1 3666 115 INFECTION, STEM CELLS AND CANCER SIGNALS. THE ASSOCIATION OF CANCER WITH PRECEDING PARASITIC INFECTIONS HAS BEEN OBSERVED FOR OVER 200 YEARS. SOME SUCH CANCERS ARISE FROM INFECTION OF TISSUE STEM CELLS BY VIRUSES WITH INSERTION OF VIRAL ONCOGENES INTO THE HOST DNA (MOUSE POLYOMA VIRUS, MOUSE MAMMARY TUMOR VIRUS). IN OTHER CASES THE VIRUS DOES NOT INSERT ITS DNA INTO THE HOST CELLS, BUT RATHER COMMANDEERS THE METABOLISM OF THE INFECTED CELLS, SO THAT THE CELLS CONTINUE TO PROLIFERATE AND DO NOT DIFFERENTIATE (HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER). CYTOPLASMIC EPSTEIN BARR VIRUS INFECTION IS ASSOCIATED WITH A SPECIFIC GENE TRANSLOCATION (IG/C-MYC) THAT ACTIVATES PROLIFERATION OF AFFECTED CELLS (BURKITT LYMPHOMA). IN CHRONIC OSTEOMYELITIS AN INFLAMMATORY REACTION TO THE INFECTION APPEARS TO ACT THROUGH PRODUCTION OF INFLAMMATORY CYTOKINES AND OXYGEN RADICAL FORMATION TO INDUCE EPITHELIAL CANCERS. INFECTION WITH HELICOBACTER PYLORI LEADS TO EPIGENETIC CHANGES IN METHYLATION AND INFECTION BY A PARASITE. CLONORCHIS SINENSIS ALSO ACTS AS A PROMOTER OF CANCER OF THE BILE DUCTS OF THE LIVER (CHOLANIOCARCINOMA). THE COMMON THREAD AMONG THESE DIVERSE PATHWAYS IS THAT THE INFECTIONS ACT TO ALTER TISSUE STEM CELL SIGNALING WITH CONTINUED PROLIFERATION OF TUMOR TRANSIT AMPLIFYING CELLS. 2011 2 5491 36 REVIEW ARTICLE: INFLAMMATION-RELATED PROMOTION OF GASTROINTESTINAL CARCINOGENESIS--A PERIGENETIC PATHWAY. CHRONIC INFLAMMATION HAS BEEN REPORTED TO ACCELERATE NEOPLASMAS IN GASTROINTESTINAL TRACT. CERTAIN BACTERIA INCLUDING HELICOBACTER PYLORI DIRECTLY INTERACT WITH HOST CELLS, INDUCE PROINFLAMMATORY CYTOKINES AND STIMULATE PRODUCTION OF FREE RADICALS. FREE RADICALS CAUSE MUTATIONS IN TARGET CELLS SO THAT NEOPLASTIC CLONES ARE ESTABLISHED. ACCUMULATION OF SUCH GENETIC ALTERATIONS MAY CAUSE MALIGNANT TRANSFORMATION OF SOME ESTABLISHED CLONES. IN ADDITION, INFLAMMATORY ALTERATIONS MAY PROMOTE GROWTH, EXPANSION AND INVASION OF GASTROINTESTINAL EPITHELIAL CELLS. THE LATTER CHANGES CAUSED BY INFLAMMATION MAY OCCUR EVEN WITHOUT FURTHER GENETIC MUTATIONS OR EPIGENETIC ALTERATIONS, AND THEREFORE MAY BE CATEGORIZED AS 'PERIGENETIC ALTERATIONS' OF NEOPLASTIC CELLS. FOR AN EXAMPLE, TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA) PLAYS PIVOTAL ROLES NOT ONLY IN THE REDUCTION BUT ALSO IN THE GROWTH, INVASION AND METASTASES OF CERTAIN NEOPLASMAS. OUR STUDIES SHOW THAT TNF-ALPHA INCREASES INTRACELLULAR RADICAL PRODUCTION, DEGRADATES E-CADHERIN / BETA-CATENIN COMPLEX AND PROMOTES DISPERSION AND MIGRATION IN EPITHELIAL CELLS TRANSFORMED WITH AN ACTIVATED SRC ONCOGENE (V-SRC). THESE DATA INDICATE THAT AN INFLAMMATORY CYTOKINE INDUCES THE MALIGNANT POTENTIAL OF SRC-ACTIVATED NEOPLASTIC CELLS. INTERESTINGLY, TNF-ALPHA ALSO INDUCED THESE PHENOTYPIC CHANGES IN NONMUTATED CELLS WHOSE C-SRC WAS ACTIVATED BY TGF-ALPHA, SUGGESTING THAT THE INVASIVE PROPERTIES OF THE CELL WERE NOT NECESSARILY RELATED TO GENE MUTATION. FURTHERMORE, CERTAIN RADICAL SCAVENGERS SUPPRESSED THE INVASIVE PHENOTYPE OF THE CELLS. THESE RESULTS INDICATE THAT PERIGENETIC ALTERATIONS ARE AN IMPORTANT TARGET OF PHARMACOLOGICAL INTERVENTION OF CARCINOGENESIS. 