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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; EXPRESSION ; IN-VIVO ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; MECHANISM ; INDUCTION ; CYCLE ; ACID ; DNA methylation ; POLYPHENOLS ; RECEPTORS ; chemoprevention ; histone deacetylase inhibitor ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HYPERMETHYLATION ; RETINOIC ACID ; HYPOMETHYLATION ; INHIBITORS ; SUPPRESSOR GENES ; HISTONE ACETYLATION ; high-throughput analysis ; CPG-ISLAND METHYLATION ; chemopreventive agents ; TUMOR-SUPPRESSOR GENES ; epigenetic ; histone modifications ; DNA METHYLTRANSFERASE INHIBITORS ; chromatin modifications ; HISTONE METHYLATION ; ABERRANT CRYPT FORMATION ; DNA methyltransferase (DNMT) ; epigenomic ; GREEN TEA POLYPHENOLS ; histone acetyl transferase (HAT) ; histone deacetylase (HDAC) ; NORDIHYDROGUAIARETIC ACID NDGA ; sirtuins ; SMALL-MOLECULE ACTIVATORS
    Abstract: The term "epigenetics" refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for prevention strategies. The present review will give a comprehensive overview of the current literature on chemopreventive agents and their influence on major epigenetic mechanisms, that is DNA methylation, histone acetylation and methylation, and microRNAs, both in vitro and in rodent and human studies, taking into consideration specific mechanisms of action, target sites, concentrations, methods used for analysis, and outcome. Chemopreventive agents with reported mechanisms targeting the epigenome include micronutrients (folate, selenium, retinoic acid, Vit. E), butyrate, polyphenols (from green tea, apples, coffee, and other dietary sources), genistein and soy isoflavones, parthenolide, curcumin, ellagitannin, indol-3-carbinol (I3C) and diindolylmethane (DIM), mahanine, nordihydroguaiaretic acid (NDGA), lycopene, sulfur-containing compounds from Allium and cruciferous vegetables (sulforaphane, phenylethyl isothiocyanate (PEITC), phenylhexyl isothiocyanate (PHI), diallyldisulfide (DADS), allyl mercaptan (AM)), antibiotics (mithramycin A, apicidin), pharmacological agents (celecoxib, DFMO, 5-aza-2'-deoxycytidine and zebularine), compounds affecting sirtuin activity (resveratrol, dihydrocoumarin, cambinol), inhibitors of histone acetyl transferases (anacardic acid, garcinol, ursodeoxycholic acid), and relatively unexplored modulators of histone lysine methylation (chaetocin, polyamine analogues, n-3 polyunsaturated fatty acids). Their effects on global DNA methylation, tumor suppressor genes silenced by promoter methylation, histone modifications, and miRNAs deregulated during carcinogenesis have potential impact on multiple mechanisms relevant for chemoprevention, including signal transduction mediated by nuclear receptors and transcription factors such as NF-kappaB, cell cycle progression, cellular differentiation, apoptosis induction, senescence and others. In vivo studies that demonstrate the functional relevance of epigenetic mechanisms for chemopreventive efficacy are still limited. Future research will need to identify best strategies for chemopreventive intervention, taking into account the importance of epigenetic mechanisms for gene regulation.
    Type of Publication: Journal article published
    PubMed ID: 21158707
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  • 2
    Keywords: CANCER ; POPULATION ; RISK ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; FOLLICULAR LYMPHOMA ; TUMORIGENESIS ; NON-HODGKIN-LYMPHOMA ; COMMON VARIANTS ; NECROSIS-FACTOR TNF ; RAL GTPASES
    Abstract: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10-21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10-10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10-8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10-13 and 3.63 x 10-11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
    Type of Publication: Journal article published
    PubMed ID: 25261932
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  • 3
    Keywords: CANCER ; IDENTIFICATION ; MUTATIONS ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; LAMB2
    Abstract: More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only approximately 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P〈5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 x 10(-13)) and FAAH2 (rs5914101, P=4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain approximately 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
    Type of Publication: Journal article published
    PubMed ID: 26239645
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