Faculty Bibliography

Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag+ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is beta-catenin, and activation of beta-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates beta-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. Beta-catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag+ vs. cag- strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of beta-catenin-dependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen

BACKGROUND: The objective was to investigate the association of Helicobacter pylori and serum pepsinogen (PG) levels with gastric adenocarcinoma. METHODS: Serum obtained from 299 patients at the time of cancer diagnosis and from 336 population-based control subjects was tested for PG I, PG II, and antibodies to H. pylori and to CagA. RESULTS: Subjects with low PG I levels or low PG I/II ratios were at increased risk for cardia and noncardia gastric cancer, whereas those with H. pylori or CagA seropositivity had an elevated risk for noncardia cancer only. Subjects seropositive for either H. pylori or CagA who had low PG I levels had the highest odds ratio (OR) (9.21 [95% confidence interval {CI}, 4.95-17.13]) for noncardia cancer, compared with subjects with neither factor. Elevated risks were also found among subjects with only 1 factor (OR, 5.40 [95% CI, 2.61-11.20] for low PG I level only; OR, 4.86 [95% CI, 5.90-8.13] for H. pylori or CagA seropositivity only). This pattern persisted when PG I/II ratio replaced PG I level and when CagA seropositivity alone replaced H. pylori immunoglobulin G or CagA seropositivity. CONCLUSIONS: The results suggest that persons with both H. pylori or CagA seropositivity and a low PG I level or PG I/II ratio are highly susceptible to development of noncardia gastric cancer

Multiple Helicobacter pylori strains may colonize an individual host. Using enzyme-linked immunosorbent assay and line probe assay (LiPA) techniques, we analyzed the prevalence of mixed H. pylori colonization in 127 subjects from Venezuela, a country of high H. pylori prevalence, from three regions representing different population groups: the Andes (Merida), where Caucasian mestizos predominate, a major city near the coast (Caracas), where Amerindian-Caucasian-African mestizos predominate, and an Amazonian community (Puerto Ayacucho), where Amerindians predominate and mestizos reflect Amerindian and Caucasian ancestry. Among 121 H. pylori-positive persons, the prevalence of cagA-positive strains varied from 50% (Merida) to 86% (Puerto Ayacucho) by LiPA. Rates of mixed colonization also varied, as assessed by LiPA of the vacA s (mean, 49%) and m (mean, 26%) regions. In total, 55% of the individuals had genotypic evidence of mixed colonization. vacA s1c, a marker of Amerindian (East Asian) origin, was present in all three populations, especially from Puerto Ayacucho (86%). These results demonstrate the high prevalence of mixed colonization and indicate that the H. pylori East Asian vacA genotype has survived in all three populations tested

In young children, the significance of stool samples transiently positive for Helicobacter pylori antigen is unknown. As part of a larger prospective study on enteric infections, stool samples were obtained from 323 children at two time points 3 months apart and tested for H. pylori antigen using a commercially available enzyme-linked immunosorbent assay (ELISA) test. Seminested PCR for a Helicobacter-specific 16S rRNA gene was performed on all 26 pairs reverting from positive to negative (transient positives), all 4 persistent antigen-positive pairs, and 10 randomly selected persistent antigen-negative pairs. Helicobacter species were amplified from the first stool samples of 15/26 (58%) of the transient positives and 1 (25%) of 4 persistent positives. No Helicobacter species were amplified from the 10 persistent negatives. Among the 15 amplicons from transient-positive stool, H. pylori was sequenced and identified from 12 (80%; 95% confidence interval, 52% to 96%) and other Helicobacter spp. were identified from three (Helicobacter canis, Helicobacter winghamensis, and MIT 99-5504). Four of the 15 remained positive by PCR for the second (antigen-negative) stool sample, including all 3 initially identified as non-H. pylori. Helicobacter bilis was amplified from the second sample of a persistent positive. Two of eight transient positives from whom serum was available had accompanying transient elevations in anti-H. pylori antibodies. Transiently positive stool ELISAs for H. pylori are common and represent H. pylori in the majority of cases where sequences can be obtained. A not-insignificant percentage of antigen-positive stools, however, may represent other Helicobacter species

Several cytokine gene polymorphisms have been associated with increased risk of distal gastric cancer (GC) and its precursor histological markers in Caucasian, Asian and Portuguese populations although little is known about their role in other ethnic groups. Our study investigates the role of the IL-1B-31, IL-1RN and TNF-A-308 gene polymorphisms as risk factors for the development of GC in a Mexican population. We studied 278 patients who were enrolled at the Hospital Universitario Dr. Jose Eleuterio Gonzalez, Universidad Autonoma de Nuevo Leon. The subjects were divided into 2 groups. Sixty-three patients with histologically confirmed distal GC (mean age = 58.8 years, range = 22-84, F:M = 0.56), and 215 patients with no evidence of distal or proximal GC (mean age = 56.1 years, range = 18-92, F:M = 1.17). The IL-1B-31 and the TNF-A-308 polymorphisms were determined by PCR-RFLP and pyrosequencing, respectively, in all cases and controls. The VNTR polymorphism in intron 2 of the 1L-1RN gene was typed by PCR in 25 cases and 201 controls. The H. pylori status was determined by histology, rapid urease test, culture and serology for non-cancer controls and by histology for the GC cases. The carriage of the proinflammatory IL-1B-31*C allele was associated with increased risk of distal GC (odds ratio [OR] = 7.63, 95% confidence interval [CI] = 1.73-46.94, p = 0.003). When cases and controls were matched by age and gender, the OR value was higher (OR = 8.05, 95% CI = 1.8-50.22, p = 0.001). When only H. pylori GC cases and controls were compared, the OR value was 7.8 (95% CI = 1.05-161.8, p = 0.04). No association was found between any of the other polymorphisms studied and distal GC. In this Mexican population, the IL-1B proinflammatory genotype increases the risk of distal GC. These findings are similar to previous reports in Caucasian populations and underscore the importance of cytokine gene polymorphisms in the development of distal GC

