1 2133 95 EPIGENETIC INACTIVATION OF THE MIR-34A IN HEMATOLOGICAL MALIGNANCIES. MIR-34A IS A TRANSCRIPTIONAL TARGET OF P53 AND IMPLICATED IN CARCINOGENESIS. WE STUDIED THE ROLE OF MIR-34A METHYLATION IN A PANEL OF HEMATOLOGICAL MALIGNANCIES INCLUDING ACUTE LEUKEMIA [ACUTE MYELOID LEUKEMIA (AML) AND ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)], CHRONIC LEUKEMIA [CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND CHRONIC MYELOID LEUKEMIA (CML)], MULTIPLE MYELOMA (MM) AND NON-HODGKIN'S LYMPHOMA (NHL). THE METHYLATION STATUS OF MIR-34A PROMOTER WAS STUDIED IN 12 CELL LINES AND 188 DIAGNOSTIC SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. MIR-34A PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS BUT METHYLATED IN 75% LYMPHOMA AND 37% MYELOMA CELL LINES. HYPOMETHYLATING TREATMENT LED TO RE-EXPRESSION OF PRI-MIR-34A TRANSCRIPT IN LYMPHOMA CELLS WITH HOMOZYGOUS MIR-34A METHYLATION. IN PRIMARY SAMPLES AT DIAGNOSIS, MIR-34A METHYLATION WAS DETECTED IN 4% CLL, 5.5% MM SAMPLES AND 18.8% OF NHL AT DIAGNOSIS BUT NONE OF ALL, AML AND CML (P = 0.011). IN MM PATIENTS WITH PAIRED SAMPLES, MIR-34A METHYLATION STATUS REMAINED UNCHANGED AT PROGRESSION. AMONGST LYMPHOID MALIGNANCIES, MIR-34A WAS PREFERENTIALLY METHYLATED IN NHL (P = 0.018), IN PARTICULAR NATURAL KILLER (NK)/T-CELL LYMPHOMA. IN CONCLUSION, AMONGST HEMATOLOGICAL MALIGNANCIES, MIR-34A METHYLATION IS PREFERENTIALLY HYPERMETHYLATED IN NHL, IN PARTICULAR NK/T-CELL LYMPHOMA, IN A TUMOR-SPECIFIC MANNER, THEREFORE THE ROLE OF MIR-34A IN LYMPHOMAGENESIS WARRANTS FURTHER STUDY. 2010 2 2132 59 EPIGENETIC INACTIVATION OF THE MIR-124-1 IN HAEMATOLOGICAL MALIGNANCIES. MIR-124-1 IS A TUMOUR SUPPRESSOR MICRORNA (MIR). EPIGENETIC DEREGULATION OF MIRS IS IMPLICATED IN CARCINOGENESIS. PROMOTER DNA METHYLATION AND HISTONE MODIFICATION OF MIR-124-1 WAS STUDIED IN 5 NORMAL MARROW CONTROLS, 4 LYMPHOMA, 8 MULTIPLE MYELOMA (MM) CELL LINES, 230 DIAGNOSTIC PRIMARY SAMPLES OF ACUTE MYELOID LEUKAEMIA (AML), ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL), CHRONIC MYELOID LEUKAEMIA (CML), CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL), MM, AND NON-HODGKIN'S LYMPHOMA (NHL), AND 53 MM SAMPLES AT STABLE DISEASE OR RELAPSE. PROMOTER OF MIR-124-1 WAS UNMETHYLATED IN NORMAL CONTROLS BUT HOMOZYGOUSLY METHYLATED IN 4 OF 4 LYMPHOMA AND 4 OF 8 MYELOMA CELL LINES. TREATMENT OF 5-AZA-2'-DEOXYCYTIDINE LED TO MIR-124-1 DEMETHYLATION AND RE-EXPRESSION OF MATURE MIR-124, WHICH ALSO ASSOCIATED WITH EMERGENCE OF EUCHROMATIC TRIMETHYL H3K4 AND CONSEQUENT DOWNREGULATION OF CDK6 IN MYELOMA CELLS HARBORING HOMOZYGOUS MIR-124-1 METHYLATION. IN PRIMARY SAMPLES AT DIAGNOSIS, MIR-124-1 METHYLATION WAS ABSENT IN CML BUT DETECTED IN 2% EACH OF MM AT DIAGNOSIS AND RELAPSE/PROGRESSION, 5% ALL, 15% AML, 14% CLL AND 58.1% OF NHL (P<0.001). AMONGST LYMPHOID MALIGNANCIES, MIR-124-1 WAS PREFERENTIALLY METHYLATED IN NHL THAN MM, CLL OR ALL. IN PRIMARY LYMPHOMA SAMPLES, MIR-124-1 WAS PREFERENTIALLY HYPERMETHYLATED IN B- OR NK/T-CELL LYMPHOMAS AND ASSOCIATED WITH REDUCED MIR-124 EXPRESSION. IN CONCLUSION, MIR-124-1 WAS HYPERMETHYLATED IN A TUMOUR-SPECIFIC MANNER, WITH A HETEROCHROMATIC HISTONE CONFIGURATION. HYPOMETHYLATION LED TO PARTIAL RESTORATION OF EUCHROMATIC HISTONE CODE AND MIR RE-EXPRESSION. INFREQUENT MIR-124-1 METHYLATION DETECTED IN DIAGNOSTIC AND RELAPSE MM SAMPLES SHOWED AN UNIMPORTANT ROLE IN MM PATHOGENESIS, DESPITE FREQUENT METHYLATION FOUND IN CELL LINES. AMONGST HAEMATOLOGICAL CANCERS, MIR-124-1 WAS MORE FREQUENTLY HYPERMETHYLATED IN NHL, AND HENCE WARRANTS FURTHER STUDY. 