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Velissari A, Vassilakopoulos TP, Angelopoulou MK, Korkolopoulou P, Bamias G, Daikos G, Konstantopoulos K, Siakantaris M. Genetic polymorphisms and risk of MALT lymphoma in Greek population. Curr Res Transl Med 2022; 70:103330. [PMID: 34979486 DOI: 10.1016/j.retram.2021.103330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 11/22/2021] [Accepted: 12/20/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE MALT lymphoma is thought to have a genetic component. Genetic studies in the greek population are rare and genetic determinants remain to be established. The current study aimed to seek correlations between genetic polymorphisms and risk of MALT lymphoma in the Greek population. PATIENTS AND METHODS 83 MALT lymphoma patients and 60 age-matched healthy outpatients were recruited. SNPs in TNFa, LTA and CTLA-4 genes and IL1RN-VNTR and GSTT1 and GSTTM1 null polymorphisms were genotyped using published PCR/PCR-RFLP methods, while two novel PCR-RFLP methods were developed for IL-22 rs7314777 and TCF19 rs7750641 SNPs. Part of the results was validated by DNA-sequencing. Statistical analysis was performed using SPSS and the SNPstats bioinformatic tool. RESULTS The mean age of the patients and controls were 55.9 and 56.2 years respectively. The majority of patients (63) suffered gastric marzinal zone lymphoma (GMZL) and 71.1% were stage I at diagnosis. A statistically significant association was noted for the CTLA-4 49A/ G G variant (OR:2.56,p: 0.006) and the TCF19 rs7750641 SNP T variant (OR: 3.86, p:0.023). CONCLUSIONS Our study confirmed a role for CTLA-4 49A/G and TCF19 rs7750641 SNPs in the Greek population. Additional studies could help confirm these associations and possibly link them to prognosis or response to treatment parameters.
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Affiliation(s)
- A Velissari
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital.
| | - T P Vassilakopoulos
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - M K Angelopoulou
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - P Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens
| | - G Bamias
- Gastrenterology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - G Daikos
- First Department of Internal Medicine, National and Kapodistrian University of Athens, Laiko General Hospital
| | - K Konstantopoulos
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
| | - M Siakantaris
- Hematology Department, National and Kapodistrian University of Athens, Laiko General Hospital
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The Role of Tumor Necrosis Factor-α (TNF-α) Polymorphisms in Gastric Cancer: a Meta-Analysis. J Gastrointest Cancer 2021; 53:756-769. [PMID: 34478034 DOI: 10.1007/s12029-021-00688-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine which may play a role in the development of gastric cancer (GC). This study aimed to investigate the association of five TNF-α polymorphisms including TNF-α-857, TNF-α-1031, TNF-α-863, TNF-α-308, and TNF-α-238 polymorphisms with GC risk. METHODS All eligible case-control studies were collected by searching PubMed, Scopus, and Web of Science. The association of the risk of GC with TNF-α polymorphisms was estimated using odds ratio (OR) and 95% confidence interval (CI). Heterogeneity was assessed via Cochrane's Q and I2 analyses. RESULTS A total of 46 publications involving 16, 715 cases with GC and 27, 998 controls were recruited. The study revealed a significant association for TNF-α 308 (recessive model: OR = 0.646, P = 0.035), TNF-α-1031 (homozygote model: OR = 1.584, P = 0.027), and TNF-α-857 (homozygote model: OR = 1.760, P = 0.001) polymorphisms with the GC risk. The results of subgroup analysis based ethnicity found a significant association between GC risk and TNF-α-857 polymorphism in Caucasian subgroup (P = 0.005) and TNF-α-1031 polymorphism and GC risk in Asians (P = 0.018). CONCLUSIONS This study suggested that TNF-α-857 and TNF-α-1031 polymorphisms may be associated with the increased gastric cancer risk.
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Malespín-Bendaña W, Machado JC, Une C, Alpízar-Alpízar W, Molina-Castro S, Ramírez-Mayorga V. The TNF-A-857*T Polymorphism is Associated with Gastric Adenocarcinoma Risk in a Costa Rican Population. Am J Med Sci 2021; 362:182-187. [PMID: 34088492 DOI: 10.1016/j.amjms.2021.01.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 10/20/2020] [Accepted: 01/28/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Costa Rica is ranked as one of the countries with highest incidence of gastric cancer worldwide. Previous studies in Costa Rican populations have revealed associations between gastric cancer risk and several cytokine polymorphisms that seem to play a role in the regulation of the expression of these proteins. In this study, we assessed associations of the polymorphisms IL-6-174 G/C, IFNGR1-56 C/T, IL-8-251 T/A and TNF-A (-857 C/T, -308 A/G) with gastric pathologies in a high-risk population of Latin America. METHODS DNA samples of 47 patients with gastric adenocarcinoma, 53 with chronic gastritis, 56 with duodenal ulcer and 94 healthy controls, were genotyped for the five mentioned SNPs. All participants were ≥50-years-old. Genotyping was performed by PCR-RFLP and 5'-nuclease PCR assay. H. pylori infection, CagA status, pepsinogen (PG) I and II blood levels were determined by ELISA. Logistic regression analysis was used to determine possible associations of the polymorphisms with cancer, gastritis and duodenal ulcer, and linear regression analysis to determine associations with blood PG levels. RESULTS A total of 86.6% of the population was positive for H. pylori; of them, 51.6% was CagA+. Patients with the TNF-A-857*T allele had an increased risk for gastritis (OR: 3.67, p = 0.015) and gastric adenocarcinoma (OR:6.15, p = 0.001). Associations between other polymorphisms and gastric diseases, or PG levels, were not found. CONCLUSIONS Our results indicate that the TNF-A-857*T SNP is among the risk factors associated with the risk of gastric cancer in Costa Rica.
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Affiliation(s)
- Wendy Malespín-Bendaña
- Institute of Health Research (INISA), University of Costa Rica, Costa Rica; School of Medicine, University of Costa Rica, Costa Rica.
| | - José Carlos Machado
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal.
| | - Clas Une
- Institute of Health Research (INISA), University of Costa Rica, Costa Rica.
| | - Warner Alpízar-Alpízar
- Centre for Research on Microscopic Structures (CIEMic), University of Costa Rica, Costa Rica; Department of Biochemistry, School of Medicine, University of Costa Rica, Costa Rica.
| | - Silvia Molina-Castro
- Institute of Health Research (INISA), University of Costa Rica, Costa Rica; Department of Biochemistry, School of Medicine, University of Costa Rica, Costa Rica.
| | - Vanessa Ramírez-Mayorga
- Institute of Health Research (INISA), University of Costa Rica, Costa Rica; Department of Public Nutrition, School of Nutrition, University of Costa Rica, Costa Rica.