2003 3 3917 40 LINK BETWEEN CHRONIC INFLAMMATION AND HUMAN PAPILLOMAVIRUS-INDUCED CARCINOGENESIS (REVIEW). INFLAMMATION IS A DEFENSE STRATEGY AGAINST INVADING AGENTS AND HARMFUL MOLECULES THAT IS ACTIVATED IMMEDIATELY FOLLOWING A STIMULUS, AND INVOLVES THE RELEASE OF CYTOKINES AND CHEMOKINES, WHICH ACTIVATE THE INNATE IMMUNE RESPONSE. THESE MEDIATORS ACT TOGETHER TO INCREASE BLOOD FLOW AND VASCULAR PERMEABILITY, FACILITATING RECRUITMENT OF EFFECTOR CELLS TO THE SITE OF INJURY. FOLLOWING RESOLUTION OF THE INJURY AND REMOVAL OF THE STIMULUS, INFLAMMATION IS DISABLED, BUT IF THE STIMULUS PERSISTS, INFLAMMATION BECOMES CHRONIC AND IS STRONGLY ASSOCIATED WITH CANCER. THIS IS LIKELY TO BE DUE TO THE FACT THAT THE INFLAMMATION LEADS TO A WOUND THAT DOES NOT HEAL, REQUIRING A CONSTANT RENEWAL OF CELLS, WHICH INCREASES THE RISK OF NEOPLASTIC TRANSFORMATION. DEBRIS FROM PHAGOCYTOSIS, INCLUDING THE REACTIVE SPECIES OF OXYGEN AND NITROGEN THAT CAUSE DAMAGE TO DNA ALREADY DAMAGED BY THE LEUKOTRIENES AND PROSTAGLANDINS, HAS AN IMPACT ON INFLAMMATION AND VARIOUS CARCINOGENIC ROUTES. THERE IS AN ASSOCIATION BETWEEN CHRONIC INFLAMMATION, PERSISTENT INFECTION AND CANCER, WHERE ONCOGENIC ACTION IS MEDIATED BY AUTOCRINE AND PARACRINE SIGNALS, CAUSING CHANGES IN SOMATIC CELLS UNDER THE INFLUENCE OF THE MICROBIAL GENOME OR OF EPIGENETIC FACTORS. AMONG THE INFECTIOUS AGENTS ASSOCIATED WITH CANCER, CERTAIN GENOTYPES OF HUMAN PAPILLOMAVIRUS (HPV) STAND OUT. HPV IS RESPONSIBLE FOR VIRTUALLY ALL CASES OF CERVICAL CANCER AND A LOWER PROPORTION OF CANCERS OF THE VAGINA, VULVA, ANUS, PENIS AND A NUMBER OF EXTRAGENITAL CANCERS. IN THE PRESENT REVIEW, RECENT ADVANCES IN THE MECHANISMS INVOLVED IN THE INFLAMMATORY RESPONSE ARE PRESENTED WITH THEIR PARTICIPATION IN THE PROCESS OF CARCINOGENESIS, EMPHASIZING THE ROLE OF CHRONIC INFLAMMATION IN THE DEVELOPMENT OF HPV-INDUCED CERVICAL CANCER. 2015 4 4060 25 MAST CELLS, ANGIOGENESIS AND LYMPHANGIOGENESIS IN HUMAN GASTRIC CANCER. GASTRIC CANCER IS DIAGNOSED IN NEARLY ONE MILLION NEW PATIENTS EACH YEAR AND IT REMAINS THE SECOND LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ALTHOUGH GASTRIC CANCER REPRESENTS A HETEROGENEOUS GROUP OF DISEASES, CHRONIC INFLAMMATION HAS BEEN SHOWN TO PLAY A ROLE IN TUMORIGENESIS. CANCER DEVELOPMENT IS A MULTISTEP PROCESS CHARACTERIZED BY GENETIC AND EPIGENETIC ALTERATIONS DURING TUMOUR INITIATION AND PROGRESSION. THE STROMAL MICROENVIRONMENT IS IMPORTANT IN MAINTAINING NORMAL TISSUE HOMEOSTASIS OR PROMOTING TUMOUR DEVELOPMENT. A PLETHORA OF IMMUNE CELLS (I.E., LYMPHOCYTES, MACROPHAGES, MAST CELLS, MONOCYTES, MYELOID-DERIVED SUPPRESSOR CELLS, TREG CELLS, DENDRITIC CELLS, NEUTROPHILS, EOSINOPHILS, NATURAL KILLER (NK) AND NATURAL KILLER T (NKT) CELLS) ARE COMPONENTS OF GASTRIC CANCER MICROENVIRONMENT. MAST CELL DENSITY IS INCREASED IN GASTRIC CANCER AND THERE IS A CORRELATION WITH ANGIOGENESIS, THE NUMBER OF METASTATIC LYMPH NODES AND THE SURVIVAL OF THESE PATIENTS. MAST CELLS EXERT A PROTUMORIGENIC ROLE IN GASTRIC CANCER THROUGH THE RELEASE OF ANGIOGENIC (VEGF-A, CXCL8, MMP-9) AND LYMPHANGIOGENIC FACTORS (VEGF-C AND VEGF-F). GASTRIC MAST CELLS EXPRESS THE PROGRAMMED DEATH LIGANDS (PD-L1 AND PD-L2) WHICH ARE RELEVANT AS IMMUNE CHECKPOINTS IN CANCER. SEVERAL CLINICAL UNDERGOING TRIALS TARGETING IMMUNE CHECKPOINTS COULD BE AN INNOVATIVE THERAPEUTIC STRATEGY IN GASTRIC CANCER. ELUCIDATION OF THE ROLE OF SUBSETS OF MAST CELLS IN DIFFERENT HUMAN GASTRIC CANCERS WILL DEMAND STUDIES OF INCREASING COMPLEXITY BEYOND THOSE ASSESSING MERELY MAST CELL DENSITY AND MICROLOCALIZATION. 