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  • GENE  (5)
  • 1
    Keywords: CANCER ; carcinoma ; SYSTEM ; HEPATOCELLULAR-CARCINOMA ; incidence ; liver ; POPULATION ; RISK ; RISKS ; GENE ; GENES ; FAMILY ; primary ; tumour ; MEMBER ; MEMBERS ; ASSOCIATION ; CANDIDATE GENE ; SUSCEPTIBILITY ; AGE ; ovarian cancer ; OVARIAN-CANCER ; CERVICAL-CANCER ; bladder cancer ; BLADDER-CANCER ; SWEDEN ; DATABASE ; SIR ; familial risk ; CARRIERS ; FAMILY-CANCER DATABASE ; bile duct ; BILE-DUCTS ; CHOLECYSTECTOMY ; GALLBLADDER-CANCER ; RELATIVES ; VIRAL-HEPATITIS
    Abstract: Background and aims: Familial risks in liver and biliary cancers have been assessed in small case control studies, usually based on reported, but not medically verified, cancers in family members. Thus the degree of familial clustering for these cancers remains to be established. Methods: The nationwide Swedish Family-Cancer Database was used, covering 10.2 million individuals for the years 1961-1998 from the Swedish Cancer Registry. Liver and biliary tract cancers were identified from 1121 offspring between the ages of 0 and 66 years and 17 131 parents. Standardised incidence ratios (SIRs) and 95% confidence intervals (Cls) were calculated for cancers in family members. Results: All cancers in the liver and biliary system showed a familial SIR of 1.65 (95% Cl 1.05- 2.46). This was mainly explained by a high risk for familial gall bladder cancer (SIR 5.21 (95% Cl 2.07-10.80)) and for familial primary liver cancer with hepatocellular carcinoma histology (SIR 4.69 (95% Cl 1.48-11.04)). For gall bladder and hepatocellular cancer, maternal transmission appeared to be favoured. Gall bladder cancer was associated with pancreatic cancer (SIR 2.39 (95% Cl 1.23-4.18)). Primary liver cancer was associated with cervical, urinary bladder, and endocrine gland tumours. Cancer in extrahepatic bile ducts was associated with ovarian cancer and that in ampulla of Vater with thyroid cancer; however, these associations may have been fortuitous. Conclusions: This study has provided the first data on familial clustering of liver and gall bladder cancers, based on medically confirmed records. The risks were so high that heritable factors were likely to contribute, possibly modified by environmental factors. The demonstration of candidate genes would help to further characterise the familial risks
    Type of Publication: Journal article published
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  • 2
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; IN-VITRO ; carcinoma ; Germany ; human ; PATHWAY ; GENE ; GENE-EXPRESSION ; microarray ; PROTEIN ; DIFFERENTIATION ; TISSUE ; PATIENT ; NF-KAPPA-B ; DNA ; recombination ; INDUCTION ; colon ; TISSUES ; ASSAY ; microarrays ; MOBILITY ; DNA-REPAIR ; REPAIR ; DNA-BINDING ; COLON-CANCER ; CHROMATIN PROTEIN ; CYTOCHROME-C ; GLYCATION END-PRODUCTS ; OVEREXPRESSION ; DNA repair ; LEVEL ; ASSAYS ; LOCUS ; INHIBITS APOPTOSIS ; BCL-2 FAMILY-MEMBERS ; REL FAMILY
    Abstract: Background: High mobility group box 1 (HMGB1) is a non-histone chromosomal protein implicated in a variety of biologically important processes, including transcription, DNA repair, V(D)J recombination, differentiation, and development. Overexpression of HMGB1 inhibits apoptosis, arguing that the molecule may act as an antiapoptotic oncoprotein. Indeed, increased expression of HMGB1 has been reported for several different tumour types. In this study, we analysed human colon carcinoma for HMGB1 as well as for c-IAP2 expression levels. c-IAP2 is an antiapoptotic protein which may be upregulated as a consequence of nuclear factor kappa B (NF kappa B) activation via HMGB1. Methods: A comparative genomic hybridisation (CGH) database comprising 1645 cases from different human tumour types was screened to detect cytogenetic changes at the HMGB1 locus. Immunohistochemical staining of human colon tissue microarrays and tumour biopsies, as well as western blot analysis of tumour lysates, were performed to detect elevated HMGB1 and c-IAP2 expression in colon carcinomas. The antiapoptotic potential of HMGB1 was analysed by measuring caspase activities, and luciferase reporter assays and quantitative polymerase chain reaction analysis were employed to confirm NFkB activation and c-IAP2 mRNA upregulation on HMGB1 overexpression. Results: According to CGH analysis, the genomic locus containing the HMGB1 gene was overrepresented in one third (35/96) of colon cancers. Correspondingly, HMGB1 protein levels were significantly elevated in 90% of the 60 colon carcinomas tested compared with corresponding normal tissues evaluable from the same patients. HMGB1 increased NFkB activity and led to co-overexpression of the antiapoptotic NFkB target gene product c-IAP2 in vitro. Furthermore, increased HMGB1 levels correlated with enhanced amounts of c-IAP2 in colon tumours analysed by us. Finally, we demonstrated that HMGB1 overexpression suppressed caspase-9 and caspase-3 activity, suggesting that HMGB1 interferes with the apoptotic machinery at the level of apoptosomal caspase-9 activation. Conclusions: We identified in vitro a molecular pathway triggered by HMGB1 to inhibit apoptosis via c-IAP2 induction. Our data indicate a strong correlation between upregulation of the apoptosis repressing HMGB1 and c-IAP2 proteins in the pathogenesis of colon carcinoma
    Type of Publication: Journal article published
    PubMed ID: 16118352
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  • 3
