IL‐1B promoter polymorphism and Epstein‐Barr virus in Dutch patients with gastric carcinoma
2003; Wiley; Volume: 107; Issue: 5 Linguagem: Inglês
10.1002/ijc.11468
ISSN1097-0215
AutoresAxel zur Hausen, J. Bart A. Crusius, Laura S. Murillo, Behrooz Z. Alizadeh, Servaas A. Morré, Chris J.L.M. Meijer, Adriaan J. C. van den Brule, A. S. Peña,
Tópico(s)Eosinophilic Esophagitis
ResumoPolymorphisms in genes of the interleukin-1 (IL1) cluster encoding cytokines IL-1β (IL1B) and IL-1 receptor antagonist (IL1RN) are associated with an increased risk for hypochlorhydria and gastric atrophy in a white population of gastric cancer relatives.1 In addition, these IL1 gene family polymorphisms are associated with an increased risk to develop gastric cancer.1, 2 The pro-inflammatory cytokine IL-1β is the most powerful acid inhibitor known and is upregulated by Helicobacter pylori (H. pylori) infection. Polymorphisms of the IL1 gene cluster thus seem to contribute to determine the outcome of H. pylori infection. The role of H. pylori in gastric carcinogenesis is well established.3 In addition the Epstein-Barr virus (EBV) is present in a significant subset of gastric carcinomas worldwide (∼10%)4, 5, 6 and persists monoclonally in all tumor cells.4, 7 In view of the high global incidence rate of gastric cancer, gastric carcinomas might comprise the largest group of EBV-associated malignancies. We have demonstrated previously that EBV-carrying and EBV-negative gastric carcinomas are characterized by distinct chromosomal aberrations,8 suggesting an important role for EBV in gastric carcinogenesis. The regular expression of the transforming viral BARF1 gene in these carcinomas provides strong evidence for a role of EBV in the etiopathogenesis of gastric cancer.9 Thus EBV-carrying gastric carcinomas are thought to form a distinct entity of gastric carcinoma. Moreover, EBV-carrying gastric carcinomas show significant differences in the distribution of promoter polymorphisms of the genes encoding the cytokines TNF-α and IL-10.10 We tested whether the bi-allelic IL1B-511 polymorphism, in European populations in absolute linkage disequilibrium with the TATA-box IL1B-31 polymorphism1 (and our own unpublished observations), is differentially distributed in gastric cancer patients compared to healthy controls in the analyzed Dutch population. In addition, patients with EBV-carrying gastric carcinomas were compared to EBV-negative gastric carcinomas. Genomic DNA of 69 gastric carcinoma tissues (17 EBV-carrying and 52 EBV-negative gastric carcinomas) and genomic DNA of 153 healthy individuals were assayed for the IL1B-31 or IL1B-511 polymorphisms with 5′ nuclease TaqMan assay/PCR-RFLP method, respectively. In addition, DNA (n = 5) extracted from corresponding nonneoplastic gastric mucosa was tested to assure that the detected polymorphisms variants were inherited and not the product of malignant transformation. Before polymorphism analyses the β-globin housekeeping gene was amplified, revealing sufficient DNA quality. Statistical analysis was carried out using χ2 test to compare the frequencies and a logistic regression model fitted to estimate gender adjusted odds ratio (OR) with 95% confidence interval (95% CI) by Stata version 7.0. Allele frequencies were within Hardy-Weinberg equilibrium in controls (p = 0.9). The genotype and allele frequencies in patients and in controls are shown in Table I. Sixty percent of patients and 48% of controls were male (p = 0.10). Genotype frequencies were not different between men and women (p-cases = 0.41; p-controls = 0.6). The frequency of genotype T/C of the IL1B-511 polymorphism was significantly (p = 0.01) lower in gastric carcinoma patients (24.6%) than in controls (45.0%) yielding an OR of 0.41 (95% CI = 0.21–0.80). The frequency of the IL1B-511 genotype T/T was 17.5% in gastric carcinoma patients compared to 11.3% in controls (OR = 1.01; 0.43–2.40). In patients, 36.6% of men as compared to 7.4% of women were positive for EBV status (p = 0.007). The frequency of genotypes between controls and patients and the corresponding ORs did not change significantly when patients were stratified for the EBV status. The frequency of genotype T/C between EBV-positive gastric carcinoma patients and controls was not significantly different (OR = 0.39; 0.11–1.39; Table I), however, most probably due to the small number of EBV positive gastric carcinomas. The frequency of IL1B-511 allele T was not significantly different between patients and controls. Chong et al.11 reported recently an upregulation of IL-1β exclusively in EBV-carrying gastric carcinoma, tested by RT-PCR and RNA in situ hybridization. Our results strongly suggest that this upregulation is not due to distinct functional genetic polymorphisms within IL1B but is induced by EBV itself. Among other cytokines the induction of IL-1β by EBV has been reported in neoplastic epithelial cells.12 In addition, we compared the distribution of the IL1B promoter polymorphism published by El-Omar et al.1 and by Machado et al.2 to our results (Table II). In gastric carcinoma patients, the genotype frequencies in our study were significantly different from those reported by El-Omar et al.1 and by Machado et al.2 Pooled analysis of the data presented by El-Omar et al.1 and by Machado et al.2 showed a highly significant (p < 0.001) increased risk of gastric cancer with genotype T/C (pooled OR = 1.81; 1.41–2.33) and with genotype T/T (pooled OR = 2.00; 1.40–2.87) compared to genotype IL1B-511 C/C. This finding is of interest because the patients were derived from Poland in the study by El-Omar et al.1 and from Portugal in the study by Machado et al.2 Both countries, in contrast to the Netherlands, are high risk areas for gastric cancer in Europe. In contrast to gastric carcinoma patients from Portugal and Poland, the incidence of heterozygotes was lower in the Dutch patients compared to the healthy control group. This indicates that the latter are at a significantly lower risk to develop gastric carcinoma when compared to T/T homozygotes. In conclusion, heterozygosity for the IL1B-511 polymorphism, and therefore for the IL1B-31 TATA-box polymorphism (genotype T/C), was found to be associated with a decreased risk for gastric carcinoma in a Dutch population. This association was not related to the EBV status of the patients. This suggests an early common molecular mechanism for the development of EBV-positive and negative gastric carcinomas. Yours sincerely, We would like to acknowledge the excellent technical assistance of M. Demirkaya and R. Heijmans, and J. van Beek for facilitating samples. Axel zur Hausen, J. Bart A. Crusius, Laura S. Murillo, Behrooz Z. Alizadeh, Servaas A. Morré, Chris J.L.M. Meijer, Adriaan J.C. van den Brule, Amado Salvador Peña
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