2019 5 2994 28 GENETIC PATHOGENESIS OF INFLAMMATION-ASSOCIATED CANCERS IN DIGESTIVE ORGANS. EPIDEMIOLOGICAL, CLINICAL, AND BIOLOGICAL STUDIES CONVINCINGLY DEMONSTRATE THAT CHRONIC INFLAMMATION PREDISPOSES TO THE DEVELOPMENT OF HUMAN CANCERS. IN DIGESTIVE ORGANS, INFLAMMATION-ASSOCIATED CANCERS INCLUDE COLITIS-ASSOCIATED COLORECTAL CANCERS, HELICOBACTER PYLORI-ASSOCIATED GASTRIC CANCER, AS WELL AS BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA ASSOCIATED WITH CHRONIC DUODENOGASTRIC-ESOPHAGEAL REFLUX. CANCER IS A GENOMIC DISEASE, AND STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR-RELATED GENES LEADS TO THE DEVELOPMENT OF TUMOR CELLS. RECENT GENOME ANALYSES SHOW THAT GENETIC ALTERATIONS, WHICH ARE EVOKED BY INFLAMMATION, ARE LATENTLY ACCUMULATED IN INFLAMED EPITHELIAL CELLS OF DIGESTIVE ORGANS. PRODUCTION OF REACTIVE OXYGEN AND ABERRANT EXPRESSION OF ACTIVATION-INDUCED CYTIDINE DEAMINASE, A NUCLEOTIDE-EDITING ENZYME, COULD BE INDUCED IN INFLAMED GASTROINTESTINAL EPITHELIAL CELLS AND PLAY A ROLE AS A GENOMIC MODULATOR OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. UNDERSTANDING THE MOLECULAR LINKAGE BETWEEN INFLAMMATION AND GENETIC ALTERATIONS WILL OPEN UP A NEW FIELD OF TUMOR BIOLOGY AND PROVIDE A NOVEL STRATEGY FOR THE PREVENTION OF INFLAMMATION-ASSOCIATED TUMORIGENESIS. 2021 6 4539 33 MULTISTAGE CARCINOGENESIS IN MOUSE SKIN. THE MOUSE SKIN MODEL OF MULTISTAGE CARCINOGENESIS HAS FOR MANY YEARS PROVIDED A CONCEPTUAL FRAMEWORK FOR STUDYING CARCINOGENESIS MECHANISMS AND POTENTIAL MEANS FOR INHIBITING SPECIFIC STAGES OF CARCINOGENESIS. THE PROCESS OF SKIN CARCINOGENESIS INVOLVES THE STEPWISE ACCUMULATION OF GENETIC CHANGE ULTIMATELY LEADING TO MALIGNANCY. INITIATION, THE FIRST STEP IN MULTISTAGE SKIN CARCINOGENESIS INVOLVES CARCINOGEN-INDUCED GENETIC CHANGES. A TARGET GENE IDENTIFIED FOR SOME SKIN TUMOR INITIATORS IS C-HA-RAS. THE SECOND STEP, THE PROMOTION STAGE, INVOLVES PROCESSES WHEREBY INITIATED CELLS UNDERGO SELECTIVE CLONAL EXPANSION TO FORM VISIBLE PREMALIGNANT LESIONS TERMED PAPILLOMAS. THE PROCESS OF TUMOR PROMOTION INVOLVES THE PRODUCTION AND MAINTENANCE OF A SPECIFIC AND CHRONIC HYPERPLASIA CHARACTERIZED BY A SUSTAINED CELLULAR PROLIFERATION OF EPIDERMAL CELLS. THESE CHANGES ARE BELIEVED TO RESULT FROM EPIGENETIC MECHANISMS SUCH AS ACTIVATION OF THE CELLULAR RECEPTOR, PROTEIN KINASE C, BY SOME CLASSES OF TUMOR PROMOTERS. THE PROGRESSION STAGE INVOLVES THE CONVERSION OF PAPILLOMAS TO MALIGNANT TUMORS, SQUAMOUS CELL CARCINOMAS. THE ACCUMULATION OF ADDITIONAL GENETIC CHANGES IN CELLS COMPRISING PAPILLOMAS HAS BEEN CORRELATED WITH TUMOR PROGRESSION, INCLUDING TRISOMIES OF CHROMOSOMES 6 AND 7 AND LOSS OF HETEROZYGOSITY. THE CURRENT REVIEW FOCUSES ON THE MECHANISMS INVOLVED IN MULTISTAGE SKIN CARCINOGENESIS, A SUMMARY OF KNOWN INHIBITORS OF SPECIFIC STAGES AND THEIR PROPOSED MECHANISMS OF ACTION, AND THE RELEVANCE OF THIS MODEL SYSTEM TO HUMAN CANCER. 