2011 3 2131 50 EPIGENETIC INACTIVATION OF THE HSA-MIR-203 IN HAEMATOLOGICAL MALIGNANCIES. MIR-203 IS A TUMOUR SUPPRESSOR MICRORNA (MIRNA). WE STUDIED THE METHYLATION OF HSA-MIR-203 IN 150 SAMPLES INCLUDING ACUTE MYELOID LEUKAEMIA (AML), ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL), CHRONIC MYELOID LEUKAEMIA (CML), CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN'S LYMPHOMA (NHL) BY METHYLATION-SPECIFIC PCR, AND MIRNA EXPRESSION BY STEM-LOOP RT-QPCR. HSA-MIR-203 PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS BUT HOMOZYGOUSLY METHYLATED IN TWO AML AND FOUR LYMPHOMA CELL LINES, IN WHICH 5-AZA-2'-DEOXYCYTIDINE TREATMENT LED TO PROMOTER DEMETHYLATION AND MIR-203 RE-EXPRESSION. RESTORATION OF MIR-203 EXPRESSION IN LYMPHOMA CELLS INHIBITED CELLULAR PROLIFERATION AND INCREASED CELL DEATH, SUGGESTING AN INHERENT TUMOUR SUPPRESSOR ACTIVITY. IN PRIMARY SAMPLES, HSA-MIR-203 METHYLATION WAS ABSENT IN CML BUT DETECTED IN 5.0% ALL, 10.0% AML, 42.0% CLL AND 38.8% OF NHL (INCLUDING SIX [60.0%] NATURAL KILLER-CELL, NINE [40.9%] B-CELL AND FOUR [23.5%] T CELL NHL). MOREOVER, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH HYPERMETHYLATION OF HSA-MIR-34A, -124A AND -196B IN NHL BUT NOT CLL. IN CLL, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH A HIGHER PRESENTING HB LEVEL (P = 0.033). THE PROJECTED 10 YEAR OVERALL SURVIVAL OF THE CLL PATIENTS WAS 58.2%, WHICH WAS IMPACTED BY RAI STAGE AND HIGH-RISK KARYOTYPES BUT NOT HSA-MIR-203 METHYLATION. HSA-MIR-203 WAS MORE FREQUENTLY METHYLATED IN LYMPHOID THAN MYELOID MALIGNANCIES (P = 0.002). IN CONCLUSION, MIR-203, A TUMOUR SUPPRESSOR GENE, WAS HYPERMETHYLATED IN A TUMOUR-SPECIFIC MANNER WITH GENE SILENCING. HSA-MIR-203 WAS MORE FREQUENTLY HYPERMETHYLATED IN LYMPHOID THAN MYELOID MALIGNANCIES. IN NHL, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH CONCOMITANT METHYLATION OF OTHER TUMOUR SUPPRESSOR MIRNAS. THE FREQUENT HSA-MIR-203 METHYLATION IN LYMPHOID MALIGNANCIES SUGGESTED A PATHOGENETIC ROLE OF HSA-MIR-203 METHYLATION. 2011 4 5056 27 PHASE I TRIAL OF LOW DOSE DECITABINE TARGETING DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA AND NON-HODGKIN LYMPHOMA: DOSE-LIMITING MYELOSUPPRESSION WITHOUT EVIDENCE OF DNA HYPOMETHYLATION. TARGETING ABERRANT DNA HYPERMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN LYMPHOMA (NHL) WITH DECITABINE MAY REVERSE EPIGENETIC SILENCING IN B-CELL MALIGNANCIES. TWENTY PATIENTS WERE ENROLLED IN TWO PHASE I TRIALS TO DETERMINE THE MINIMUM EFFECTIVE PHARMACOLOGICAL DOSE OF DECITABINE IN PATIENTS WITH RELAPSED/REFRACTORY CLL (N = 16) AND NHL (N = 4). PATIENTS RECEIVED 1-3 CYCLES OF DECITABINE. DOSE-LIMITING TOXICITY (DLT) WAS OBSERVED IN 2 OF 4 CLL AND 2 OF 2 NHL PATIENTS RECEIVING DECITABINE AT 15 MG/M(2) PER D DAYS 1-10, CONSISTING OF GRADE 3-4 THROMBOCYTOPENIA AND HYPERBILIRUBINAEMIA. SIX PATIENTS WITH CLL RECEIVED DECITABINE AT 10 MG/M(2) PER D DAYS 1-10 WITHOUT DLT; HOWEVER, RE-EXPRESSION OF METHYLATED GENES OR CHANGES IN GLOBAL DNA METHYLATION WERE NOT OBSERVED. THEREFORE, A 5-DAY DECITABINE SCHEDULE WAS EXAMINED. WITH 15 MG/M(2) PER D DECITABINE DAYS 1-5, DLT OCCURRED IN 2 OF 6 CLL AND 2 OF 2 NHL PATIENTS, CONSISTING OF GRADE 3-4 NEUTROPENIA, THROMBOCYTOPENIA, AND FEBRILE NEUTROPENIA. EIGHT PATIENTS HAD STABLE DISEASE. IN 17 PATIENTS, THERE WERE NO SIGNIFICANT CHANGES IN GENOME-WIDE METHYLATION OR IN TARGET GENE RE-EXPRESSION. IN CONCLUSION, DOSE-LIMITING MYELOSUPPRESSION AND INFECTIOUS COMPLICATIONS PREVENTED DOSE ESCALATION OF DECITABINE TO LEVELS ASSOCIATED WITH CHANGES IN GLOBAL METHYLATION OR GENE RE-EXPRESSION IN CLL AND NHL. 2010 5 5462 17 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS. 2022 6 5613 27 SAFETY AND EFFICACY OF ABEXINOSTAT, A PAN-HISTONE DEACETYLASE INHIBITOR, IN NON-HODGKIN LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PHASE II STUDY. HISTONE DEACETYLASE INHIBITORS ARE MEMBERS OF A CLASS OF EPIGENETIC DRUGS THAT HAVE PROVEN ACTIVITY IN T-CELL MALIGNANCIES, BUT LITTLE IS KNOWN ABOUT THEIR EFFICACY IN B-CELL LYMPHOMAS. ABEXINOSTAT IS AN ORALLY AVAILABLE HYDROXAMATE-CONTAINING HISTONE DEACETYLASE INHIBITOR THAT DIFFERS FROM APPROVED INHIBITORS; ITS UNIQUE PHARMACOKINETIC PROFILE AND ORAL DOSING SCHEDULE, TWICE DAILY FOUR HOURS APART, ALLOWS FOR CONTINUOUS EXPOSURE AT CONCENTRATIONS REQUIRED TO EFFICIENTLY KILL TUMOR CELLS. IN THIS PHASE II STUDY, PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA RECEIVED ORAL ABEXINOSTAT AT 80 MG BID FOR 14 DAYS OF A 21-DAY CYCLE AND CONTINUED UNTIL PROGRESSIVE DISEASE OR UNACCEPTABLE TOXICITY. A TOTAL OF 100 PATIENTS WITH B-CELL MALIGNANCIES AND T-CELL LYMPHOMAS WERE ENROLLED BETWEEN OCTOBER 2011 AND JULY 2014. ALL PATIENTS RECEIVED AT LEAST ONE DOSE OF STUDY DRUG. PRIMARY REASONS FOR DISCONTINUATION INCLUDED PROGRESSIVE DISEASE (56%) AND ADVERSE EVENTS (25%). GRADE 3 OR OVER ADVERSE EVENTS AND ANY SERIOUS ADVERSE EVENTS WERE REPORTED IN 88% AND 73% OF PATIENTS, RESPECTIVELY. THE MOST FREQUENTLY REPORTED GRADE 3 OR OVER TREATMENT-EMERGENT RELATED ADVERSE EVENTS WERE THROMBOCYTOPENIA (80%), NEUTROPENIA (27%), AND ANEMIA (12%). AMONG THE 87 PATIENTS EVALUABLE FOR EFFICACY, OVERALL RESPONSE RATE WAS 28% (COMPLETE RESPONSE 5%), WITH HIGHEST RESPONSES OBSERVED IN PATIENTS WITH FOLLICULAR LYMPHOMA (OVERALL RESPONSE RATE 56%), T-CELL LYMPHOMA (OVERALL RESPONSE RATE 40%), AND DIFFUSE LARGE B-CELL LYMPHOMA (OVERALL RESPONSE RATE 31%). FURTHER INVESTIGATION OF THE SAFETY AND EFFICACY OF ABEXINOSTAT IN FOLLICULAR LYMPHOMA, T-CELL LYMPHOMA, AND DIFFUSE LARGE B-CELL LYMPHOMA IMPLEMENTING A LESS DOSE-INTENSE WEEK-ON-WEEK-OFF SCHEDULE IS WARRANTED. (TRIAL REGISTERED AT: EUDRACT-2009-013691-47). 2017 7 1424 29 DIFFERENTIAL DNA METHYLATION OF GENE PROMOTERS IN SMALL B-CELL LYMPHOMAS. IMPROVED CARE OF PATIENTS WITH SMALL B-CELL LYMPHOMAS (SBCLS) IS LIKELY TO RESULT FROM THE ONGOING DISCOVERY OF MOLECULAR MARKERS THAT BETTER DEFINE THESE MALIGNANT NEOPLASMS. WE IDENTIFIED MULTIPLE GENE LOCI WHOSE DNA METHYLATION PATTERNS DIFFERED BETWEEN 3 TYPES OF SBCL: B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA, MANTLE CELL LYMPHOMA, AND GRADES I AND II FOLLICULAR LYMPHOMA. THIS ANALYSIS WAS PERFORMED USING AN OLIGONUCLEOTIDE MICROARRAY THAT ALLOWED DETERMINATION OF THE DNA METHYLATION STATUS OF 156 LOCI IN 38 GENES. COMBINED BISULFITE RESTRICTION ANALYSIS AND METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WERE USED TO VALIDATE THE DIFFERENTIAL METHYLATION OF 6 OF THESE GENES. BY USING NON-HODGKIN LYMPHOMA CELL LINES AS MODELS, THESE GENES WERE EXAMINED FURTHER FOR METHYLATION AND GENE EXPRESSION RELATIONSHIPS. THIS STUDY ILLUSTRATES NONRANDOM EPIGENETIC ALTERATIONS IN SBCLS THAT SEEM TO PREFERENTIALLY INVOLVE LYMPHOMAS OF GERMINAL CENTER DERIVATION. 2005 8 147 24 ABERRANT EPIGENETIC GENE REGULATION IN LYMPHOID MALIGNANCIES. IN LYMPHOID MALIGNANCIES, ABERRANT EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS INFLUENCE CHROMATIN ARCHITECTURE AND CAN RESULT IN ALTERED GENE EXPRESSION. THESE ALTERATIONS COMMONLY AFFECT GENES THAT PLAY IMPORTANT ROLES IN THE CELL CYCLE, APOPTOSIS, AND DNA REPAIR IN NON-HODGKIN LYMPHOMA (NHL). THE ABILITY TO IDENTIFY EPIGENETIC MODIFICATIONS TO THESE IMPORTANT GENES HAS INCREASED EXPONENTIALLY DUE TO ADVANCES IN TECHNOLOGY. AS A RESULT, THERE ARE WELL-DEFINED, GENE-SPECIFIC EPIGENETIC ABERRATIONS ASSOCIATED WITH NHL COMPRISING FOLLICULAR LYMPHOMA (FL), MANTLE CELL LYMPHOMA (MCL), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AND DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). THE IDENTIFICATION OF THESE GENES IS IMPORTANT BECAUSE THEY MAY BE USED AS BIOMARKERS FOR PROGNOSIS, DIAGNOSIS AND IN DEVELOPING IMPROVED TREATMENT STRATEGIES. ALSO IMPORTANT, IN THE CONTROL OF GENE EXPRESSION, IS THE PACKAGING OF DNA WITHIN THE NUCLEUS OF A CELL. THIS PACKAGING CAN BE DISTORTED BY EPIGENETIC ALTERATIONS AND MAY ALTER THE ACCESSIBILITY OF CERTAIN REGIONS OF THE GENOME IN CANCER CELLS. THIS REVIEW DISCUSSES THE IMPACT OF KNOWN EPIGENETIC ABERRATION ON THE REGULATION OF GENE EXPRESSION IN NHL AND PROVIDES INSIGHT INTO THE SPATIAL CONFORMATION OF THE GENOME (DNA PACKAGING) IN ACUTE LYMPHOBLASTIC LEUKEMIA. 2013 9 6373 17 THE ROLE OF MIRNAS AND EPIGENETIC MECHANISMS IN PRIMARY GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA. GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA IS A RARE LOW-GRADE B-CELL NON-HODGKIN LYMPHOMA ASSOCIATED WITH HELICOBACTER PYLORI INFECTION AND THE SUBSEQUENT CHRONIC INFLAMMATION. SIGNIFICANT PROGRESS IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE HAS ALREADY BEEN MADE. HOWEVER, THE EXACT MOLECULAR PATHWAYS OF LYMPHOMAGENESIS REMAIN UNCLEAR. FURTHERMORE, DIFFICULTIES REGARDING ACCURATE DIAGNOSIS OF GASTRIC MALT LYMPHOMA AND ITS DISCRIMINATION FROM GASTRITIS OR OTHER LYMPHOMA SUBTYPES ARISE. RECENT STUDIES EVALUATE THE ROLE OF MIRNAS AND EPIGENETIC ALTERATIONS ON MALT LYMPHOMA PATHOGENESIS AND PROGNOSIS. THIS REVIEW CRITICALLY SUMMARIZES THE MOST IMPORTANT DATA ON THE ROLE OF MIRNAS AND EPIGENETICS IN MALT LYMPHOMAS PATHOGENESIS, PROGNOSIS AND TREATMENT. 2016 10 1044 25 CLINICAL CHARACTERISTICS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKIN B-CELL LYMPHOMA: A MULTICENTER RETROSPECTIVE STUDY. BACKGROUND: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATED WITH B-CELL LYMPHOMA IS A HIGHLY AGGRESSIVE DISEASE WITH UNCLEAR CLINICAL FEATURES AND HAS NO STANDARD TREATMENT. PATIENTS AND METHODS: WE ANALYZED THE CLINICAL CHARACTERISTICS OF 31 PATIENTS FROM TWO INDIVIDUAL CENTERS. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS ONLY 1.5 MONTHS. BOTH UNIVARIATE AND MULTIVARIATE ANALYSES, BASED ON LYMPHOMA OR HLH-RELATED CHARACTERISTICS, REVEALED THAT PATIENTS WITH HIGH EPSTEIN-BARR VIRUS (EBV) DNA LOAD AND >/= 2 EXTRANODAL LESIONS, OR HYPOFIBRINOGENEMIA, RESPECTIVELY, SHOWED SIGNIFICANTLY POORER OVERALL SURVIVAL. INTERESTINGLY, SOME PATIENTS WITH HIGH EBV DNA LOAD HAD EBV-POSITIVE NATURAL KILLER (NK) AND/OR T CELLS, WHICH MAY BE RELATED TO THE COEXISTENCE OF IMMUNODEFICIENCY AND/OR CHRONIC ACTIVE EBV INFECTION. MOLECULAR GENETICS EXAMINATION CONFIRMED THAT 47.4% (9/19) OF PATIENTS HAD COMPLEX KARYOTYPES, 37.5% (3/8) OF PATIENTS HAD TP53 DELETIONS, AND 21.34% (3/14) OF PATIENTS HAD TP53 MUTATION OR ALTERATION OF MALIGNANCY-RELATED PATHWAYS, INCLUDING BCR/NF-KAPPAB, JAK-STAT, AND EPIGENETIC REGULATORY PATHWAYS, WHICH MAY PROVIDE CLUES TO CHOOSE TARGETS FOR THERAPY. TREATMENT REGIMENS CONTAINING ETOPOSIDE, ANTI-CD20 MONOCLONAL ANTIBODIES, OR ANTHRACYCLINES IMPROVED PATIENT PROGNOSIS (P = .0183, .025, AND .0436, RESPECTIVELY). PATIENTS WITH INFECTIONS HAD SIGNIFICANTLY SHORTER SURVIVAL THAN THOSE WITHOUT INFECTIONS (P = .00019). CONCLUSION: THE PATIENTS' PERFORMANCE STATUS, NUMBER OF EXTRANODAL LESIONS, HIGH EBV DNA LOAD, AND HYPOFIBRINOGENEMIA ARE POOR PROGNOSTIC FACTORS FOR HLH ASSOCIATED WITH B-CELL LYMPHOMA. MOLECULAR GENETIC HIGH-RISK FACTORS ARE OF PARTICULAR IMPORTANCE BECAUSE THESE FACTORS CAN PROVIDE INFORMATION FOR PROGNOSIS PREDICTION, TREATMENT DECISIONS, AND DISEASE SURVEILLANCE. 