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  • 1
    Keywords: CANCER ; CELLS ; DISEASE ; GENE ; PROTEIN ; INFECTION ; ASSOCIATION ; ESCHERICHIA-COLI ; PRECANCEROUS LESIONS ; COMPLETE GENOME SEQUENCE ; VIRULENCE FACTORS ; CAG-PATHOGENICITY ISLAND ; CODON USAGE BIAS ; IV SECRETION SYSTEM
    Abstract: Helicobacter pylori (HP) is a bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa. Persistent Hp infection often induces gastritis and is associated with the development of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Virulent HP isolates harbor the cag (cytotoxin-associated genes) pathogenicity island (cagPAI), a 40 kb stretch of DNA that encodes components of a type IV secretion system (T4SS). This T4SS forms a pilus for the injection of virulence factors into host target cells, such as the CagA oncoprotein. We analyzed the genetic variability in cagA and other selected genes of the HP cagPAI (cagC, cagE, cagL, cagT, cagV and cag Gamma) using DNA extracted from frozen gastric biopsies or from clinical isolates. Study subjects were 95 cagA+ patients that were histologically diagnosed with chronic gastritis or gastric cancer in Venezuela and Mexico, areas with high prevalence of Hp infection. Sequencing reactions were carried out by both Sanger and next-generation pyrosequencing (454 Roche) methods. We found a total of 381 variants with unambiguous calls observed in at least 10% of the originally tested samples and reference strains. We compared the frequencies of these genetic variants between gastric cancer and chronic gastritis cases. Twenty-six SNPs (11 non-synonymous and 14 synonymous) showed statistically significant differences (P〈0.05), and two SNPs, in position 1039 and 1041 of cagE, showed a highly significant association with cancer (p-value = 2.07x10), and the variant codon was located in the VirB3 homology domain of Agrobacterium. The results of this study may provide preliminary information to target antibiotic treatment to high-risk individuals, if effects of these variants are confirmed in further investigations.
    Type of Publication: Journal article published
    PubMed ID: 22235308
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  • 2
    Keywords: POPULATION ; POLYMORPHISMS ; BLADDER-CANCER ; STOMACH-CANCER ; PRECANCEROUS LESIONS ; STEM-CELL ANTIGEN ; METAANALYSIS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; VENEZUELA
    Abstract: SNPs in the Prostate Stem Cell Antigen (PSCA) gene have been found associated with gastric cancer (GC) risk in a genome-wide association study. This association has been replicated in several populations. In this study we assessed the impact of PSCA genotype on the risk of advanced gastric precancerous lesions and GC. We used baseline gastric histopathology data and DNA from frozen gastric biopsies of 2045 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela, and 180 cases of GC from the same area. We analyzed 3 SNPs in the PSCA gene (rs2294008, rs9297976 and rs12155758) which were previously found to be associated with GC risk in Europeans. The T allele of rs2294008 was found to be associated with a higher prevalence of atrophic gastritis (OR = 1.44; 95% CI 1.03-2.01 for the dominant model) and intestinal metaplasia (OR = 1.50; 95% CI 1.13-1.98 for the dominant model). We also confirmed the association with higher risk of gastric cancer (OR = 2.34; 95% CI 1.36-4.01 for the allele carriers). SNP rs12155758 was not associated with risk of gastric preneoplastic lesions, but we confirmed its association with higher GC risk (OR 1.95; 95% CI 1.29-2.97 for dominant model). We tested the relevance of the presence of the Helicobacter pylori cagA gene, which is known to increase the risk of more severe gastric lesions, but we did not find any clearcut interaction with PSCA SNPs in defining risk of gastric precancerous lesions or cancer.