1992 7 376 27 AN EPI(C)GENETIC WAR: PATHOGENS, CANCER AND HUMAN GENOME. CANCER IS CHARACTERIZED BY INTER- AND INTRA-TUMOR HETEROGENEITY AND THIS IS ALSO OBSERVED IN THE CONTEXT OF CANCERS CAUSED BY PATHOGENS. NEARLY 20% OF ALL CANCERS ARE ATTRIBUTABLE TO PATHOGENIC ORGANISMS. PATHOGENIC INFECTIONS RESULT IN DEREGULATION OF GENE EXPRESSION BOTH BY GENETIC AND EPIGENETIC MECHANISMS, THEREBY CAUSING MALIGNANT TRANSFORMATION. ANOTHER CHARACTERISTIC OF PATHOGEN-INDUCED CANCERS IS THE OCCURRENCE OF CHRONIC INFLAMMATION DUE TO ACTIVATION OF THE INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM. THIS REVIEW FOCUSES ON THE EPIGENETIC CHANGES INDUCED BY ONCOVIRUSES, PARASITES, CANCER-CAUSING BACTERIA AND 'ENDOGENOUS PATHOGENS' TO TRIGGER HOST CELL PROLIFERATION INDEFINITELY AS WELL AS THE INFLAMMATION ASSOCIATED WITH PATHOGEN-INDUCED CANCERS. THE OPPORTUNITY OF TARGETING COMPONENTS OF BOTH PATHOGEN AND HOST EPIGENETIC MACHINERY TO LIMIT TUMOR PROGRESSION IS ALSO DISCUSSED. 2018 8 5785 25 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 9 3525 27 IL-1BETA, IL-8, AND MATRIX METALLOPROTEINASES-1, -2, AND -10 ARE ENRICHED UPON MONOCYTE-BREAST CANCER CELL COCULTIVATION IN A MATRIGEL-BASED THREE-DIMENSIONAL SYSTEM. BREAST CANCER REMAINS THE FIRST CANCER-RELATED CAUSE OF DEATH IN WOMEN WORLDWIDE, PARTICULARLY IN DEVELOPING COUNTRIES IN WHICH MOST CASES ARE DIAGNOSED IN LATE STAGES. ALTHOUGH MOST CANCER STUDIES ARE BASED IN THE GENETIC OR EPIGENETIC CHANGES OF THE TUMOR CELLS, IMMUNE CELLS WITHIN THE TUMOR STROMA OFTEN COOPERATE WITH CANCER PROGRESSION. PARTICULARLY, MONOCYTES ARE ATTRACTED TO THE TUMOR PRIMARY SITE IN WHICH THEY ARE DIFFERENTIATED INTO TUMOR-ASSOCIATED MACROPHAGES THAT FACILITATE TUMOR CELL INVASION AND METASTASIS. IN THIS STUDY, WE USED THREE-DIMENSIONAL CULTURES TO FORM ACINI-LIKE STRUCTURES TO ANALYZE THE INFLAMMATORY SECRETION PROFILE OF TUMOR CELLS INDIVIDUALLY OR IN CO-CULTURE WITH MONOCYTES. BREAST CANCER CELL LINES AND PRIMARY ISOLATES FROM EIGHT MEXICAN PATIENTS WITH BREAST CANCER WERE USED. WE FOUND HIGH LEVELS OF RANTES/CCL5, MCP-1/CCL2, AND G-CSF IN THE BREAST CANCER INDIVIDUAL CULTURES, SUPPORTING AN IMPORTANT RECRUITMENT CAPACITY OF MONOCYTES, BUT ALSO OF NEUTROPHILS. THE CO-CULTURES OF THE TUMOR CELLS AND MONOCYTES WERE SIGNIFICANTLY ENRICHED WITH THE POTENT PRO-INFLAMMATORY CYTOKINES INTERLEUKIN (IL)-1BETA AND IL-8, KNOWN TO SUPPORT MALIGNANT PROGRESSION. WE ALSO FOUND THAT THE INTERACTION OF TUMOR CELLS WITH MONOCYTES PROMOTED HIGH LEVELS OF MATRIX METALLOPROTEINASES (MMP)-1, MMP-2, AND MMP-10. OUR STUDY SUPPORTS THAT A KEY EVENT FOR MALIGNANT PROGRESSION IS THE RECRUITMENT OF DIFFERENT IMMUNE CELL POPULATIONS, WHICH HELP TO SUSTAIN AND ENHANCE A CHRONIC INFLAMMATORY MICROENVIRONMENT THAT HIGHLY FAVORS TUMOR MALIGNANCY. 2017 10 6906 22 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 11 208 33 ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) LINKING IMMUNITY, CHRONIC INFLAMMATION, AND CANCER. ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) IS CRITICALLY INVOLVED IN CLASS SWITCH RECOMBINATION AND SOMATIC HYPERMUTATION OF IG LOCI RESULTING IN DIVERSIFICATION OF ANTIBODIES REPERTOIRE AND PRODUCTION OF HIGH-AFFINITY ANTIBODIES AND AS SUCH REPRESENTS A PHYSIOLOGICAL TOOL TO INTRODUCE DNA ALTERATIONS. THESE PROCESSES TAKE PLACE WITHIN GERMINAL CENTERS OF SECONDARY LYMPHOID ORGANS. UNDER PHYSIOLOGICAL CONDITIONS, AID IS EXPRESSED PREDOMINANTLY IN ACTIVATED B LYMPHOCYTES. BECAUSE OF THE MUTAGENIC AND RECOMBINOGENIC POTENTIAL OF AID, ITS EXPRESSION AND ACTIVITY IS TIGHTLY REGULATED ON DIFFERENT LEVELS TO MINIMIZE