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Kuo SH, Wu MS, Yeh KH, Lin CW, Hsu PN, Chen LT, Cheng AL. Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Cancers (Basel) 2019; 11:547. [PMID: 30999581 PMCID: PMC6520890 DOI: 10.3390/cancers11040547] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/09/2019] [Accepted: 04/12/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.
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Affiliation(s)
- Sung-Hsin Kuo
- Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Cancer Research Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 106, Taiwan.
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Cancer Research Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 106, Taiwan.
| | - Chung-Wu Lin
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
| | - Ping-Ning Hsu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan 704, Taiwan.
| | - Ann-Lii Cheng
- Cancer Research Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 106, Taiwan.
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
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TNFR1 single nucleotide polymorphisms are not associated with cervical HPV-induced pre-malignant lesion but regulate in situ cervical TNFR1 expression. Oncotarget 2019; 10:953-965. [PMID: 30847024 PMCID: PMC6398171 DOI: 10.18632/oncotarget.26627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 01/14/2019] [Indexed: 11/25/2022] Open
Abstract
TNF-α is involved in HPV infection control by triggering cell signaling through binding in specific receptors TNFR1 and TNFR2. Genetic polymorphisms in these receptors may influence TNF-α signaling. Herein, we investigated TNFR1 rs767455 and rs2234649 single nucleotide polymorphisms, and TNFR1 protein expression in cervical squamous intraepithelial lesions (SIL) to identify their role in cervical pre-malignant development. SIL patients (n = 179) and healthy volunteers (n = 227) were enrolled for TNFR1 genotyping analysis by PCR-RFLP in blood samples and TNFR1 protein expression in cervical tissue by immunohistochemistry. No statistical differences regard genotypes and allelic frequencies for both polymorphisms were observed. Cervical TNFR1-expressing cells were rare in epithelium and basal layer regardless the groups. However, a progressive increase in infiltrating cells was observed in the stromal area, mainly in high SIL (HSIL) group compared to low SIL (LSIL, p < 0.001) and control (p < 0.001) groups. TNFR1-expressing cells frequency was higher in TNFR1 rs767455AG/GG (p < 0.001), and in rs2234649AA (p < 0.001) genotypes carries in HSIL subgroup. These data indicated that TNFR1-expression is abrogated in cervical epithelium, where HPV-induced pre-malignant lesion occurs, increasing its frequency in inflammatory cells in stroma, and is genetically controlled by TNFR1 rs767455AG/GG and rs234649AA genotypes. These biomarkers may be useful to identify cervical precancerous lesions progression.
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An updated association between TNF-α -238G/A polymorphism and gastric cancer susceptibility in East Asians. Biosci Rep 2018; 38:BSR20181231. [PMID: 30413607 PMCID: PMC6294626 DOI: 10.1042/bsr20181231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/20/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022] Open
Abstract
Polymorphisms in the tumor necrosis factor α (TNF-α) gene are emerging as key determinants of gastric diseases. The TNF-α-238G/A single-nucleotide polymorphism (SNP) is the most extensively studied. However, this association is inconsistent amongst different populations. We therefore conducted an updated meta-analysis to obtain a more precise estimate of the association of TNF-α-238G/A polymorphism with gastric cancer (GC) risk. A comprehensive search of PubMed, Embase, Chinese (CNKI and WanFang) databases was performed to identify relevant studies through 5 May 2018. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association. Fourteen studies were included in our meta-analysis involving 2999 cases and 4685 controls. There was no significant association between TNF-α-238G/A polymorphism and GC risk in the overall populations. In the subgroup analysis, we found that TNF-α-238G/A polymorphism was associated with the increased risk of GC amongst Asians, especially in Chinese, but not in Caucasians. Subgroup analysis by genotyping methods revealed increased risk for other methods. In conclusion, our present meta-analysis shows that TNF-α-238G/A polymorphism is associated with the risk of GC in East Asian individuals.
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Xu T, Kong Z, Zhao H. Relationship Between Tumor Necrosis Factor-α rs361525 Polymorphism and Gastric Cancer Risk: A Meta-Analysis. Front Physiol 2018; 9:469. [PMID: 29867530 PMCID: PMC5962813 DOI: 10.3389/fphys.2018.00469] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/13/2018] [Indexed: 12/17/2022] Open
Abstract
Tumor necrosis factor (TNF)-α, a major part in inflammatory, infectious and tumor processes, and is pivotal at the early stages of gastric cancer. Relationship between its risk and TNF-α rs361525 polymorphism has been demonstrated, but remains conflicting and controversial. Therefore, a meta-analysis was conducted to more precisely estimate this relationship. PubMed, Web of Science, EMBASE and CNKI were comprehensively searched to find out relevant articles through October 5, 2017. The strength of the relationship was assessed using pooled odds ratios and 95% confidence intervals. Totally 20 articles were included involving 4,084 cases and 7,010 controls. No significant relationship between TNF-α rs361525 polymorphism and increased GC risk was found in the whole populations. Subgroup analyses uncovered TNF-α rs361525 polymorphism intensified the risk of GC among Asians under five models, but decreased the risk of GC among Caucasiansin the allelic and dominant models. Subgroup analysis by genotyping methods revealed increased risk for other methods. In conclusion, this meta-analysis suggests TNF-α rs361525 polymorphism is related to the risk of GC, especially for Asians.
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Affiliation(s)
- Tianshu Xu
- Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhijun Kong
- Department of General Surgery, Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou, China
| | - Hui Zhao
- Department of General Surgery, Wuxi Third People's Hospital, Wuxi, China
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Gross SA, Paustenbach DJ. Shanghai Health Study (2001-2009): What was learned about benzene health effects? Crit Rev Toxicol 2017; 48:217-251. [PMID: 29243948 DOI: 10.1080/10408444.2017.1401581] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The Shanghai Health Study (SHS) was a large epidemiology study conducted as a joint effort between the University of Colorado and Fudan University in Shanghai, China. The study was funded by members of the American Petroleum Institute between 2001 and 2009 and was designed to evaluate the human health effects associated with benzene exposure. Two arms of the SHS included: an occupational-based molecular epidemiology study and several hospital-based case control studies. Consistent with historical literature, following sufficient exposure to relatively high airborne concentrations and years of exposure, the SHS concluded that exposure to benzene resulted in an increased risk of various blood and bone marrow abnormalities such as benzene poisoning, aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Non-Hodgkin lymphoma (NHL) was not significantly increased for the exposures examined in this study. Perhaps the most important contribution of the SHS was furthering our understanding of the mechanism of benzene-induced bone marrow toxicity and the importance of identifying the proper subset of MDS relevant to benzene. Investigators found that benzene-exposed workers exhibited bone marrow morphology consistent with an immune-mediated inflammatory response. Contrary to historic reports, no consistent pattern of cytogenetic abnormalities was identified in these workers. Taken together, findings from SHS provided evidence that the mechanism for benzene-induced bone marrow damage was not initiated by chromosome abnormalities. Instead, chronic inflammation, followed by an immune-mediated response, is likely to play a more significant role in benzene-induced disease initiation and progression than previously thought.
