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  • CANCERS  (3)
  • 1
    Keywords: CANCER ; PATIENT ; SWEDEN ; GASTRIC-CANCER ; familial cancer ; MUTATION CARRIERS ; gastric cancer ; CANCERS
    Type of Publication: Journal article published
    PubMed ID: 16698758
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; carcinoma ; CELL ; Germany ; human ; MODEL ; GENES ; transcription ; DIFFERENTIATION ; TISSUE ; TIME ; IFN-GAMMA ; MECHANISM ; TRANSCRIPTION FACTOR ; tumour ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; NO ; TRANSCRIPTION FACTORS ; HUMANS ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; EFFICIENT ; LYMPHOCYTES ; COLORECTAL CANCERS ; PROBES ; PERFORIN ; T-LYMPHOCYTES ; T lymphocyte ; REJECTION ; OVEREXPRESSION ; EFFECTOR ; T lymphocytes ; molecular ; MOLECULAR-MECHANISM ; FOXP3 ; TGF-BETA ; MOLECULAR-MECHANISMS ; LEVEL ; function ; lymph node metastases ; LYMPH-NODE ; correlation ; EVALUATE ; GUT ; CANCERS ; regulatory T cells ; colorectal ; IFN-GAMMA PRODUCTION ; MEDIATED SUPPRESSION ; REGULATED EXPRESSION
    Abstract: Background/aims: An efficient cytolytic T cell function is essential for immune mediated rejection of colorectal cancer. However, the molecular mechanisms driving T cell mediated cancer rejection are still poorly understood. Here, we assessed the relevance of the T-box transcription factor eomesodermin in colorectal cancer. Methods/results: By analysing tissue probes from 88 different colorectal tumours, a significant ( p〈0.02) inverse correlation between eomesodermin expression in colorectal cancers and the presence of lymph node metastases could be shown, whereas no such correlation was noted for the master transcription factor of regulatory T cells, FoxP3 and CD8alpha expression. To evaluate whether this effect might be due to effects of eomesodermin on tumour infiltrating CD8 T cells, we subsequently analysed the regulated expression and function of this transcription factor in human T cells. Whereas overexpression of this factor induced perforin but not granzyme expression, siRNA mediated suppression of eomesodermin expression led to significantly reduced IFN-gamma production, perforin levels and cytolytic activity of CD8 T cells. Furthermore, TGF-beta and IL4 could be identified as important inducer of eomesodermin expression. Conclusion: These data define for the first time a regulatory role of eomesodermin for CD8 T cell activity in humans. Our findings are consistent with a model in which eomesodermin expression in tumour infiltrating T cells regulates cytolytic functions of CD8 T cells via perforin expression. These data provide novel insights into control mechanisms governing the functional activity of human CD8 T lymphocytes via T-box transcription factors in cancer
    Type of Publication: Journal article published
    PubMed ID: 17566017
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  • 3
    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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