THE RISK OF UNWANTED DNA DAMAGE. HOWEVER, CHRONIC INFLAMMATION AND, PROBABLY, COMBINATION OF OTHER NOT-YET-IDENTIFIED FACTORS ARE ABLE TO CREATE A MICROENVIRONMENT SUFFICIENT FOR TRIGGERING AN ABERRANT AID EXPRESSION IN B CELLS AND, IMPORTANTLY, IN NON-B-CELL BACKGROUND. UNDER THESE CIRCUMSTANCES, AID MAY TARGET ALSO NON-IG GENES, INCLUDING CANCER-RELATED GENES AS ONCOGENES, TUMOR SUPPRESSOR GENES, AND GENOMIC STABILITY GENES, AND MODULATE BOTH GENETIC AND EPIGENETIC INFORMATION. DESPITE ONGOING PROGRESS, THE COMPLETE UNDERSTANDING OF FUNDAMENTAL ASPECTS IS STILL LACKING AS (1) WHAT ARE THE CRUCIAL FACTORS TRIGGERING AN ABERRANT AID EXPRESSION/ACTIVITY INCLUDING THE IMPACT OF TH2-DRIVEN INFLAMMATION AND (2) TO WHAT EXTENT MAY ABERRANT AID IN HUMAN NON-B CELLS LEAD TO ABNORMAL CELL STATE ASSOCIATED WITH AN INCREASED RATE OF GENOMIC ALTERATIONS AS POINT MUTATIONS, SMALL INSERTIONS OR DELETIONS, AND/OR RECURRENT CHROMOSOMAL TRANSLOCATIONS DURING SOLID TUMOR DEVELOPMENT AND PROGRESSION. 2012 12 5292 28 PROSTATIC INFLAMMATION ENHANCES BASAL-TO-LUMINAL DIFFERENTIATION AND ACCELERATES INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. CHRONIC INFLAMMATION HAS BEEN SHOWN TO PROMOTE THE INITIATION AND PROGRESSION OF DIVERSE MALIGNANCIES BY INDUCING GENETIC AND EPIGENETIC ALTERATIONS. IN THIS STUDY, WE INVESTIGATE AN ALTERNATIVE MECHANISM THROUGH WHICH INFLAMMATION PROMOTES THE INITIATION OF PROSTATE CANCER. ADULT MURINE PROSTATE EPITHELIA ARE COMPOSED PREDOMINANTLY OF BASAL AND LUMINAL CELLS. PREVIOUS STUDIES REVEALED THAT THE TWO LINEAGES ARE LARGELY SELF-SUSTAINED WHEN RESIDING IN THEIR NATIVE MICROENVIRONMENT. TO INTERROGATE WHETHER TISSUE INFLAMMATION ALTERS THE DIFFERENTIATION PROGRAM OF BASAL CELLS, WE CONDUCTED LINEAGE TRACING OF BASAL CELLS USING A K14-CREER;MTMG MODEL IN CONCERT WITH A MURINE MODEL OF PROSTATITIS INDUCED BY INFECTION FROM THE UROPATHOGENIC BACTERIA CP9. WE SHOW THAT ACUTE PROSTATITIS CAUSES TISSUE DAMAGE AND CREATES A TISSUE MICROENVIRONMENT THAT INDUCES THE DIFFERENTIATION OF BASAL CELLS INTO LUMINAL CELLS, AN ALTERATION THAT RARELY OCCURS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. PREVIOUSLY WE SHOWED THAT A MOUSE MODEL WITH PROSTATE BASAL CELL-SPECIFIC DELETION OF PHOSPHATASE AND TENSIN HOMOLOG (K14-CREER;PTEN(FL/FL)) DEVELOPS PROSTATE CANCER WITH A LONG LATENCY, BECAUSE DISEASE INITIATION IN THIS MODEL REQUIRES AND IS LIMITED BY THE DIFFERENTIATION OF TRANSFORMATION-RESISTANT BASAL CELLS INTO TRANSFORMATION-COMPETENT LUMINAL CELLS. HERE, WE SHOW THAT CP9-INDUCED PROSTATITIS SIGNIFICANTLY ACCELERATES THE INITIATION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA IN THIS MODEL. OUR RESULTS DEMONSTRATE THAT INFLAMMATION RESULTS IN A TISSUE MICROENVIRONMENT THAT ALTERS THE NORMAL PROSTATE EPITHELIAL CELL DIFFERENTIATION PROGRAM AND THAT THROUGH THIS CELLULAR PROCESS INFLAMMATION ACCELERATES THE INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. 