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Jirásko R, Holčapek M, Khalikova M, Vrána D, Študent V, Prouzová Z, Melichar B. MALDI Orbitrap Mass Spectrometry Profiling of Dysregulated Sulfoglycosphingolipids in Renal Cell Carcinoma Tissues. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2017; 28:1562-1574. [PMID: 28361385 DOI: 10.1007/s13361-017-1644-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/24/2017] [Accepted: 02/25/2017] [Indexed: 06/07/2023]
Abstract
Matrix-assisted laser desorption/ionization coupled with Orbitrap mass spectrometry (MALDI-Orbitrap-MS) is used for the clinical study of patients with renal cell carcinoma (RCC), as the most common type of kidney cancer. Significant changes in sulfoglycosphingolipid abundances between tumor and autologous normal kidney tissues are observed. First, sulfoglycosphingolipid species in studied RCC samples are identified using high mass accuracy full scan and tandem mass spectra. Subsequently, optimization, method validation, and statistical evaluation of MALDI-MS data for 158 tissues of 80 patients are discussed. More than 120 sulfoglycosphingolipids containing one to five hexosyl units are identified in human RCC samples based on the systematic study of their fragmentation behavior. Many of them are recorded here for the first time. Multivariate data analysis (MDA) methods, i.e., unsupervised principal component analysis (PCA) and supervised orthogonal partial least square discriminant analysis (OPLS-DA), are used for the visualization of differences between normal and tumor samples to reveal the most up- and downregulated lipids in tumor tissues. Obtained results are closely correlated with MALDI mass spectrometry imaging (MSI) and histologic staining. Important steps of the present MALDI-Orbitrap-MS approach are also discussed, such as the selection of best matrix, correct normalization, validation for semiquantitative study, and problems with possible isobaric interferences on closed masses in full scan mass spectra. Graphical Abstract ᅟ.
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Affiliation(s)
- Robert Jirásko
- Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210, Pardubice, Czech Republic.
| | - Michal Holčapek
- Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210, Pardubice, Czech Republic
| | - Maria Khalikova
- Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210, Pardubice, Czech Republic
| | - David Vrána
- Department of Oncology, Faculty of Medicine and Dentistry, Palacký University, I.P. Pavlova 6, 775 20, Olomouc, Czech Republic
| | - Vladimír Študent
- Department of Urology, Faculty of Medicine and Dentistry, Palacký University, I.P. Pavlova 6, 775 20, Olomouc, Czech Republic
| | - Zuzana Prouzová
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University, I.P. Pavlova 6, 775 20, Olomouc, Czech Republic
| | - Bohuslav Melichar
- Department of Oncology, Faculty of Medicine and Dentistry, Palacký University, I.P. Pavlova 6, 775 20, Olomouc, Czech Republic
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Zheng W, Zhang S, Zhang S, Min L, Wang Y, Xie J, Hou Y, Tian X, Cheng J, Liu K, Xu D, Yu X, Liu Z, Lv Y, Liang N, Zhang J, Liu F, Tian Y. The relationship between tumor necrosis factor-α polymorphisms and gastric cancer risk: An updated meta-analysis. Biomed Rep 2017; 7:133-142. [PMID: 28804625 PMCID: PMC5526040 DOI: 10.3892/br.2017.934] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 06/21/2017] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to evaluate the relationship between tumor necrosis factor-α (TNF-α) and the development of gastric cancer, and to investigate whether it can be used as a biological marker for gastric cancer. In the current study, a new meta-analysis was performed to assess the association between TNF-α gene polymorphisms and gastric cancer susceptibility. Subgroup analyses based on ethnicity, control population source and non-cardia cancers were also conducted. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. TNF-α 308 polymorphisms indicated a significant relationship with gastric cancer risk among a normal population [GA/AA vs. GG; 1.17 (1.10–1.23)]. In analysis stratified by ethnicity, TNF-α 238 displayed an association with gastric cancer risk in eastern populations [GA/AA vs. GG: 1.24 (1.02–1.50)], but not in western populations [GA/AA vs. GG: 0.96 (0.79–1.18)]. The overall ORs (95% CIs) for TNF-α 857, TNF-α 1031 and TNF-α 863 were 1.13 (1.04–1.24), 0.94 (0.85–1.05) and 0.89 (0.78–1.02), respectively, under dominant genetic model comparison. Among the above three SNPs, only TNF-α 857 was robustly associated with gastric cancer inclination, and this association remained consistently robust when limited to non-cardia gastric cancers [GA/AA vs. GG: 1.16 (1.03–1.31)]. TNF-α 308 and TNF-α 857 genotypes were potential risk factors of statistical significance in gastric cancer, and TNF-α 238 indicated to be significantly associated with gastric cancer risk only in eastern populations. TNF-α 1031 and TNF-α 863 were not significantly associated with gastric cancer risk.
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Affiliation(s)
- Wenxian Zheng
- Department of Oncology, Shanghai Jiaotong University Affiliated Sixth People Hospital, Shanghai 200233, P.R. China
| | - Shuisheng Zhang
- Department of Abdominal Surgical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Shenfeng Zhang
- Department of Oncology, Zaozhuang Municipal Hospital of Shandong Province, Zaozhuang, Shandong 277101, P.R. China
| | - Li Min
- Department of Gastroenterology, Beijing Medical University, National Clinical Center for Digestive Disease Center, Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Yihong Wang
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jian Xie
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Yong Hou
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Xiufang Tian
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jian Cheng
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Kun Liu
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Deguo Xu
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Xinshuang Yu
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Zhen Liu
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Yajuan Lv
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Ning Liang
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Jiandong Zhang
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Fengjun Liu
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
| | - Yuan Tian
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China
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Tumor Necrosis Factor- α T-857C (rs1799724) Polymorphism and Risk of Cancers: A Meta-Analysis. DISEASE MARKERS 2016; 2016:4580323. [PMID: 28115787 PMCID: PMC5223007 DOI: 10.1155/2016/4580323] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 12/04/2016] [Accepted: 12/06/2016] [Indexed: 01/08/2023]
Abstract
Objectives. To investigate the potential association of tumor necrosis factor-α T-857C polymorphism with susceptibility to the five common malignant tumors. Materials and Methods. A comprehensive search of PubMed/Medline, Embase, and Web of Science databases was performed up to November 2015. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. Subgroup analysis, heterogeneity analyses, and publication bias were also texted in the meta-analysis. Results. A total of twenty-two publications involving 5215 cases and 6755 controls were recruited. Overall, the meta-analysis revealed an increased risk between the TNF-α T-857C polymorphism and gastric cancer susceptibility in T versus C model, heterozygote genetic model, and dominant genetic model. An increased risk between the TNF-α T-857C polymorphism and hepatocellular cancer susceptibility in homozygote genetic model and recessive genetic model was also found. No significant association was found between the TNF-α T-857C polymorphism and colorectal cancer, cervical cancer, and prostate cancer. Conclusions. Our meta-analyses suggest that TNF-α T-857C polymorphism may be associated with increased risk of gastric cancer and hepatocellular cancer development. Therefore, the TNF-α T-857C polymorphism could be considered as one possible risk factor of gastric cancer and hepatocellular cancer according to our study.