    Type of Publication: Journal article published
    PubMed ID: 24023815
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  • 3
    Keywords: CANCER ; POPULATION ; RISK ; PROTEIN ; NF-KAPPA-B ; INFECTION ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; ALPHA ; cytokines ; STAGE ; LESIONS ; NUMBER ; NECROSIS-FACTOR-ALPHA ; HIGH-RISK ; EPITHELIAL-CELLS ; POPULATIONS ; PREVALENCE ; GASTRIC-CANCER ; HELICOBACTER-PYLORI ; TNF-ALPHA ; PRECANCEROUS LESIONS ; CYTOKINE ; REGRESSION ; ASSOCIATIONS ; gastric cancer ; MONOCYTE CHEMOATTRACTANT PROTEIN-1 ; INTERVAL ; HELICOBACTER-PYLORI INFECTION ; odds ratio ; AA ; Helicobacter pylori ; intestinal metaplasia ; premalignant ; stomach cancer ; INTERLEUKIN-1 POLYMORPHISMS ; CAGA PROTEIN ; CHEMOTACTIC CYTOKINES ; CHINESE POPULATION ; premalignant lesions
    Abstract: Helicobacter pylori (HP) infection affects over 50 % of the world's population. The prevalence is over 90% in populations at high risk for gastric cancer, but clinical outcomes of the infection are highly variable and thus host genetic factors have been suggested to play a role in its outcomes in addition to bacterial factors. In this study, we examined the effects of common functional genetic polymorphisms of several proinflammatory cytokines known to be overexpressed in HP-infected gastric mucosa on the risk of various stages of gastric premalignant lesions. The odds ratios (ORs) and 95% confidence intervals (CI) for atrophic gastritis, intestinal metaplasia and dysplasia were estimated by multinominal logistic regression analysis among 2,033 Venezuelan subjects. There was a significant effect of IL8-251A allele on the prevalence of dysplasia (p = 0.021). The OR associated with the A-allele was 1.34 (95% CI: 0.82-2.18) for heterozygotes and 2.00 (95% CI: 1.13-3.56) for homozygotes, compared with the TT genotype. Furthermore, there was a statistically significant interaction between the number of A-alleles and HP cag A genotype (p = 0.009), suggesting that the A-allele increased the risk of dysplasia only when cag A was present. The OR for the AA compared with TT genotype was 3.22 (95% CI: 1.60-6.52) in this group. There were no associations with other proinflammatory cytokines studied, i.e., IL1 beta, 1L6, monocyte chemoattractant protein I (MCP1) and TNF alpha, or with other stages of premalignant lesions. The present study provides important evidence suggesting host-bacterial interactions in the development of gastric precancerous lesions. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16671087
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  • 4
    Keywords: CANCER ; EXPRESSION ; MODEL ; MODELS ; POPULATION ; RISK ; GENE ; INFECTION ; RISK-FACTORS ; CARCINOGENESIS ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; ALPHA ; STAGE ; LESIONS ; CIGARETTE-SMOKING ; risk factors ; smoking ; RATES ; PREVALENCE ; HELICOBACTER-PYLORI ; PRECANCEROUS LESIONS ; signaling ; CYTOKINE ; REGRESSION ; INCREASE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; INTERVAL ; HELICOBACTER-PYLORI INFECTION ; ROLES ; INCREASED RISK ; odds ratio ; RISK-FACTOR ; Helicobacter pylori ; intestinal metaplasia ; stomach cancer ; ENVIRONMENTAL-FACTORS ; premalignant lesions ; anti-inflammatory cytokines ; IL-10 ; INTERLEUKIN-4 RECEPTOR GENE
    Abstract: Objectives The aim of the study was to assess the effects of genetic polymorphisms in anti-inflammatory mediators, i.e., IL10, IL4 and IL4R on the prevalence of gastric precancerous lesions and their interactions with other environmental factors. Methods The study population consisted of 2,033 Venezuelan subjects known to have extremely high Helicobacter Pylori (HP) infection rates. The odds ratios (OR) and 95% confidence intervals (CI) associated with these polymorphisms were estimated by multinominal logistic regression models for gastric precursor lesions. Results We found a 60% increase in risk of intestinal metaplasia (IM) and dysplasia combined (OR 1.62, 95% CI: 1.10-2.38) among the carriers of the IL10-1082 low activity allele. This increased risk was more pronounced for dysplasia than for IM. On the other hand, homozygotes with the low activity allele of the A398G polymorphism in the IL4R gene had a modest increase in risk of atrophic gastritis (OR = 1.52, 95% CI: 1.05-2.21), compared with homozygotes of the high activity allele. There were no statistically significant synergetic interactions between these polymorphisms and environmental risk factors (low fruit intake, high starchy vegetable intake and cigarette smoking) for these lesions. Conclusion While the results of the present study suggest roles of genetic variability in these anti-inflammatory mediators in different stages of gastric carcinogenesis, there is high likelihood that they were chance findings due to multiple comparisons
    Type of Publication: Journal article published
    PubMed ID: 17006724
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