2014 13 3950 19 LNFLAMMATION-INDUCED EPIGENETIC SWITCHES IN CANCER. THE LINK BETWEEN INFLAMMATION AND CANCER IS WELL ESTABLISHED. CHRONIC INFLAMMATION PROMOTES CANCER INITIATION AND PROGRESSION. VARIOUS STUDIES SHOWED THAT THE UNDERLYING MECHANISMS INVOLVE EPIGENETIC ALTERATIONS. THESE EPIGENETIC ALTERATIONS MIGHT CULMINATE INTO AN EPIGENETIC SWITCH THAT TRANSFORMS PREMALIGNANT CELLS INTO TUMOR CELLS OR NON-INVASIVE INTO INVASIVE TUMOR CELLS, THEREBY PROMOTING METASTASIS. EPIGENETIC SWITCHES REQUIRE AN INITIATING EVENT, WHICH CAN BE INFLAMMATION, WHEREAS THE RESULTING PHENOTYPE IS INHERITED WITHOUT THE INITIATING SIGNAL. EPIGENETIC SWITCHES ARE INDUCED AND MAINTAINED BY DNA METHYLATION, HISTONE MODIFICATIONS, POLYCOMB GROUP (PCG)/TRITHORAX GROUP (TRXG) PROTEINS, AND FEEDBACK LOOPS CONSISTING OF TRANSCRIPTION FACTORS AND MICRORNAS. SINCE EPIGENETIC SWITCHES ARE REVERSIBLE, THEY MIGHT REPRESENT AN IMPORTANT BASIS FOR THE DESIGN OF NOVEL ANTICANCER THERAPEUTICS. THIS REVIEW SUMMARIZES PUBLISHED EVIDENCE OF EPIGENETIC SWITCHES IN CANCER DEVELOPMENT THAT ARE INDUCED BY INFLAMMATION. 2016 14 2377 36 EPIGENETIC REGULATION OF TUMOR SUPPRESSORS BY HELICOBACTER PYLORI ENHANCES EBV-INDUCED PROLIFERATION OF GASTRIC EPITHELIAL CELLS. HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS (EBV) ARE TWO WELL-KNOWN CONTRIBUTORS TO CANCER AND CAN ESTABLISH LIFELONG PERSISTENT INFECTION IN THE HOST. THIS LEADS TO CHRONIC INFLAMMATION, WHICH ALSO CONTRIBUTES TO DEVELOPMENT OF CANCER. ASSOCIATION WITH H. PYLORI INCREASES THE RISK OF GASTRIC CARCINOMA, AND COEXISTENCE WITH EBV ENHANCES PROLIFERATION OF INFECTED CELLS. FURTHER, H. PYLORI-EBV COINFECTION CAUSES CHRONIC INFLAMMATION IN PEDIATRIC PATIENTS. WE HAVE ESTABLISHED AN H. PYLORI-EBV COINFECTION MODEL SYSTEM USING HUMAN GASTRIC EPITHELIAL CELLS. WE SHOWED THAT H. PYLORI INFECTION CAN INCREASE THE ONCOGENIC PHENOTYPE OF EBV-INFECTED CELLS AND THAT THE CYTOTOXIN-ASSOCIATED GENE (CAGA) PROTEIN ENCODED BY H. PYLORI STIMULATED EBV-MEDIATED CELL PROLIFERATION IN THIS COINFECTION MODEL SYSTEM. THIS LED TO INCREASED EXPRESSION OF DNA METHYL TRANSFERASES (DNMTS), WHICH REPROGRAMMED CELLULAR TRANSCRIPTIONAL PROFILES, INCLUDING THOSE OF TUMOR SUPPRESSOR GENES (TSGS), THROUGH HYPERMETHYLATION. THESE FINDINGS PROVIDE NEW INSIGHTS INTO A MOLECULAR MECHANISM WHEREBY COOPERATIVITY BETWEEN TWO ONCOGENIC AGENTS LEADS TO ENHANCED ONCOGENIC ACTIVITY OF GASTRIC CANCER CELLS.IMPORTANCE WE HAVE STUDIED THE COOPERATIVITY BETWEEN H. PYLORI AND EBV, TWO KNOWN ONCOGENIC AGENTS. THIS LED TO AN ENHANCED ONCOGENIC PHENOTYPE IN GASTRIC EPITHELIAL CELLS. WE NOW DEMONSTRATE THAT EBV-DRIVEN EPIGENETIC MODIFICATIONS ARE ENHANCED IN THE PRESENCE OF H. PYLORI, MORE SPECIFICALLY, IN THE PRESENCE OF ITS CAGA SECRETORY ANTIGEN. THIS RESULTS IN INCREASED PROLIFERATION OF THE INFECTED GASTRIC CELLS. OUR FINDINGS NOW ELUCIDATE A MOLECULAR MECHANISM WHEREBY EXPRESSION OF CELLULAR DNA METHYL TRANSFERASES IS INDUCED INFLUENCING INFECTION BY EBV. HYPERMETHYLATION OF THE REGULATORY GENOMIC REGIONS OF TUMOR SUPPRESSOR GENES RESULTS IN THEIR SILENCING. THIS DRASTICALLY AFFECTS THE EXPRESSION OF CELL CYCLE, APOPTOSIS, AND DNA REPAIR GENES, WHICH DYSREGULATES THEIR ASSOCIATED PROCESSES, AND PROMOTION OF THE ONCOGENIC PHENOTYPE. 