2021 11 6831 32 [HYPERMETHYLATION OF DAP-KINASE GENE CPG ISLAND IN MALIGNANT LYMPHOMA WITH B-CELL PHENOTYPE]. DEATH-ASSOCIATED PROTEIN-KINASE(DAP-KINASE) IS A PRO-APOPTOTIC SERINE/THREONINE KINASE WITH A DEATH DOMAIN, WHICH IS INVOLVED IN APOPTOSIS INDUCED BY INTERFERON-GAMMA, TUMOR NECROSIS FACTOR-ALPHA, AND FAS LIGAND. EPIGENETIC DOWN-REGULATION OF DAP-KINASE GENE EXPRESSION BY HYPERMETHYLATION OF ITS PROMOTER REGION WAS REPORTED IN CERTAIN KINDS OF MALIGNANCIES. PREVIOUS PATHO-EPIDEMIOLOGICAL STUDIES INDICATED THAT THYROID LYMPHOMA(TL) EVOLVES AMONG ACTIVE LYMPHOID CELLS IN CHRONIC LYMPHOCYTIC THYROIDITIS(CLTH). WITH THE USE OF METHYLATION SPECIFIC POLYMERASE CHAIN REACTION, METHYLATION STATUS OF DAP-KINASE CPG ISLAND WAS EXAMINED IN THYROID LESIONS OF 19 CASES WITH TL AND 9 WITH CLTH. FREQUENCY OF METHYLATION WAS HIGHER IN TL CASES(16 OF 19, 84.2%) THAN IN CLTH CASES(2 OF 9, 22.2%) (P < 0.01). DNA EXTRACTED FROM PERIPHERAL BLOOD LEUKOCYTES FROM TL AND CLTH CASES NEVER SHOWED METHYLATION, INDICATING THAT THE METHYLATION OCCURRED SOMATICALLY IN LESIONAL LYMPHOCYTES IN THE THYROID. WE ALSO EXAMINED THE METHYLATION STATUS OF DAP-KINASE GENE IN 16 CASES OF T-CELL MALIGNANCIES INCLUDING EIGHT ADULT T-CELL LEUKEMIA/LYMPHOMA AND 24 NK/T-CELL, 34 B-CELL, AND TWO IMMUNOPHENOTYPICALLY UNDETERMINED LYMPHOMAS. FREQUENCY OF METHYLATION WAS HIGHER IN B-CELL(27 OF 34, 79.4%) THAN IN T-CELL MALIGNANCIES(EIGHT OF 16, 50%) (P < 0.05). FIFTEEN OF 24(62.5%) NK/T-CELL LYMPHOMAS SHOWED DNA METHYLATION. HEMATOPOIETIC CELL LINES WITH A METHYLATED GENE WERE RESISTANT TO APOPTOSIS. TREATMENT OF THE CELLS WITH A DEMETHYLATING AGENT RESTORED APOPTOTIC CELL DEATH IN ONE B-CELL LYMPHOMA CELL LINE WITH DNA METHYLATION. OUR RESULTS SUGGESTED THAT SUPPRESSION OF DAP-KINASE EXPRESSION BY DNA METHYLATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF B-CELL MALIGNANCIES. 2001 12 4432 20 MOLECULAR CHARACTERIZATION OF RICHTER SYNDROME IDENTIFIES DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS WITH POOR PROGNOSIS. RICHTER SYNDROME (RS) IS THE TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO AGGRESSIVE LYMPHOMA, MOST COMMONLY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). WE CHARACTERIZE 58 PRIMARY HUMAN RS SAMPLES BY GENOME-WIDE DNA METHYLATION AND WHOLE-TRANSCRIPTOME PROFILING. OUR COMPREHENSIVE APPROACH DETERMINES RS DNA METHYLATION PROFILE AND UNRAVELS A CLL EPIGENETIC IMPRINT, ALLOWING CLL-RS CLONAL RELATIONSHIP ASSESSMENT WITHOUT THE NEED OF THE INITIAL CLL TUMOR DNA. DNA METHYLATION- AND TRANSCRIPTOMIC-BASED CLASSIFIERS WERE DEVELOPED, AND TESTING ON LANDMARK DLBCL DATASETS IDENTIFIES A POOR-PROGNOSIS, ACTIVATED B-CELL-LIKE DLBCL SUBSET IN 111/1772 SAMPLES. THE CLASSIFICATION ROBUSTLY IDENTIFIES PHENOTYPES VERY SIMILAR TO RS WITH A SPECIFIC GENOMIC PROFILE, ACCOUNTING FOR 4.3-8.3% OF DE NOVO DLBCLS. IN THIS WORK, RS MULTI-OMICS CHARACTERIZATION DETERMINES ONCOGENIC MECHANISMS, ESTABLISHES A SURROGATE MARKER FOR CLL-RS CLONAL RELATIONSHIP, AND PROVIDES A CLINICALLY RELEVANT CLASSIFIER FOR A SUBSET OF PRIMARY "RS-TYPE DLBCL" WITH UNFAVORABLE PROGNOSIS. 2023 13 4548 30 MUTATION ANALYSIS OF THE FAS AND TNFR APOPTOTIC CASCADE GENES IN HEMATOLOGICAL MALIGNANCIES. OBJECTIVE: THE EXISTENCE OF PROPERLY FUNCTIONING APOPTOTIC PATHWAYS IS OF UTMOST IMPORTANCE IN THE MAINTENANCE OF A NORMAL CELL COUNT. SEVERAL GROUPS HAVE SEARCHED FOR MUTATIONS IN THE FAS RECEPTOR, A WELL-CHARACTERIZED APOPTOTIC PROTEIN CARRYING A DEATH DOMAIN, AND REPORTED THE EXISTENCE OF RARE MUTATIONS IN MULTIPLE MYELOMA, T-ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL), AND ADULT T-CELL LEUKEMIA. OUR AIM WAS TO EXPAND THESE SEARCHES BY LOOKING FOR MUTATIONS IN THE DEATH DOMAINS OF FAS, FADD, TNFR, TRADD, AND RIP, IN THE PROMOTER