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Luo M, Yang Y, Luo D, Liu L, Zhang Y, Xiao F, Yang J, Zhang C, Fu S, Luo Z. Tumor necrosis factor-alpha promoter polymorphism 308 G/A is not significantly associated with esophageal cancer risk: a meta-analysis. Oncotarget 2016; 7:79901-79913. [PMID: 27821804 PMCID: PMC5346759 DOI: 10.18632/oncotarget.13093] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 10/21/2016] [Indexed: 12/18/2022] Open
Abstract
Many studies have investigated the association between Tumor necrosis factor-α-308 G>A (rs1800629) and the risk of esophageal cancer. However, their results are inconsistent. Therefore, we performed a meta-analysis of available data to investigate any possible association between this polymorphism and esophageal cancer risk. We searched PubMed, EMBASE, Web of Science, and the CNKI database for articles published up to 2016. Crude and adjusted odds ratio with 95% confidence intervals were calculated using fixed or random effects models. We used a dominant model (GA+AA vs GG), a recessive model (AA vs GG+GA), an over-dominant model (GG+AA vs GA), and allele frequency (G vs A) to identify any association. Eleven studies with 5617 participants were included in the meta-analysis. Our results suggest that TNF-α-308 G>A (rs1800629) is not significantly associated with a risk of esophageal squamous cell carcinoma and esophageal adenocarcinoma. For genetic association studies, negative results of meta-analysis have a high level of evidence, and these results are important in this era of high-throughput sequencing-based precision medicine.
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Affiliation(s)
- Ming Luo
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yuan Yang
- School of Life Sciences, Fudan University, Shanghai, China
| | - Dongmei Luo
- School of Mathematics and Physics, Anhui University of technology, Maanshan, Anhui, China
| | - Liang Liu
- Department of Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Yuening Zhang
- Medical Scientific Research Center, Guangxi Medical University, Nanning, Guangxi, China
| | - Feifan Xiao
- Medical Scientific Research Center, Guangxi Medical University, Nanning, Guangxi, China
| | - Jingcheng Yang
- School of Life Sciences, Fudan University, Shanghai, China
| | - Chengdong Zhang
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
- School of Life Sciences, Fudan University, Shanghai, China
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shen Fu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhiguo Luo
- Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
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Ying HY, Yu BW, Yang Z, Yang SS, Bo LH, Shan XY, Wang HJ, Zhu YJ, Wu XS. Interleukin-1B 31 C>T polymorphism combined with Helicobacter pylori-modified gastric cancer susceptibility: evidence from 37 studies. J Cell Mol Med 2016; 20:526-36. [PMID: 26805397 PMCID: PMC4759475 DOI: 10.1111/jcmm.12737] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 10/16/2015] [Indexed: 12/25/2022] Open
Abstract
Gastric cancer is one of the most common malignancies worldwide. Interleukin‐1‐beta (IL‐1β) is a pro‐inflammatory cytokine and potent inhibitor of gastric acid secretion. Some studies provided evidence of the association between IL‐1B 31 polymorphism and gastric cancer risk while other studies did not. Therefore, we conducted a comprehensive meta‐analysis to reassess the association. A systematic literature search of the PubMed and EMBASE databases identified 37 studies with 6108 cases and 8980 controls for this meta‐analysis. The crude odd ratios (ORs) and the 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Meta‐regression was used to determine the major source of heterogeneity across the studies. The pooled analysis did not suggest the significant association of IL‐1B 31 C>T polymorphism with gastric cancer risk. Stratified analysis was performed by ethnicity, source of control, genotype method, and indicated a significantly increased gastric cancer risk associated with IL‐1B 31T variant in the population‐based subgroup (heterozygous model: OR = 1.22, 95% CI = 1.03–1.45). Moreover, stratified analysis by Helicobacter pylori infection status indicated that IL‐1B 31 polymorphism increased gastric cancer risk in infection‐positive subgroup (homozygous model: OR = 1.35, 95% CI = 1.02–1.78; heterozygous model: OR = 1.31, 95% CI = 1.04–1.66; recessive model: OR = 1.29, 95% CI = 1.04–1.61). The study suggested that IL‐1B 31 polymorphism might confer susceptibility to gastric cancer in the presence of H. pylori infection, indicating a gene–environment interaction in gastric carcinogenesis.