    Keywords: EXPRESSION ; Germany ; human ; DISEASE ; GENE ; GENES ; METABOLISM ; DIFFERENTIATION ; cell cycle ; CYCLE ; SEQUENCE ; SEQUENCES ; ARRAYS ; ATROPHY ; SMALL-INTESTINE ; expression profiling ; CELL-DIFFERENTIATION ; DISORDERS ; LEVEL ; AXES ; CRYPT ; DUODENUM ; FUNCTIONAL-GROUPS
    Abstract: Background and aims: Perturbation of differentiation of the crypt-villus axis of the human small intestine is associated with several intestinal disorders of clinical importance. At present, differentiation of small intestinal enterocytes in the crypt-villus axis is not well characterised. Subjects and methods: Expression profiling of microdissected enterocytes lining the upper part of crypts or the middle of villi was performed using the Affymetrix X3P arrays and several methods for confirmation. Results: A total of 978 differentially expressed sequences representing 778 unique UniGene IDs were found and categorised into four functional groups. In enterocytes lining the upper part of crypts, cell cycle promoting genes and transcription/translation related genes were predominantly expressed, whereas in enterocytes lining the middle of villi, high expression of cell cycle inhibiting genes, metabolism related genes, and vesicle/transport related genes was found. Conclusion: Two types of enterocytes were dissected at the molecular level, the non-absorptive enterocyte located in the upper part of crypts and the absorptive enterocyte found in the middle of villi. These data improve our knowledge about the physiology of the crypt-villus architecture in human small intestine and provide new insights into pathophysiological phenomena, such as villus atrophy, which is clinically important
    Type of Publication: Journal article published
    PubMed ID: 16556670
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; DISEASE ; SITES ; GENE ; GENE-EXPRESSION ; SAMPLES ; transcription ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; T cells ; T-CELL ; AMPLIFICATION ; immunohistochemistry ; gene expression ; ASSAY ; resistance ; INDUCED APOPTOSIS ; PATHOGENESIS ; EPITHELIAL-CELLS ; INVOLVEMENT ; KAPPA-B ; expression profiling ; microdissection ; ULCERATIVE-COLITIS ; inflammation ; INFLAMMATORY-BOWEL-DISEASE ; CANDIDATE GENES ; INTERCELLULAR-ADHESION MOLECULE-1 ; FAS LIGAND ; DYSFUNCTION ; POLYMERASE ; DEATH LIGAND ; MONOCYTE ADHESION
    Abstract: Aims: Both epithelial barrier dysfunction and apoptosis resistance of immune cells contribute to the pathogenesis of Crohn's disease. The soluble decoy receptor 3 (DcR3) acts in an anti-apoptotic manner by neutralising the death ligand CD95L. Here, we investigated the possible involvement of DcR3 in Crohn's disease. Methods: The epithelial fraction of human small intestinal mucosa samples was obtained by laser microdissection. Expression of DcR3 was examined by global gene expression profiling, quantitative reverse transcription polymerase chain reaction, immunoblot analysis, and immunohistochemistry. DcR3 concentrations in the serum of patients with Crohn's disease were measured by enzyme-linked immunosorbent assay. Apoptosis assays were performed to study the effects of DcR3 in intestinal epithelial cells and lamina propria T cells. Results: DcR3 is over-expressed in the epithelial layer of ileum specimens in patients with Crohn's disease, both at actively inflamed and non-active sites. DcR3 serum levels are significantly elevated in patients with active and non-active Crohn's disease as compared to healthy controls. The expression of DcR3 in intestinal epithelial cells is induced by tumour necrosis factor a. Increased DcR3 expression is associated with activation of nuclear factor kappa B (NF-kappa B) and results in protection of intestinal epithelial cells and lamina propria T cells from CD95L-induced apoptosis. Conclusions: DcR3 may promote inflammation in Crohn's disease by inhibiting CD95L-induced apoptosis of epithelial and immune cells as well as by inducing NF-kappa B activation
    Type of Publication: Journal article published
    PubMed ID: 19039087
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  • 5
    Keywords: CANCER ; COMMON ; RISK ; GENE ; GENES ; DNA ; colon ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; HUMANS ; MUTATION ; REPAIR ; MEN ; OBESITY ; risk factors ; smoking ; cancer risk ; DAMAGE ; COLON-CANCER ; INSTABILITY ; microsatellite instability ; MUTATIONS ; STABILITY ; DIET ; GERMLINE ; RISK ASSESSMENT ; ALCOHOL ; HETEROGENEITY ; ADULT ; colon cancer ; interaction ; MLH1 ; methods ; GENOTYPE ; GENOTYPE DATA ; female ; Male ; INCREASED RISK ; CANCERS ; CANCER-RISK ; Aged ; Middle Aged ; Gene Frequency ; MSH6 ; DNA Mismatch Repair ; United States ; INVESTIGATE ; Lifestyle factors ; Nuclear Proteins/*genetics ; *Life Style ; Adaptor Proteins,Signal Transducing/*genetics ; Colonic Neoplasms/*genetics ; Colorectal Neoplasms,Hereditary Nonpolyposis/genetics ; Diet/adverse effects ; DNA Mismatch Repair/*genetics ; DNA-Binding Proteins/*genetics ; Germ-Line Mutation/genetics ; Mutation,Missense/genetics ; Polymorphism,Genetic/*genetics
    Abstract: BACKGROUND: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. METHODS: A study was conducted to examine whether MLH1 (-93G〉A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity. RESULTS: The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G〉A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03). CONCLUSIONS: The MSH6 Gly39Glu and MLH1 -93G〉A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.
    Type of Publication: Journal article published
    PubMed ID: 18523027
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