2018 15 194 28 ACETYLSHIKONIN SUPPRESSES INVASION OF PORPHYROMONAS GINGIVALIS?INFECTED YD10B ORAL CANCER CELLS BY MODULATING THE INTERLEUKIN-8/MATRIX METALLOPROTEINASE AXIS. THE DEVELOPMENT OF PHARMACEUTICAL AGENTS POSSESSING ANTI?INVASIVE AND ANTI?METASTATIC ABILITIES, AS WELL AS APOPTOTIC ACTIVITY, IS IMPORTANT IN DECREASING THE INCIDENCE AND RECURRENCE OF ORAL CANCER. CANCER CELLS ARE KNOWN TO ACQUIRE INVASIVENESS NOT ONLY THROUGH EPIGENETIC CHANGES, BUT ALSO FROM INFLAMMATORY STIMULI WITHIN THE TUMOR MICROENVIRONMENT. ACCORDINGLY, THE IDENTIFICATION OF AGENTS THAT CAN SUPPRESS THE INFLAMMATION?PROMOTED INVASIVENESS OF CANCER CELLS MAY BE IMPORTANT IN TREATING CANCER AND IMPROVING THE PROGNOSIS OF PATIENTS WITH CANCER. ACETYLSHIKONIN, A FLAVONOID WITH ANTI?INFLAMMATORY ACTIVITY, INHIBITS PROLIFERATION AND INDUCES APOPTOSIS OF ORAL CANCER CELLS. IN THE PRESENT STUDY, THE ANTI?INVASIVE EFFECT OF ACETYLSHIKONIN ON YD10B ORAL CANCER CELLS INFECTED WITH PORPHYROMONAS GINGIVALIS, A MAJOR PATHOGEN OF CHRONIC PERIODONTITIS, AND THE MECHANISMS INVOLVED WERE INVESTIGATED. FIRSTLY, WE EXAMINED WHETHER P. GINGIVALIS INFECTION INCREASED THE INVASIVENESS OF YD10B CELLS. RESULTS SUGGESTED THAT YD10B ORAL CANCER CELLS BECOME MORE AGGRESSIVE WHEN THEY ARE INFECTED WITH P. GINGIVALIS. SECONDLY, ACETYLSHIKONIN SIGNIFICANTLY INHIBITED THE INVASION OF P. GINGIVALIS?INFECTED YD10B CELLS BY SUPPRESSING IL?8 RELEASE AND IL?8?DEPENDENT MMP RELEASE. THESE DATA SUGGEST THAT ACETYLSHIKONIN MAY BE A USEFUL PREVENTIVE AND THERAPEUTIC CANDIDATE FOR ORAL CANCER THAT IS CHRONICALLY INFECTED WITH PERIODONTAL PATHOGENS. 2018 16 4438 27 MOLECULAR FINDINGS IN BARRETT'S EPITHELIUM. BARRETT'S METAPLASIA IS A PREMALIGNANT CONDITION AND REMAINS THE NUMBER ONE RISK FACTOR FOR DEVELOPING ADENOCARCINOMA. THE HISTOLOGIC CHANGES LEADING TO ADENOCARCINOMA ARE ACCOMPANIED BY GENETIC DISTURBANCES OF THE EPITHELIAL CELLS ITSELF AS WELL AS THE SURROUNDING STROMA. GENETIC AND EPIGENETIC EVENTS AFFECT THE CELL CYCLE, LEADING TO GROWTH SELF-SUFFICIENCY AND IGNORATION OF ANTIGROWTH SIGNALS. THE BALANCE OF CELL TURNOVER IS INSTABLE BY AVOIDANCE OF APOPTOSIS AND A GENERAL LIMITLESS OF THE REPLICATIVE POTENTIAL OF THE (MUTATED) STEM CELLS. SUSTAINED ANGIOGENESIS, NOT ONLY A CONSEQUENCE OF CHRONIC INFLAMMATION, MAY PRECEDE INVASION OF GENETICALLY INSTABLE (ANEUPLOID) CELLS. THE PRINCIPAL GENETIC CHANGES IN BARRETT'S CARCINOGENESIS ARE COMPARABLE TO THOSE KNOWN FROM OTHER EPITHELIAL MALIGNANCIES. LOSS OF P16 GENE EXPRESSION (BY DELETION OR HYPERMETHYLATION), THE LOSS OF P53 EXPRESSION (BY MUTATION AND DELETION), THE INCREASE IN CYCLIN EXPRESSION, AND THE LOSSES OF RB, APC AS WELL AS VARIOUS CHROMOSOMAL LOCI HAVE BEEN REPORTED. SINCE THESE GENETIC OR EPIGENETIC ALTERATIONS ARE NEITHER TUMOR NOR STAGE SPECIFIC, THEY COULD NOT GAIN DIAGNOSTIC SIGNIFICANCE AS BIOMARKERS UNTIL NOW. 2004 17 5767 29 SPECIES-SPECIFIC ROLE OF GENE-ADJACENT RETROELEMENTS IN HUMAN AND MOUSE GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (HP) INFECTION PROMOTES THE RECRUITMENT OF BONE MARROW STEM CELLS INTO CHRONIC GASTRITIS LESIONS. SOME OF THESE MARROW STEM CELLS CAN DIFFERENTIATE INTO GASTRIC EPITHELIAL CELLS AND NEOPLASTIC CELLS. WE PROPOSE THAT HP-ASSOCIATED METHYLATION COULD STABILIZE TRANS-DIFFERENTIATION OF MARROW-DERIVED STEM CELLS AND THAT AN UNSTABLE METHYLATION STATUS IS ASSOCIATED WITH A RISK OF GASTRIC CANCER. PATHOBIOLOGIC BEHAVIOR OF EXPERIMENTAL MOUSE GASTRIC CANCER IS MILD COMPARED TO INVASIVE AND METASTATIC HUMAN GASTRIC CANCER. DIFFERENCES IN EPIGENETIC STABILIZATION OF ADULT CELL PHENOTYPES BETWEEN HUMANS AND MICE COULD PROVIDE A FOUNDATION TO EXPLORE THE DEVELOPMENT OF INVASIVE AND METASTATIC GASTRIC CANCER. RETROELEMENTS ARE HIGHLY REPETITIVE SEQUENCES THAT PLAY AN ESSENTIAL ROLE IN THE GENERATION OF SPECIES DIVERSITY. IN THIS REVIEW, WE ANALYZED RETROELEMENTS ADJACENT TO HUMAN AND MOUSE HOUSEKEEPING GENES AND PROPOSED A POSSIBLE EPIGENETIC MECHANISM FOR HP-ASSOCIATED CARCINOGENESIS. 