REGION OF FAS, AND IN THE PROTEASE DOMAIN OF CASPASE 10, IN A LARGER VARIETY OF HEMATOLOGICAL MALIGNANCIES, SOME OF WHICH EXPRESS AN APOPTOSIS-RESISTANT PHENOTYPE. METHODS: WE EXTRACTED RNA AND DNA SAMPLES FROM 92 HEMATOLOGICAL MALIGNANCIES: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL; 31 CASES), CHRONIC MYELOGENOUS LEUKEMIA (CML; 28 CASES), ESSENTIAL THROMBOCYTHEMIA (ET; 8 CASES), ACUTE LYMPHOCYTIC LEUKEMIA (ALL; 6 CASES), ACUTE MYELOBLASTIC LEUKEMIA (AML; 6 CASES), HAIRY-CELL LEUKEMIA (HCL; 3 CASES), BURKITT'S LYMPHOMA (3 CASES), POLYCYTHEMIA VERA (PV; 3 CASES), MYELOFIBROSIS (2 CASES), AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML; 2 CASES) AND PERFORMED PCR-SSCP AND SEQUENCE ANALYSIS ON THESE SAMPLES. RESULTS: FIVE POLYMORPHIC PATTERNS WERE FOUND: THREE IN THE DEATH DOMAIN OF THE FAS GENE IN CML PATIENTS, ONE IN THE PROMOTER OF THIS GENE IN A CLL PATIENT, AND THE FIFTH IN THE DEATH DOMAIN OF THE TRADD GENE IN A CML PATIENT. NO MUTATIONS, ALTERING AMINO ACIDS, WERE FOUND IN THESE GENES IN ANY OF THE AFOREMENTIONED MALIGNANCIES. CONCLUSIONS: THESE OBSERVATIONS IMPLY THAT MUTATIONS IN THE DEATH DOMAINS OF FAS, FADD, TNFR, TRADD, AND RIP AND IN THE PROTEASE DOMAIN OF CASPASE 10 ARE NOT A MAJOR CAUSE FOR FAILURE OF APOPTOSIS IN HEMATOLOGICAL MALIGNANCIES, MAINLY CML AND CLL. REGULATORY AND EPIGENETIC ABNORMALITIES IN THESE APOPTOTIC CASCADE MEMBERS AND ABERRATIONS IN OTHER COMPONENTS OF ALL DEATH MACHINERY SHOULD BE LOOKED FOR. 2001 14 5274 23 PROMOTER METHYLATION OF P16 AND EDNRB GENE IN LEUKEMIA PATIENTS IN TAIWAN. BOTH EPIGENETIC AND GENETIC ALTERNATIONS ARE INVOLVED IN CANCER FORMATION. IN THIS STUDY, WE HAVE IDENTIFIED THE METHYLATION FREQUENCY OF P16 AND ENDOTHELIN RECEPTOR TYPE B (EDNRB) OF 26 LEUKEMIA PATIENTS AND 8 RANDOMLY SELECTED NORMAL BLOOD DONORS IN TAIWAN. PROMOTER METHYLATION OF P16 WAS DETECTED IN 85% OF ACUTE LYMPHOCYTIC LEUKEMIA (ALL), 83% IN ACUTE MYELOID LEUKEMIA (AML) WHEREAS NO METHYLATION WAS DETECTED IN CHRONIC MYELOID LEUKEMIA (CML) IN BLAST CRISIS. HYPERMETHYLATION OF EDNRB WAS OBSERVED IN 92% OF ALL, 75% AML AND 100% IN CML IN BLAST CRISIS. NO ABERRANT METHYLATION OF P16 AND EDNRB WAS FOUND IN 8 NORMAL BLOOD DONORS. TAKEN TOGETHER, ABERRANT METHYLATION OF P16 AND EDNRB WAS HIGHLY PREVALENT IN LEUKEMIA PATIENTS IN TAIWAN. 2008 15 27 21 A B-CELL EPIGENETIC SIGNATURE DEFINES THREE BIOLOGIC SUBGROUPS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH CLINICAL IMPACT. PROSPECTIVE IDENTIFICATION OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DESTINED TO PROGRESS WOULD GREATLY FACILITATE THEIR CLINICAL MANAGEMENT. RECENTLY, WHOLE-GENOME DNA METHYLATION ANALYSES IDENTIFIED THREE CLINICOBIOLOGIC CLL SUBGROUPS WITH AN EPIGENETIC SIGNATURE RELATED TO DIFFERENT NORMAL B-CELL COUNTERPARTS. HERE, WE DEVELOPED A CLINICALLY APPLICABLE METHOD TO IDENTIFY THESE SUBGROUPS AND TO STUDY THEIR CLINICAL RELEVANCE. USING A SUPPORT VECTOR MACHINE APPROACH, WE BUILT A PREDICTION MODEL USING FIVE EPIGENETIC BIOMARKERS THAT WAS ABLE TO CLASSIFY CLL PATIENTS ACCURATELY INTO THE THREE SUBGROUPS, NAMELY NAIVE B-CELL-LIKE, INTERMEDIATE AND MEMORY B-CELL-LIKE CLL. DNA METHYLATION WAS QUANTIFIED BY HIGHLY REPRODUCIBLE BISULFITE PYROSEQUENCING ASSAYS IN TWO INDEPENDENT CLL SERIES. IN THE INITIAL SERIES (N=211), THE THREE SUBGROUPS SHOWED DIFFERENTIAL LEVELS OF IGHV (IMMUNOGLOBULIN HEAVY-CHAIN LOCUS) MUTATION (P<0.001) AND VH USAGE (P<0.03), AS WELL AS DIFFERENT CLINICAL FEATURES AND OUTCOME IN TERMS OF TIME TO FIRST TREATMENT (TTT) AND OVERALL SURVIVAL (P<0.001). A MULTIVARIATE COX MODEL SHOWED THAT EPIGENETIC CLASSIFICATION WAS THE STRONGEST PREDICTOR OF TTT (P<0.001) ALONG WITH BINET STAGE (P<0.001). THESE FINDINGS WERE CORROBORATED IN A VALIDATION SERIES (N=97). IN THIS STUDY, WE DEVELOPED A SIMPLE AND ROBUST METHOD USING EPIGENETIC BIOMARKERS TO CATEGORIZE CLLS INTO THREE SUBGROUPS WITH DIFFERENT CLINICOBIOLOGIC FEATURES AND OUTCOME. 