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  • 1
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    Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention
    PLoS ONE 7 (1), e29605- 
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    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
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=31007
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  • 2
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    Genetic polymorphisms in mediators of inflammation and gastric precancerous lesions
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    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; Germany ; POPULATION ; RISK ; GENE ; GENES ; NITRIC-OXIDE SYNTHASE ; INFECTION ; CARCINOGENESIS ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; NO ; PROMOTER ; RATES ; VARIABILITY ; HELICOBACTER-PYLORI ; INTERFERON-GAMMA ; inflammation ; ONCOLOGY ; RE ; SNPs ; GRADE ; HELICOBACTER-PYLORI INFECTION ; USA ; nitric oxide synthase ; cyclooxygenase ; PROMOTER VARIANT ; Helicobacter pylori ; HIGH-RISK POPULATION ; VENEZUELA ; NUCLEOTIDE ; ANTRUM ; gastric premalignant lesions ; interferon gamma ; VACA
    Abstract: Chronic inflammation induced by Helicobacter pylori is a key process in gastric carcinogenesis. We hypothesized that genetic polymorphisms in important mediators of H. pylori-induced inflammation may influence the risk of developing various grades of precancerous lesions. We studied the associations between single nucleotide polymorphisms (SNPs) in cyclooxygenase 1 and 2 (PTGS1 and PTGS2), inducible nitric oxide synthase (NOS2A), interferon gamma (IFNG) and its receptor (IFNGR1), and risk of gastric precancerous lesions in a Venezuelan population characterized by high rates of H. pylori infection. We found no association of precancerous lesions with SNPs in PTGS1 and in IFNG. A nonsynonymous SNP of NOS2A (Ser608Leu) and an SNP located in the promoter of IFNGR1 (C-56T) were associated with higher risk of atrophic gastritis [odds ratio (OR)= 1.37, 95% confidence interval (CI)=1.01-1.86, and OR=1.49, 95% CI=1.01-2.19, respectively]. Two SNPs; of PTGS2 were associated with risk of dysplasia (OR = 1.60, 95% CI = 1.01 -2.54, and OR = 0.66, 95% CI = 0.43-0.99). We conclude that genetic variability in the genes we studied does not play a major role in the early stages of gastric carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 18287876
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=5678
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  • 3
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    Endogenous sex steroids and risk of cervical carcinoma: results from the EPIC study
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    Keywords: CANCER ; carcinoma ; MODEL ; RISK ; TUMORS ; INFECTION ; ASSOCIATION ; HEALTH ; WOMEN ; cervical intraepithelial neoplasia ; VALIDITY ; nutrition ; BREAST-CANCER RISK ; POSTMENOPAUSAL WOMEN ; SERUM ; ESTROGEN ; HORMONES ; COLLABORATIVE REANALYSIS ; CONTRACEPTIVES ; INDIVIDUAL DATA
    Abstract: Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC). Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection-related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E(2)); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone-binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E(2) were calculated from absolute concentrations of T, E(2), and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression. Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile 5.16, 95% CI, 1.50-20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E(2), fE(2), and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR 3.14; 95% CI, 1.21-9.37), whereas E(2) and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women. Conclusions: Our findings suggest for the first time that T and possibly E(2) may be involved in the etiology of ICC. Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring.