2018 18 4888 33 OXIDATIVE DAMAGE IN THE PROGRESSION OF CHRONIC LIVER DISEASE TO HEPATOCELLULAR CARCINOMA: AN INTRICATE PATHWAY. THE HISTO-PATHOLOGIC AND MOLECULAR MECHANISMS LEADING TO INITIATION AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STILL ILL-DEFINED; HOWEVER, THERE IS INCREASING EVIDENCE THAT THE GRADUAL ACCUMULATION OF MUTATIONS, GENETIC AND EPIGENETIC CHANGES WHICH OCCUR IN PRENEOPLASTIC HEPATOCYTES RESULTS IN THE DEVELOPMENT OF DYSPLASTIC FOCI, NODULES, AND FINALLY, OVERT HCC. AS WELL AS MANY OTHER NEOPLASIAS, LIVER CANCER IS CONSIDERED AN "INFLAMMATORY CANCER", ARISING FROM A CONTEXT OF INFLAMMATION, AND CHARACTERIZED BY INFLAMMATION-RELATED MECHANISMS THAT FAVOR TUMOR CELL SURVIVAL, PROLIFERATION, AND INVASION. MOLECULAR MECHANISMS THAT LINK INFLAMMATION AND NEOPLASIA HAVE BEEN WIDELY INVESTIGATED, AND IT HAS BEEN WELL ESTABLISHED THAT INFLAMMATORY CELLS RECRUITED AT THESE SITES WITH ONGOING INFLAMMATORY ACTIVITY RELEASE CHEMOKINES THAT ENHANCE THE PRODUCTION OF REACTIVE OXYGEN SPECIES. THE LATTER, IN TURN, PROBABLY HAVE A MAJOR PATHOGENIC ROLE IN THE CONTINUUM STARTING FROM HEPATITIS FOLLOWED BY CHRONIC INFLAMMATION, AND ULTIMATELY LEADING TO CANCER. THE RELATIONSHIP AMONGST CHRONIC LIVER INJURY, FREE RADICAL PRODUCTION, AND DEVELOPMENT OF HCC IS EXPLORED IN THE PRESENT REVIEW, PARTICULARLY IN THE LIGHT OF THE COMPLEX NETWORK THAT INVOLVES OXIDATIVE DNA DAMAGE, CYTOKINE SYNTHESIS, TELOMERE DYSFUNCTION, AND MICRORNA REGULATION. 2014 19 2943 21 GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES IN GASTRIC CANCER. BOTH GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR SUPPRESSOR AND TUMOR-RELATED GENES INVOLVED IN THE PATHOGENESIS OF GASTRIC CANCER ARE REVIEWED HERE, AND MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS ARE PROPOSED. GASTRIC CARCINOMAS ARE BELIEVED TO EVOLVE FROM NATIVE GASTRIC MUCOSA OR INTESTINAL METAPLASTIC MUCOSA THAT UNDERGOES GENETIC AND EPIGENETIC ALTERATIONS INVOLVING EITHER THE SUPPRESSOR PATHWAY (DEFECTS IN TUMOR SUPPRESSOR GENES) OR MUTATOR PATHWAY (DEFECTS IN DNA MISMATCH REPAIR GENES). METHYLATION OF E-CADHERIN IN NATIVE GASTRIC MUCOSA RESULTS IN UNDIFFERENTIATED CARCINOMAS (SUPPRESSOR PATHWAY), WHILE METHYLATION OF HMLHI RESULTS IN DIFFERENTIATED FOVEOLAR-TYPE CARCINOMAS (MUTATOR PATHWAY). THE MAJORITY OF DIFFERENTIATED GASTRIC CARCINOMAS HOWEVER, ARISE FROM INTESTINAL METAPLASTIC MUCOSA AND EXHIBIT STRUCTURAL ALTERATIONS OF TUMOR SUPPRESSOR GENES, ESPECIALLY P53. THEY APPEAR TO BE RELATED TO CHRONIC INJURY, PERHAPS DUE TO HELICOBACTER PYLORI INFECTION. APPROXIMATELY 20% OF DIFFERENTIATED CARCINOMAS (ORDINARY-TYPE) HAVE EVIDENCE OF MUTATOR PATHWAY TUMORIGENESIS. MUTATIONS OF E-CADHERIN ARE MAINLY INVOLVED IN THE PROGRESSION OF DIFFERENTIATED CARCINOMAS TO UNDIFFERENTIATED TUMORS. THE MOLECULAR PATHWAYS OF GASTRIC CARCINOGENESIS DEPEND ON THE HISTOLOGICAL BACKGROUND, AND GASTRIC CARCINOMAS SHOW DISTINCT BIOLOGICAL BEHAVIORS AS A RESULT OF DISCERNIBLE CELLULAR GENETIC AND EPIGENETIC ALTERATIONS. 2002 20 4558 26 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006