALL SURVIVAL (HR, 2.34; P = 0.03) BUT NOT DISTANT METASTASIS AFTER RCHT IN BOTH COHORTS. HYPOXIA-M STATUS WAS INVERSELY ASSOCIATED WITH CD8 T-CELL INFILTRATION IN BOTH COHORTS. HYPOXIA-M WAS FURTHER PROGNOSTIC IN THE TCGA-PANCANCER COHORT (HR, 1.83; P = 0.04), UNDERSCORING THE BREADTH OF THIS CLASSIFIER FOR PREDICTING TUMOR HYPOXIA STATUS. CONCLUSIONS: OUR FINDINGS HIGHLIGHT AN UNEXPLORED AVENUE FOR DNA METHYLATION-BASED CLASSIFIERS AS BIOMARKERS OF TUMORAL HYPOXIA FOR IDENTIFYING HIGH-RISK FEATURES IN PATIENTS WITH HNSCC TUMORS. SEE RELATED COMMENTARY BY HEFT NEAL AND BRENNER, P. 2954. 2023