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Affiliation(s)
- Hua-Yong Ying
- Department of Laboratory Medicine, Jinhua Central Hospital, Jinhua, Zhejiang, China
| | - Bei-Wei Yu
- Department of Laboratory Medicine, Jinhua People's Hospital, Jinhua, Zhejiang, China
| | - Zong Yang
- The Fifth Medical Team, Xinjiang Uygur Autonomous Region Corps of Chinese People's Armed Police Forces, Xinjiang, China
| | - Shan-Shan Yang
- Department of Laboratory Medicine, Jinhua Woman & Children Health Hospital, Jinhua, Zhejiang, China
| | - Li-Hong Bo
- Department of Laboratory Medicine, Jinhua Central Hospital, Jinhua, Zhejiang, China
| | - Xiao-Yun Shan
- Department of Laboratory Medicine, Jinhua Central Hospital, Jinhua, Zhejiang, China
| | - Hui-Jiao Wang
- Department of Laboratory Medicine, Jinhua People's Hospital, Jinhua, Zhejiang, China
| | - Yi-Jun Zhu
- Department of Laboratory Medicine, Jinhua Central Hospital, Jinhua, Zhejiang, China
| | - Xue-Song Wu
- School of Humanities and Social Science, Harbin Medical University, Harbin, Heilongjiang, China
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The influence of cytokine gene polymorphisms on the risk of developing gastric cancer in patients with Helicobacter pylori infection. Radiol Oncol 2015; 49:256-64. [PMID: 26401131 PMCID: PMC4577222 DOI: 10.2478/raon-2014-0041] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 08/27/2014] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Helicobacter pylori infection is the main cause of gastric cancer. The disease progression is influenced by the host inflammatory responses, and cytokine single nucleotide polymorphisms (SNPs) may have a role in the course of the disease. The aim of our study was to investigate proinflammatory cytokine polymorphisms, previously associated with the development of gastric cancer, in a Slovenian population. PATIENTS AND METHODS In total 318 patients and controls were selected for the study and divided into three groups: (i) patients with gastric cancer (n = 58), (ii) patients with chronic gastritis (n = 60) and (iii) healthy control group (n = 200). H. pylori infection in patient groups was determined by serology, histology and culture. Four proinflammatory gene polymorphisms were determined (IL-1β, IL-1ra, TNF-α, TLR-4) in all subjects. RESULTS We found a statistically significant difference between males and females for the groups (p = 0.025). Odds ratio (OR) for gastric cancer risk for females was 0.557 (95% confidence interval [CI]: 0.233-1.329) and for chronic gastritis 2.073 (95% CI: 1.005-4.277). IL-1B-511*T/T homozygous allele for cancer group had OR = 2.349 (95% CI: 0.583-9.462), heterozygous IL-1B-511*T had OR = 1.470 (95% CI: 0.583-3.709) and heterozygotes in TNF-A-308 genotype for chronic gastritis had OR = 1.402 (95% CI: 0.626-3.139). Other alleles had OR less than 1. CONCLUSIONS We could not prove association between gastric cancer and chronic gastritis due to H. pylori in any cytokine SNPs studied in Slovenian population. Other SNPs might be responsible besides infection with H. pylori for the progression from atrophy to neoplastic transformation.
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Liao F, Hsu YC, Kuo SH, Yang YC, Chen JP, Hsu PN, Lin CW, Chen LT, Cheng AL, Fann CSJ, Lin JT, Wu MS. Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma. Blood Cancer J 2014; 4:eXX. [PMID: 25303370 PMCID: PMC4220648 DOI: 10.1038/bcj.2014.70] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 08/22/2014] [Accepted: 08/29/2014] [Indexed: 02/07/2023] Open
Abstract
Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.
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MESH Headings
- CD4-Positive T-Lymphocytes/metabolism
- Cell Line, Tumor
- Female
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Helicobacter Infections/genetics
- Helicobacter Infections/metabolism
- Helicobacter Infections/therapy
- Helicobacter pylori
- Humans
- Interleukins/biosynthesis
- Interleukins/genetics
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/metabolism
- Lymphoma, B-Cell, Marginal Zone/microbiology
- Lymphoma, B-Cell, Marginal Zone/therapy
- Male
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Polymorphism, Single Nucleotide
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/microbiology
- Stomach Neoplasms/therapy
- Interleukin-22
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Affiliation(s)
- F Liao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Y-C Hsu
- Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
- Center for Database Research, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - S-H Kuo
- Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Y-C Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - J-P Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - P-N Hsu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - C-W Lin
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - L-T Chen
- National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan
| | - A-L Cheng
- Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - C S J Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - J-T Lin
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - M-S Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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16
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Park MJ, Hyun MH, Yang JP, Yoon JM, Park S. Effects of the interleukin-1β-511 C/T gene polymorphism on the risk of gastric cancer in the context of the relationship between race and H. pylori infection: a meta-analysis of 20,000 subjects. Mol Biol Rep 2014; 42:119-34. [PMID: 25258120 DOI: 10.1007/s11033-014-3748-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 09/16/2014] [Indexed: 12/11/2022]
Abstract
The interleukin (IL)-1β-511 C/T polymorphism has been shown to be functional and to contribute to the risk of gastric cancer. However, the relationship between the IL-1β-511 C/T polymorphism and gastric carcinogenesis remains inconclusive. A systematical electronic search was conducted of the MEDLINE, EMBASE, and CENTRAL databases. A random and a fixed effects model were exploited to estimate summary odds ratios and 95 % confidence intervals. Subgroup and sensitivity analyses were carried out with respect to ethnicity, quality assessment scores, control sources, genotyping methods, cancer histopathology and location, and Helicobacter pylori (H. pylori) infection. A total of 45 studies containing 9,066 cases of gastric cancer and 11,192 control subjects satisfied the inclusion criteria. The IL-1β-511 C/T polymorphism was found to enhance the risk of stomach cancer for overall and HWE-satisfying studies. Asians showed a positive relationship in both the overall and HWE-satisfying groups, whereas Caucasians did not. Based on subgroup analysis, H. pylori infection and genotype analysis using PCR-RFLP methods increase the association between IL-1β-511 T allele carrier and risk of stomach cancer. A positive relationship was found between the IL-1β-511 C/T SNP and stomach carcinoma susceptibility, and the results suggest that Asian ethnicity, H. pylori infection and methodologically, PCR-RFLP genotyping strengthen this relationship. Reflecting on prevalence of H. pylori in Asian countries, additional studies on the IL-1β-511 C/T SNP in the context of ethnicity and H. pylori infection may provide key insights into the mechanism underlying gastric cancer carcinogenesis. It was found PCR-RFLP is the most reliable genotyping method, and thus, it is recommendable to adopt it to determine the presence of the IL-1β-511 C/T SNP.
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Affiliation(s)
- Min-Jeong Park
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Inchon-ro 73, Seongbuk-gu, Seoul, 136-705, Korea
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17
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Yang JP, Hyun MH, Yoon JM, Park MJ, Kim D, Park S. Association between TNF-α-308 G/A gene polymorphism and gastric cancer risk: a systematic review and meta-analysis. Cytokine 2014; 70:104-14. [PMID: 25125137 DOI: 10.1016/j.cyto.2014.07.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2014] [Revised: 06/18/2014] [Accepted: 07/14/2014] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Tumor necrosis factor-alpha (TNF-α) has been found to be associated with gastric carcinogenesis, but individually published results have been inconclusive. The aim of this study was to explore the relationship between the TNF-α-308 G/A polymorphism and gastric cancer risk. METHODS MEDLINE, EMBASE and the COCHRANE library databases were searched for relevant articles to identify all available data. The odds ratios (ORs) with 95% confidence intervals (95% CIs) from each study were used to assess the association between the TNF-α-308 G/A polymorphism and gastric cancer risk. RESULTS This meta-analysis included 30 studies (32 datasets) involving 7009 gastric cancer cases and 12,119 control subjects. Overall, a significant association was found between the TNF-α-308 G/A polymorphism and gastric cancer in AA+GA vs. GG (dominant contrast model) (OR=1.20, 95% CI=1.07-1.34, p=0.001). With stratification based on ethnicity, the TNF-α-308 G/A polymorphism was correlated with gastric cancer risk in Caucasians, using the dominant contrast model (OR=0.74, 95% CI=0.57-0.96, p=0.02), but not in East Asians and other ethnic groups. In the comprehensive subgroup analysis, a significant association was also found in recent articles (published after 2005), population-based high-quality studies, hospital-based high-quality studies, studies using the TaqMan method and non-cardia subgroups. However, the TNF-α-308 G/A polymorphism was not associated with specific histological types of gastric cancer risk. CONCLUSIONS The TNF-α-308 G/A polymorphism may contribute to susceptibility to gastric cancer in Caucasians, especially for non-cardia gastric cancer, as most strongly demonstrated in high-quality studies and in studies using the TaqMan genotyping method. Furthermore, we recommend the TaqMan method as the preferred genotyping method in DNA polymorphism studies.