2015 16 2090 31 EPIGENETIC DYSREGULATION OF THE WNT SIGNALLING PATHWAY IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BACKGROUND: WNT SIGNALLING HAS RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF CANCER. METHODS: THIS STUDY INVESTIGATED THE ACTIVITY OF WNT SIGNALLING IN PERIPHERAL BLOOD CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) LYMPHOCYTES, AND THE METHYLATION STATUS OF SEVEN SOLUBLE WNT ANTAGONIST GENES, INCLUDING WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 AND SFRP5, BY USING METHYLATION-SPECIFIC PCR IN THE PERIPHERAL BLOOD CLL LYMPHOCYTES AND BONE MARROW SAMPLES OF PATIENTS WITH CLL AT DIAGNOSIS. RESULTS: IN THE PERIPHERAL BLOOD CLL LYMPHOCYTES, CONSTITUTIVE ACTIVATION OF WNT SIGNALLING WAS DETECTED, ASSOCIATED WITH HYPERMETHYLATION OF THE SOLUBLE WNT INHIBITOR GENES. IN THE DIAGNOSTIC CLL MARROW SAMPLES, METHYLATION OF THE SEVEN GENES WAS DETECTED IN UP TO 36.4% OF SAMPLES. MOREOVER, 23 (52.3%) PATIENTS HAD METHYLATION OF AT LEAST ONE OF THE SEVEN GENES, OF WHOM 14 (60.8%) HAD METHYLATION OF TWO OR MORE WNT INHIBITOR GENES. APART FROM AN ASSOCIATION OF ADVANCED AGE WITH DKK3 METHYLATION, THERE WAS NO ASSOCIATION OF GENE HYPERMETHYLATION WITH EITHER CLINICAL CHARACTERISTICS (INCLUDING AGE, GENDER, LYMPHOCYTE COUNT AT DIAGNOSIS, RAI STAGE AND POOR-RISK KARYOTYPE) OR SURVIVAL. CONCLUSION: WNT SIGNALLING IS CONSTITUTIVELY ACTIVATED IN CLL B LYMPHOCYTES IN ASSOCIATION WITH METHYLATION OF MULTIPLE SOLUBLE WNT ANTAGONIST GENES. METHYLATION OF THESE SOLUBLE WNT ANTAGONIST GENES, OCCASIONALLY MULTIPLE GENES, IN PRIMARY CLL MARROW SAMPLES SUGGESTS AN IMPORTANT ROLE IN CLL PATHOGENESIS. MOREOVER, THIS STUDY UNDERSCORED THE IMPORTANCE OF STUDYING METHYLATION OF A PANEL OF, BUT NOT INDIVIDUAL, GENES REGULATING A CELLULAR PATHWAY. 2008 17 940 18 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 18 941 21 CHRONIC LYMPHOCYTIC LEUKEMIA B-CELL NORMAL CELLULAR COUNTERPART: CLUES FROM A FUNCTIONAL PERSPECTIVE. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY THE CLONAL EXPANSION OF SMALL MATURE-LOOKING CD19+ CD23+ CD5+ B-CELLS THAT ACCUMULATE IN THE BLOOD, BONE MARROW, AND LYMPHOID ORGANS. TO DATE, NO CONSENSUS HAS BEEN REACHED CONCERNING THE NORMAL CELLULAR COUNTERPART OF CLL B-CELLS AND SEVERAL B-CELL TYPES HAVE BEEN PROPOSED. CLL B-CELLS HAVE REMARKABLE PHENOTYPIC AND GENE EXPRESSION PROFILE HOMOGENEITY. IN RECENT YEARS, THE MOLECULAR AND CELLULAR BIOLOGY OF CLL HAS BEEN ENRICHED BY SEMINAL INSIGHTS THAT ARE LEADING TO A BETTER UNDERSTANDING OF THE NATURAL HISTORY OF THE DISEASE. IMMUNOPHENOTYPIC AND MOLECULAR APPROACHES (INCLUDING IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE GENE MUTATIONAL STATUS, TRANSCRIPTIONAL AND EPIGENETIC PROFILING) COMPARING THE NORMAL B-CELL SUBSET AND CLL B-CELLS PROVIDE SOME NEW INSIGHTS INTO THE NORMAL CELLULAR COUNTERPART. FUNCTIONAL CHARACTERISTICS (INCLUDING ACTIVATION REQUIREMENTS AND PROPENSITY FOR PLASMA CELL DIFFERENTIATION) OF CLL B-CELLS HAVE NOW BEEN INVESTIGATED FOR 50 YEARS. B-CELL SUBSETS DIFFER SUBSTANTIALLY IN TERMS OF THEIR FUNCTIONAL FEATURES. ANALYSIS OF SHARED FUNCTIONAL CHARACTERISTICS MAY REVEAL SIMILARITIES BETWEEN NORMAL B-CELL SUBSETS AND CLL B-CELLS, ALLOWING SPECULATIVE ASSIGNMENT OF A NORMAL CELLULAR COUNTERPART FOR CLL B-CELLS. IN THIS REVIEW, WE SUMMARIZE CURRENT DATA REGARDING PERIPHERAL B-CELL DIFFERENTIATION AND HUMAN B-CELL SUBSETS AND SUGGEST POSSIBILITIES FOR A NORMAL CELLULAR COUNTERPART BASED ON THE FUNCTIONAL CHARACTERISTICS OF CLL B-CELLS. HOWEVER, A DEFINITIVE NORMAL CELLULAR COUNTERPART CANNOT BE ATTRIBUTED ON THE BASIS OF THE AVAILABLE DATA. WE DISCUSS THE FUNCTIONAL CHARACTERISTICS REQUIRED FOR A CELL TO BE LOGICALLY CONSIDERED TO BE THE NORMAL COUNTERPART OF CLL B-CELLS. 