OBJECTIVE: Mutations in the codon 72 of exon 4 in the p53 gene have been associated with higher risk in the development of several types of cancer. This polymorphism occurs with two alleles encoding either arginine (CGC) or proline (CCC). The aim of this study was to assess the role of the codon 72 polymorphism of p53 in the risk for the development of distal gastric cancer (GC) in a Mexican population. MATERIAL AND METHODS: We studied 247 patients who were enrolled at the Servicio de Gastroenterologia, Hospital Universitario 'Dr. Jose Eleuterio Gonzalez' Universidad Autonoma de Nuevo Leon. The study group included 65 distal GC cases [mean age, 58.2 (22-84), median = 60, F:M = 0.6] and 182 patients without evidence of GC [mean age 53.9 (18-89), median = 53, F:M = 1.07) as the control group. The polymorphism in the codon 72 of the p53 gene was determined by PCR-RFLP in all the patients. RESULTS: As expected, the majority of GC patients were old male. We found a previously unknown association of the Arg/Arg genotype and distal GC (OR: 1.96, 95% confidence interval [CI] = 1.06-3.61, p =0.03). Because of age and gender differences, cases and controls were matched in those two variables and the association of Arg/Arg genotype with distal GC persisted (OR: 2.29, 95% CI = 1.22-4.32, p = 0.01). When cases and controls were matched by age, gender, H. pylori positivity and excluding patients with atrophic gastritis and/or intestinal metaplasia (n=97) the association was stronger (OR = 2.37, 95% CI = 1.18-4.77, p = 0.01). CONCLUSIONS: The results of this study suggest that the carriage of the Arg/Arg genotype could be associated with the development of distal GC in this Mexican population

Background: Little is known about the prevalence of Helicobacter pylori and the presence of specific genotypes in Uruguay. Aims: To determine the prevalence of H. pylori in symptomatic individuals in Uruguay, to assess the prevalence of bacterial genotypes, and evaluate the association between specific genotypes and endoscopic findings. Patients: 32 patients presenting to the Hospital de Clinicas in Montevideo for upper endoscopy were enrolled. Methods: H. pylori status was determined by rapid urease test and by culture of gastric biopsy specimens from the antrum and body. H. pylori vacA genotypes were determined by PCR. Results: The prevalence of H. pylori was 66% based on culture and rapid urease test. Analysis of the vacA gene by PCR, we found a high proportion of multiple infections (42.9%). The s1a allele was found in 47.6% of patients and s1b was found in 33.3%. We could not demonstrate a significant association between infection with H. pylori, nor specific bacterial genotypes, and endoscopic findings. Conclusions: The prevalence of H. pylori in symptomatic patients in Montevideo is lower than typically found in developing countries probably as result of the low sensitivity of the two invasive tests used. The vacA genotypes of H. pylori found in Uruguay differs from the rest of Latin America with 47.6% bearing the s1a vacA allele. These results confirmed that European descendents different from Spain and Portugal are important part of the Uruguayan population

BACKGROUND: The goal of this study was to determine the importance of Helicobacter pylori CagA+, VacA+, and HLA-DQA1 alleles in a Mexican population with gastric cancer (GC). METHODS: We studied a group of Mexican patients (cases) with distal GC (n=22) or high-grade dysplasia (HGD; n=8) (mean age, 62.7 years, F : M=0.3; age range, 33-84 years) and 77 ethnically matched non-GC controls (mean age, 47.1 years; F : M=1.96; age range, 17-92 years). Both cases and controls were H. pylori-positive by at least two of the following diagnostic tests: rapid urease test, histology, culture, or serology. The presence of antibodies to CagA and VacA proteins was determined by Western blot, and the HLA-DQA1 typing was carried out by a polymerase chain reaction (PCR) sequence-specific primer method. RESULTS: The carriage of H. pylori CagA+, VacA+ strains was associated with GC or HGD (odds ratio [OR], 6.07; 95% confidence interval [CI], 1.56-27.57; P=0.005). The allele frequency of DQA1*0503 was significantly lower in the GC-HGD group than in the non-GC group (OR, 0.13; 95% CI, 0.02-0.59). Logistic regression analysis identified the carriage of HLA-DQA1*0503 as an independent protective factor for GC (OR, 0.19; 95% CI, 0.04-0.94) and colonization with H. pylori CagA+, VacA+ strains as an independent risk factor for GC (OR, 6.15; 95% CI, 1.69-22.37). CONCLUSIONS: Infection with H. pylori CagA+, VacA+ strains represents a significant risk for the development of GC. The absence of HLA-DQA1*0503 could be a host risk factor for the development of GC in Mexican patients