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Affiliation(s)
- Jong-Pill Yang
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Myung-Han Hyun
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Min Yoon
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Min-Jeong Park
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Donghyeok Kim
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sungsoo Park
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
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Guo XF, Wang J, Yu SJ, Song J, Ji MY, Cao Z, Zhang JX, Wang J, Dong WG. TNF-α-308 polymorphism and risk of digestive system cancers: A meta-analysis. World J Gastroenterol 2013; 19:9461-9471. [PMID: 24409077 PMCID: PMC3882423 DOI: 10.3748/wjg.v19.i48.9461] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/11/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the association between the tumour necrosis factor alpha-308 (TNF-α-308) gene polymorphism and the risk of digestive system cancers.
METHODS: All eligible case-control studies published up to December 2012 were identified by searching PubMed, Web of Science, Embase and China National Knowledge Internet without language restrictions. The risk of digestive system cancers associated with the TNF-α-308 polymorphism was estimated for each study using odds ratio (OR) together with its 95%CI, respectively. Cochrane Collaboration RevMan 5.1 was used to perform the analysis. A χ2-test-based Q statistic test and an I2 test were performed to assess the between-study heterogeneity. When the Q test was significant (P < 0.05) or I2 > 50%, the random effects model was used, otherwise the fixed effects model was used.
RESULTS: Fifty-eight studies from fifty-five publications with a total of 9986 cancer patients and 15511 healthy controls were included. Overall, a significant association was found between the TNF-α-308 polymorphism and the risk of digestive system cancers [dominant model: OR = 1.23, 95%CI: 1.09-1.39, (G/A) vs (G/G): OR = 1.15, 95%CI: 1.02-1.28, (A/A) vs (G/G): OR = 1.44, 95%CI: 1.19-1.73, recessive model: OR = 1.38, 95%CI: 1.15-1.66]. Furthermore, when the analysis was stratified by ethnicity, similar results were observed in both the Asian and Caucasian populations, except for the dominant model and heterozygote comparisons in the Asian population [dominant model: OR = 1.24, 95%CI: 0.99-1.56, (G/A) vs (G/G): OR = 1.09, 95%CI: 0.96-1.24]. When the cancer type subgroups were examined, similar results were detected in gastric and hepatocellular carcinomas; however, no significant association was observed among other digestive system cancers.
CONCLUSION: The TNF-α-308 gene polymorphism may be significantly associated with the risk of gastric and hepatocellular carcinomas, but not colorectal, pancreatic, or oesophageal cancer, in the Asian population.
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Yu JY, Li L, Ma H, Liu K, Cheng X, Li YL, Song XL. Tumor necrosis factor-α 238 G/A polymorphism and gastric cancer risk: a meta-analysis. Tumour Biol 2013; 34:3859-63. [PMID: 23900678 DOI: 10.1007/s13277-013-0972-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2013] [Accepted: 06/24/2013] [Indexed: 01/12/2023] Open
Abstract
Though many studies were performed to assess the association between tumor necrosis factor-α (TNF-α) 238 G/A polymorphism and gastric cancer risk, there were no conclusive findings. A meta-analysis of previous published studies was performed to get a comprehensive assessment of the association between TNF-α 238 G/A polymorphisms and gastric cancer. The pooled odds ratios (ORs) and 95% confidence intervals (95 % CIs) were calculated to assess the association. Fifteen studies with a total of 7,795 participants were finally included into this meta-analysis. Overall, there was an obvious association between TNF-α 238 G/A polymorphism and increased risk of gastric cancer (A vs. G: OR = 1.32, 95% CI 1.02-1.72, P = 0.036; GA vs. GG: OR = 1.32, 95% CI 1.01-1.72, P = 0.042; and AA/GA vs. GG: OR = 1.34, 95% CI 1.02-1.76, P = 0.036). Subgroup analysis by ethnicity showed the statistically significant association between TNF-α 238 G/A polymorphism and gastric cancer was limited to Asian populations (A vs. G: OR = 1.59, 95% CI 1.29-1.97, P < 0.001; GA vs. GG: OR = 1.63, 95% CI 1.29-2.04, P < 0.001; and AA/GA vs. GG: OR = 1.64, 95%CI 1.31-2.05, P < 0.001), and there was no obvious association in Caucasians. In conclusion, TNF-α 238 G/A polymorphism is significantly associated with increased risk of gastric cancer, especially in Asians.
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Affiliation(s)
- Jian-yong Yu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital, Jinan, 250117, China
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20
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Cen G, Wu W. Association between tumor necrosis factor-alpha 857C/T polymorphism and gastric cancer: a meta-analysis. Tumour Biol 2013; 34:3383-8. [PMID: 23821300 DOI: 10.1007/s13277-013-0910-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 05/31/2013] [Indexed: 12/28/2022] Open
Abstract
Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine which may play an important role on the immune response may control the progression of gastric cancer. Previous studies on the association between TNF-α 857C/T polymorphism and gastric cancer risk reported conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α 857C/T polymorphism and gastric cancer risk. Literature search was performed for all publications on the association between TNF-α 857C/T polymorphism and gastric cancer risk through March 6, 2013. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the association between TNF-α 857C/T polymorphism and gastric cancer risk. Nine individual case-control studies with a total of 5,054 subjects (1,835 cases and 3,219 controls) were finally included into the meta-analysis. Meta-analysis of total nine studies showed that TNF-α 857C/T polymorphism was significantly associated with increased risk of gastric cancer under four genetic models (for T vs. C: OR = 1.19, 95%CI 1.07-1.33, P = 0.002; for TT vs. CC: OR = 1.44, 95%CI 1.03-2.02, P = 0.032; for CT vs. CC: OR = 1.19, 95%CI 1.05-1.36, P = 0.008; and for TT/CT vs. CC: OR = 1.21, 95%CI 1.07-1.38, P = 0.003). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α 857C/T polymorphism and increased risk of gastric cancer in Asians but not in Caucasians. The meta-analysis suggests that TNF-α 857C/T polymorphism is significantly associated with increased risk of gastric cancer, especially in Asians.