2018 19 6613 30 ULTRADEEP BISULFITE SEQUENCING ANALYSIS OF DNA METHYLATION PATTERNS IN MULTIPLE GENE PROMOTERS BY 454 SEQUENCING. WE DEVELOPED A NOVEL APPROACH FOR CONDUCTING MULTISAMPLE, MULTIGENE, ULTRADEEP BISULFITE SEQUENCING ANALYSIS OF DNA METHYLATION PATTERNS IN CLINICAL SAMPLES. A MASSIVELY PARALLEL SEQUENCING-BY-SYNTHESIS METHOD (454 SEQUENCING) WAS USED TO DIRECTLY SEQUENCE >100 BISULFITE PCR PRODUCTS IN A SINGLE SEQUENCING RUN WITHOUT SUBCLONING. WE SHOWED THE UTILITY, ROBUSTNESS, AND SUPERIORITY OF THIS APPROACH BY ANALYZING METHYLATION IN 25 GENE-RELATED CPG RICH REGIONS FROM >40 CASES OF PRIMARY CELLS, INCLUDING NORMAL PERIPHERAL BLOOD LYMPHOCYTES, ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), FOLLICULAR LYMPHOMA (FL), AND MANTLE CELL LYMPHOMA (MCL). A TOTAL OF 294,631 SEQUENCES WAS GENERATED WITH AN AVERAGE READ LENGTH OF 131 BP. ON AVERAGE, >1,600 INDIVIDUAL SEQUENCES WERE GENERATED FOR EACH PCR AMPLICON FAR BEYOND THE FEW CLONES (<20) TYPICALLY ANALYZED BY TRADITIONAL BISULFITE SEQUENCING. COMPREHENSIVE ANALYSIS OF CPG METHYLATION PATTERNS AT A SINGLE DNA MOLECULE LEVEL USING CLUSTERING ALGORITHMS REVEALED DIFFERENTIAL METHYLATION PATTERNS BETWEEN DISEASES. A SIGNIFICANT INCREASE IN METHYLATION WAS DETECTED IN ALL AND FL SAMPLES COMPARED WITH CLL AND MCL. FURTHERMORE, A PROGRESSIVE SPREADING OF METHYLATION WAS DETECTED FROM THE PERIPHERY TOWARD THE CENTER OF SELECT CPG ISLANDS IN THE ALL AND FL SAMPLES. THE ULTRADEEP SEQUENCING ALSO ALLOWED SIMULTANEOUS ANALYSIS OF GENETIC AND EPIGENETIC DATA AND REVEALED AN ASSOCIATION BETWEEN A SINGLE NUCLEOTIDE POLYMORPHISM AND THE METHYLATION PRESENT IN THE LRP1B PROMOTER. THIS NEW GENERATION OF METHYLOME SEQUENCING WILL PROVIDE DIGITAL PROFILES OF ABERRANT DNA METHYLATION FOR INDIVIDUAL HUMAN CANCERS AND OFFERS A ROBUST METHOD FOR THE EPIGENETIC CLASSIFICATION OF TUMOR SUBTYPES. 2007 20 4922 25 PARENTAL AGE AND RISK OF LYMPHOID NEOPLASMS. HIGH PARENTAL AGE AT CHILDBIRTH HAS REPEATEDLY BEEN LINKED TO CHILDHOOD MALIGNANCIES, WHILE FEW STUDIES HAVE FOCUSED ON THE OFFSPRING'S RISK OF ADULT CANCER. IN THIS POPULATION-BASED CASE-CONTROL STUDY, WE IDENTIFIED 32,000 PATIENTS WITH LYMPHOID NEOPLASMS, DIAGNOSED AT AGES 0-79 YEARS DURING THE PERIOD 1987-2011, AND 160,000 MATCHED CONTROLS IN SWEDEN. USING PROSPECTIVELY REGISTERED DATA ON THEIR FIRST-DEGREE RELATIVES, WE EVALUATED THE IMPACT OF PARENTAL AGE ON THE RISK OF LYMPHOID NEOPLASMS BY SUBTYPE. OVERALL, EACH 5-YEAR INCREMENT IN MATERNAL AGE WAS ASSOCIATED WITH A 3% INCREASE IN INCIDENCE OF OFFSPRING LYMPHOID NEOPLASMS (HAZARD RATIO = 1.03, 95% CONFIDENCE INTERVAL: 1.02, 1.04). THE ASSOCIATION WAS SIMILAR FOR PATERNAL AGE AND PRESENT EVEN AMONG INDIVIDUALS OLDER THAN 70 YEARS OF AGE AT DIAGNOSIS. STRATIFIED ANALYSES FURTHER REVEALED THAT THE ASSOCIATION WAS LIMITED TO CERTAIN SUBTYPES, MOSTLY OF INDOLENT NATURE. RISKS OF CHRONIC LYMPHOCYTIC LEUKEMIA, FOLLICULAR LYMPHOMA, AND MANTLE CELL LYMPHOMA WERE 5%-10% HIGHER PER 5-YEAR INCREMENT IN MATERNAL AGE, BUT NO ASSOCIATIONS WERE OBSERVED FOR ACUTE LYMPHOBLASTIC LEUKEMIA, PLASMA CELL NEOPLASMS, OR DIFFUSE LARGE B-CELL LYMPHOMA. THESE FINDINGS INDICATED THAT PRENATAL GENETIC OR EPIGENETIC CHANGES INFLUENCE RISK OF ADULT LYMPHOID NEOPLASMS AND SUGGEST A DIFFERENCE IN THIS ASSOCIATION BETWEEN AGGRESSIVE AND INDOLENT LYMPHOMA SUBTYPES. 2017