    Type of Publication: Journal article published
    PubMed ID: 21994406
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=27803
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  • 4
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    Host-bacterial interaction in the development of gastric precancerous lesions in a high risk population for gastric cancer in Venezuela
    International Journal of Cancer 119 (7), 1666-1671 
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    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
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=3339
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  • 5
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    Genetic polymorphisms in anti-inflammatory cytokine signaling and the prevalence of gastric precancerous lesions in Venezuela
    Cancer Causes and Control 17 (9), 1183-1191 
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    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
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=3340
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  • 6
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    Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signaling and gastric precancerous lesions in a population at high risk for gastric cancer
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    Keywords: CANCER ; POPULATION ; RISK ; GENE ; GENES ; GENETIC POLYMORPHISMS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; MUTATIONS ; MYOCARDIAL-INFARCTION ; PREVALENCE ; ULCERATIVE-COLITIS ; CROHNS-DISEASE ; INFLAMMATORY-BOWEL-DISEASE ; ASSOCIATIONS ; PROMOTER POLYMORPHISM ; development ; CD14 GENE ; HELICOBACTER-PYLORI INFECTION ; GENOTYPE ; lipopolysaccharide ; Helicobacter pylori ; stomach cancer ; premalignant lesions ; ASP299GLY POLYMORPHISM ; RECEPTOR-4 GENE
    Abstract: As Helicobacter pylori (HP) is a Gram-negative bacterium, we investigated the associations between several functional polymorphisms in genes involved in lipopolysaccharide (LPS) signaling and the prevalence of various stages of gastric premalignant lesions in a Venezuelan population. The two NOD2 polymorphisms, del3020insC and Gly908Arg, were too infrequent to study their associations with gastric lesions. The risk of intestinal metaplasia (IM) was significantly increased among subjects with the CD14 T-260 allele compared to those without this allele. A similar, but nonsignificant increase in risk for dysplasia was observed among homozygotes of this allele. There was no association between TLR4 Asp299Gly polymorphism and any type of lesions, except for a slight nonsignificant increase in risk of IM associated with the AA genotype among subjects with a higher histological HP score. These results suggest that genetic polymorphisms in HP LPS signaling may be implicated in the development of intermediate stages of gastric premalignant lesions
    Type of Publication: Journal article published
    PubMed ID: 17171451
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=4614
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  • 7
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    Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions
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    Keywords: CANCER ; carcinoma ; DIAGNOSIS ; FOLLOW-UP ; RISK ; GENE ; GENES ; ACCURACY ; DNA ; INFECTION ; MARKER ; CARCINOGENESIS ; ASSOCIATION ; POLYMORPHISMS ; VARIANTS ; TRIAL ; LESIONS ; PROGRESSION ; EXPERIENCE ; DIFFERENCE ; RATES ; POLYMERASE-CHAIN-REACTION ; STOMACH ; INDIVIDUALS ; CHAIN-REACTION ; chemoprevention ; GASTRIC-CANCER ; HELICOBACTER-PYLORI ; BIOPSY ; CHAIN ; ONCOLOGY ; REGRESSION ; RE ; VARIANT ; INCREASE ; polymerase chain reaction ; gastric cancer ; development ; INTERVAL ; methods ; GENOTYPE ; TESTS ; STRAINS ; USA ; odds ratio ; SPECIMENS ; Helicobacter pylori ; BIOPSIES ; LOGISTIC-REGRESSION ; CAGA ; gastric ; HIGH-RISK POPULATION ; VENEZUELA
    Abstract: Background Helicobacter pylori infection is associated with the development of gastric cancer. Although infection with an H. pylori strain containing the cytotoxin-associated (cag A) gene (a marker for a pathogenicity island) may increase the risk of atrophic gastritis and gastric cancer, the relationship of variants in pathogenic H. pylori genes to the severity and progression of precancerous lesions is not well defined. Methods Gastric biopsy specimens were obtained at enrollment from 2145 participants in a chemoprevention trial in Tachira State, Venezuela, and examined histologically to determine the severity of precancerous lesions. The presence of H. pylori DNA in gastric biopsies and the strain type according to presence or absence of the cagA gene were detected by polymerase chain reaction and specific probes. The relationship between H. pylori DNA and histologic diagnosis was analyzed by polytomous logistic regression. Rates of progression and regression of precancerous lesions were determined from biopsies from additional annual gastroscopies (mean follow-up = 3.5 years). All statistical tests were two-sided. Results At enrollment, there was a strong association between cagA-positive H. pylori infection and the severity of gastric precancerous lesions, but cagA-negative H. pylori was associated only with chronic gastritis. Using individuals with normal mucosa or superficial gastritis as control subjects, the odds ratio for dysplasia was 15.5 (95% confidence interval [CI] = 6.42 to 37.2) in cagA-positive individuals compared with uninfected individuals and 0.90 (95% CI = 0.37 to 2.17) for individuals infected with cagA-negative H. pylori compared with uninfected individuals. Individuals infected with cagA-positive H. pylori appeared more likely to experience progression (and less likely to experience regression) of precancerous lesions than those infected with cagA-negative H. pylori, but the differences did not attain statistical significance. Conclusions This large epidemiologic study shows a strong relationship between the presence of H. pylori DNA in gastric biopsies and the severity of precancerous lesions that is specific to cagA-positive strains. The association between H. pylori and gastric carcinoma may have been previously underestimated due to the poor accuracy of serologic H. pylori markers and lack of discrimination by cagA genotype
    Type of Publication: Journal article published
    PubMed ID: 17728213
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=4979
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