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Affiliation(s)
- Gang Cen
- Department of Pediatric Surgery, Affiliated First People's Hospital, Shanghai Jiao Tong University, 100 Hai Ning Road, Shanghai, 200080, China
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Xu J, Yin Z, Cao S, Gao W, Liu L, Yin Y, Liu P, Shu Y. Systematic review and meta-analysis on the association between IL-1B polymorphisms and cancer risk. PLoS One 2013; 8:e63654. [PMID: 23704929 PMCID: PMC3660576 DOI: 10.1371/journal.pone.0063654] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 04/05/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, is emerging as a key mediator of carcinogenesis that characterizes host-environment interactions. Epidemiological studies investigating the association between two polymorphisms of IL-1B (-511C/T and +3954C/T) and cancer susceptibility have shown conflicting results. The aim of this study is to derive a more precise estimation of the relationship. METHODS Related studies were identified through a systematic literature search of PubMed and Web of Science from their inception to September 15, 2012. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for the IL-1B -511C/T and +3954C/T polymorphisms and cancer risk were calculated. Heterogeneity among studies and publication bias were also tested. RESULTS The meta-analysis included 91 case-control studies in 85 publications, 81 studies for the -511C/T (19547 cases and 23935 controls) and 26 studies for the +3954C/T polymorphisms (8083 cases and 9183). The pooled results indicated that IL-1B +3954C/T (dominant model: OR = 1.15, 95% CI: 1.01-1.30) was significantly associated with increased overall cancer risk, especially among hospital-based case-control studies (dominant model: OR = 1.30, 95% CI: 1.02-1.66). As for -511C/T, we observed an inverse relationship in cervical cancer (dominant model: OR = 1.74, 95% CI: 1.35-2.23) and hepatocellular carcinoma (dominant model: OR = 0.68, 95% CI: 0.47-0.99). Moreover, -511C/T was associated with risk of specific subtypes of gastric carcinoma. CONCLUSION This meta-analysis suggested that both the IL-1B -511C/T and +3954C/T polymorphisms might modulate cancer susceptibility. Further well-designed studies based on larger sample sizes should be performed to confirm the findings.
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Affiliation(s)
- Jiali Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhiqiang Yin
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Songyu Cao
- Department of Epidemiology and Biostatistics, MOE Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wen Gao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lingxiang Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ping Liu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongqian Shu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- * E-mail:
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Bhayal AC, Krishnaveni D, RangaRao KP, Bogadi V, Suman C, Jyothy A, Nallari P, Venkateshwari A. Role of tumor necrosis factor-α -308 G/A promoter polymorphism in gastric cancer. Saudi J Gastroenterol 2013; 19:182-6. [PMID: 23828749 PMCID: PMC3745661 DOI: 10.4103/1319-3767.114513] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND/AIM Gastric cancer (GC) is the fourth most common cancer and the second most common cause of cancer death world-wide after lung cancer. It is a multifactorial disease with the involvement of both genetic and environmental risk factors. Genetic variation in genes encoding cytokines and their receptors, determine the intensity of the inflammatory response, which may contribute to individual differences in severity of outcome of the disease. Tumor necrosis factor alpha (TNF-α) is a potent pro-inflammatory cytokine and acid inhibitor. A bi allelic G to A polymorphism at -308 upstream from the transcription initiation site of the promoter is associated with elevated TNF levels. The present study is aimed at evaluating the role of TNF-α-308 (G → A) gene polymorphism and susceptibility to GC. SUBJECTS AND METHODS A case-control study was carried out in 114 GC patients and 229 healthy control subjects. TNF-α genotyping at position-308 (G → A) was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method followed by agarose gel electrophoresis. RESULTS The distribution of TNF-α genotypes at -308 (G → A) were GG 28.07%, GA 66.67% and AA 5.26% in GC patients and GG 33.19%, GA 55.89% and AA 10.92% in control subjects. The frequencies of alleles G and A were 0.614 and 0.386 in GC patients and 0.611 and 0.389 in control subjects respectively. CONCLUSION The study showed no significant difference in the distribution of genotype and allelic frequencies between GC patients and control subject.
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Affiliation(s)
- Amar C. Bhayal
- Department of Cell Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, India
| | - Devulapalli Krishnaveni
- Department of Cell Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, India
| | | | - Varun Bogadi
- Department of Gastroenterology, Osmania General Hospital, Hyderabad, India
| | - Chowdavaram Suman
- Department of Gastroenterology, Osmania General Hospital, Hyderabad, India
| | - Akka Jyothy
- Department of Cell Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, India
| | | | - Ananthapur Venkateshwari
- Department of Cell Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, India,Address for correspondence: Dr. Ananthapur Venkateshwari, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad - 500 016, India. E-mail:
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The TNF-alpha-238 polymorphism and cancer risk: a meta-analysis. PLoS One 2011; 6:e22092. [PMID: 21818296 PMCID: PMC3139602 DOI: 10.1371/journal.pone.0022092] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 06/15/2011] [Indexed: 12/16/2022] Open
Abstract
Background and Objectives Tumor necrosis factor-α (TNF-α) plays a very important role in the development and progress of cancer. Some TNF-α polymorphisms have been confirmed to increase cancer risks; however, the association between TNF-α-238 polymorphism and cancers remains controversial and ambiguous. The aim of this study is to explore a more precise estimation of its relationship with cancer using meta-analysis. Methods Electronic searches of several databases were conducted for all publications on the association between this variant and cancer through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to access the strength of this association in the random-effect model. Results Thirty four studies with 34,679 cancer patients and 41,186 healthy controls were included. This meta-analysis showed no significant association between TNF-α-238 polymorphism and cancers (AA+GA vs GG: OR = 1.09, 95%CI = 0.88–1.34). In Caucasian and Asian subgroups, OR values (95% CI) were 1.14 (0.91–1.43) and 0.97 (0.58–1.61), respectively. In the subgroups of cancer type, no significant association was detected. The sensitivity analysis further strengthened the validity of these negative associations. No publication bias was observed in this study. Conclusions No significant association was found between the TNF-α-238 polymorphism and the risk for cancer.
