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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
    Abstract: BACKGROUND: Increased levels of thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) are associated with differentiated thyroid carcinoma (TC) risk, but strong epidemiological evidence is lacking. METHODS: Three hundred fifty-seven incident TC case patients (n = 300 women and 57 men; mean age at blood collection = 51.5 years) were identified in the EPIC cohort study and matched with 2 (women) or 3 (men) control subjects using incidence density sampling. Matching included study center, sex, age, date, time, and fasting status at blood collection. Levels of total and free (f) thyroxine (T4) and triiodo-thyronine (T3), TSH, Tg, and anti-Tg antibodies (TgAb) were measured by commercially available immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. All statistical tests were two-sided. RESULTS: TC risk was positively associated with Tg (OR for the highest vs lowest quartile = 9.15; 95% CI = 5.28 to 15.90; P 〈 .001) and negatively associated with TSH level (OR = 0.56; 95% CI = 0.38 to 0.81; P = .001). Odds ratios were not modified by adjustment for weight and height and were consistent across sexes, age groups, and countries. The association with Tg was stronger in follicular than papillary TC. The odds ratio for TgAb-positivity was 1.50 (95% CI = 1.05 to 2.15; P = .03). Among case patients, TSH level was stable over time, whereas Tg level was higher in proximity to TC diagnosis. Areas under the receiver operating characteristic curve were 57% and 74% for TSH and Tg level, respectively. CONCLUSIONS: High Tg levels precede by up to 8 years the detection of TC, pointing to a long sojourn time of the disease. Low TSH levels may predispose to TC onset. Neither marker has sufficient accuracy to be a screening test.
    Type of Publication: Journal article published
    PubMed ID: 24824312
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  • 4
    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
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  • 5
    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
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  • 6
    Keywords: POPULATION ; ASSOCIATION ; antibodies ; PANCREATIC-CANCER ; SEROPREVALENCE ; GROUP ALLELES ; ANTIGEN-BINDING ADHESIN ; SECRETOR STATUS ; IV SECRETION ; LEWIS
    Abstract: A higher incidence of stomach cancer in ABO blood type A individuals than in those with blood type O has been known for a long time. We studied this association in relation to Helicobacter pylori (Hp) of different cagA status. For our study, we used baseline gastric histopathology data and DNAs from frozen gastric biopsies of 2,077 subjects enrolled in a chemoprevention trial for gastric precancerous lesions in Venezuela. We analyzed six single nucleotide polymorphisms in the ABO gene, and we assessed the presence of the Hp cagA gene. Odds ratios (ORs) for risk of advanced precancerous gastric lesions were calculated using individuals with normal gastric epithelium or non-atrophic gastritis as a reference. Among individuals carrying a cagA negative Hp infection or no Hp infection, those with blood type A had a lower risk of intestinal metaplasia (IM) and dysplasia than those with blood type O (OR=0.60; 95% CI 0.38-0.94). In carriers of cagA positive Hp strains, individuals with blood type A had a higher risk of IM or dysplasia than those with blood type O (OR=1.42, 95% CI 1.09-1.86) and a higher risk if compared to subjects carrying cagA negative strain and non-A blood group (OR=3.82, 95% CI=2.80-5.20). The interaction between Hp cagA status and blood type was statistically significant (p=0.0006). We showed that SNPs in the ABO gene, predictive of ABO blood groups, are associated with risk of advanced precancerous gastric lesions in individuals infected with Hp, but the assessment of the risk is strictly dependent on cagA status.
    Type of Publication: Journal article published
    PubMed ID: 23319424
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  • 7
    Abstract: BACKGROUND: New oral treatments with very high cure rates have the potential to revolutionize global management of hepatitis C virus (HCV), but population-based data on HCV infection are missing in many low and middle-income countries (LMIC). METHODS: Between 2004 and 2009, dried blood spots were collected from age-stratified female population samples of 9 countries: China, Mongolia, Poland, Guinea, Nepal, Pakistan, Algeria, Georgia and Iran. HCV antibodies were detected by a multiplex serology assay using bead-based technology. RESULTS: Crude HCV prevalence ranged from 17.4% in Mongolia to 0.0% in Iran. In a pooled model adjusted by age and country, in which associations with risk factors were not statistically heterogeneous across countries, the only significant determinants of HCV positivity were age (prevalence ratio for 〉/=45 versus 〈35 years = 2.84, 95%CI 2.18-3.71) and parity (parous versus nulliparous = 1.73, 95%CI 1.02-2.93). Statistically significant increases in HCV positivity by age, but not parity, were seen in each of the three countries with the highest number of HCV infections: Mongolia, Pakistan, China. There were no associations with sexual partners nor HPV infection. HCV prevalence in women aged 〉/=45 years correlated well with recent estimates of female HCV-related liver cancer incidence, with the slight exception of Pakistan, which showed a higher HCV prevalence (5.2%) than expected. CONCLUSIONS: HCV prevalence varies enormously in women worldwide. Medical interventions/hospitalizations linked to childbirth may have represented a route of HCV transmission, but not sexual intercourse. Combining dried blood spot collection with high-throughput HCV assays can facilitate seroepidemiological studies in LMIC where data is otherwise scarce.
    Type of Publication: Journal article published
    PubMed ID: 28168002
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  • 8
    Abstract: BACKGROUND: Increased levels of thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) are associated with differentiated thyroid carcinoma (TC) risk, but strong epidemiological evidence is lacking. METHODS: Three hundred fifty-seven incident TC case patients (n = 300 women and 57 men; mean age at blood collection = 51.5 years) were identified in the EPIC cohort study and matched with 2 (women) or 3 (men) control subjects using incidence density sampling. Matching included study center, sex, age, date, time, and fasting status at blood collection. Levels of total and free (f) thyroxine (T4) and triiodo-thyronine (T3), TSH, Tg, and anti-Tg antibodies (TgAb) were measured by commercially available immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. All statistical tests were two-sided. RESULTS: TC risk was positively associated with Tg (OR for the highest vs lowest quartile = 9.15; 95% CI = 5.28 to 15.90; P 〈 .001) and negatively associated with TSH level (OR = 0.56; 95% CI = 0.38 to 0.81; P = .001). Odds ratios were not modified by adjustment for weight and height and were consistent across sexes, age groups, and countries. The association with Tg was stronger in follicular than papillary TC. The odds ratio for TgAb-positivity was 1.50 (95% CI = 1.05 to 2.15; P = .03). Among case patients, TSH level was stable over time, whereas Tg level was higher in proximity to TC diagnosis. Areas under the receiver operating characteristic curve were 57% and 74% for TSH and Tg level, respectively. CONCLUSIONS: High Tg levels precede by up to 8 years the detection of TC, pointing to a long sojourn time of the disease. Low TSH levels may predispose to TC onset. Neither marker has sufficient accuracy to be a screening test.
    Type of Publication: Journal article published
    PubMed ID: 24824312
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  • 9
    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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  • 10
    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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