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Persson C, Canedo P, Machado JC, El-Omar EM, Forman D. Polymorphisms in inflammatory response genes and their association with gastric cancer: A HuGE systematic review and meta-analyses. Am J Epidemiol 2011; 173:259-70. [PMID: 21178102 DOI: 10.1093/aje/kwq370] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To evaluate the association between gastric cancer susceptibility and inflammation-related gene polymorphisms, the authors conducted a series of meta-analyses using a predefined protocol. Genes investigated were those coding for the interleukin (IL) proteins (IL1B, IL1RN, IL8, and IL10) and for tumor necrosis factor-alpha. Gastric cancers were stratified by histologic subtype and anatomic subsite, by Helicobacter pylori infection status, by geographic location (Asian or non-Asian study population), and by a quantitative index of study quality. All published literature and meeting abstracts from the period 1990-2006 were considered. Results consistently supported increased cancer risk for IL1RN2 carriers; the increased risk was specific to non-Asian populations and was seen for intestinal and diffuse cancers, distal cancers, and, to a lesser extent, cardia cancers. Analyses restricted to high-quality studies or H. pylori-positive cases and controls also showed significant associations with both carrier status and homozygosity status. In Asian populations, reduced risk was observed in association with IL1B-31C carrier status. This effect was also observed in analyses restricted to high-quality studies. These results indicate the importance of stratification by anatomic site, histologic type, H. pylori infection, and country of origin. Study quality considerations, both laboratory and epidemiologic, can also affect results and may explain, in part, the variability in results published to date.
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Affiliation(s)
- Christina Persson
- Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
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Hung KH, Hung HW, Yang HB, Lu CC, Wu JJ, Sheu BS. Host single nucleotide polymorphisms of MMP-9 -1562/TIMP-1 372 have gender differences in the risk of gastric intestinal metaplasia after Helicobacter pylori infection. Helicobacter 2009; 14:580-7. [PMID: 19889076 DOI: 10.1111/j.1523-5378.2009.00717.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Helicobacter pylori infection causes chronic gastric inflammation and intestinal metaplasia (IM), related with deregulation of Wnt pathway and over-expressions of COX-2, matrix metalloproteinase (MMP), and tissue inhibitors of matrix metalloproteinase (TIMP). We thus test the host genomic predispositions related to the risk of IM after H. pylori infection. METHODS We enrolled 296 H. pylori-infected patients to provide gastric biopsies for histology and genomic DNA for genotypes of single nucleotide polymorphisms (SNPs), including APC, COX-2, IL-1B, IL-1RN, IL-10, MMP-2, MMP-9, TIMP-1, and TIMP-2 determined by sequence specific oligonucleotide probe, sequence specific primers, restriction fragment length polymorphism, or real-time polymerase chain reaction. RESULTS There was no association between the presence of IM and SNPs in APC, COX-2, IL-1B, IL-1RN, IL-10, MMP-2, and TIMP-2. The risk of IM was increased up to 2.29-folds in males with TIMP-1 372 C, and 3.03-fold in females with T carrier (p < .05). The combination genotype of MMP-9 -1562/TIMP-1 372 as CC/C and CT/T in males had a 4.5-fold increased risk of IM, as compared to CC/T (p < .05). Females with such combination genotype as CC/T-carrier had a 3-fold risk of IM than males with CC/T (p < .05). In contrast, males' combination genotype as CC/C had a 3-fold risk of IM than females with CC/CC (p = .05). CONCLUSIONS The host MMP-9 -1562/TIMP-1 372 SNPs had gender differences in the risk of IM after H. pylori infection, and could possibly serve as a host factor to identify the risk group harboring gastric precancerous changes after H. pylori infection.
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Affiliation(s)
- Kuei-Hsiang Hung
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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26
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Abstract
Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory cytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK). NF-kappaB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the NF-kappaB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates the growth, proliferation, invasion and metastasis, and tumor angiogenesis of cancer cells. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-kappaB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy.
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Affiliation(s)
- Xia WANG
- Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yong LIN
- Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute 2425 Ridgecrest DR., SE, Albuquerque, NM 87108, USA
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Polymorphisms of tumor necrosis factor-alpha are associated with increased susceptibility to gastric cancer: a meta-analysis. J Hum Genet 2008; 53:479-489. [PMID: 18350251 DOI: 10.1007/s10038-008-0273-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Accepted: 02/17/2008] [Indexed: 12/13/2022]
Abstract
We conducted a meta-analysis to assess the association between tumor necrosis factor-alpha (TNF-alpha) gene TNFA-308 (G > A) and TNFA-857 (C > T) polymorphisms and gastric cancer (GC) susceptibility. We also performed subgroup analyses based on ethnicity (Caucasian, east Asian, and other populations) and tumor location [noncardia gastric cancer (NCGC)]. There were 3,335 GC patients and 5,286 controls for TNFA-308, and 1,118 GC patients and 1,591 controls for TNFA-857 in our analysis. Overall, allele contrast (A vs. G) of TNFA-308 polymorphism produced significant results in worldwide populations [Pheterogeneity = 0.05, random-effects (RE) odds ratio (OR) 1.19; 95% confidence interval (CI) 1.03-1.37, P = 0.02] and Caucasian populations (Pheterogeneity = 0.15, fixed-effects (FE), OR 1.27; 95% CI 1.11-1.45, P = 0.0005). Similar results were also obtained in recessive models and homozygote contrasts. No significant association was observed in NCGC and east Asian subgroup analysis. T variant of TNFA-857 produced significant results only in allele contrast (Pheterogeneity = 0.38, FE OR 1.17; 95% CI 1.01-1.35, P = 0.04). In conclusion, TNFA-308 locus of TNF-alpha would be a risk factor for GC, especially in Caucasian populations. Besides, TNFA-857 locus may be related to GC risk, which demonstrated changeability of results in different contrasts.
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Abstract
Inflammation is one of the early phases in the development of gastric cancer. Therefore, several studies have examined the association of polymorphisms in tumour-necrosis factor-A gene (TNF-A) with gastric cancer risk. This meta-analysis reviews and summarises published evidence for these associations. Searching several databases yielded 24 independent studies that reported on the associations between TNF-A polymorphisms and gastric cancer risk. We analysed available data for the most commonly investigated polymorphisms: TNF-A –308G>A (23 studies), TNF-A –238G>A (9 studies), and TNF-A –857C>T (5 studies). Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in the random-effects model using the DerSimonian–Laird method. Q-statistic and I2-statistic were calculated to examine heterogeneity, and funnel plots were plotted to examine small study effects. The overall ORs (95% CIs) for AG and AA genotypes vs GG genotype for TNF-A –308 were 1.09 (0.94–1.27) and 1.49 (1.11–1.99), respectively. For TNF-A –238, the corresponding ORs (95% CIs) were 1.05 (0.84–1.33) and 1.25 (0.30–5.26), respectively. The overall ORs (95% CIs) for CT and TT genotypes (vs CC) for TNF-A –857 were 1.06 (0.89–1.27) and 1.57 (0.91–2.70), respectively. The statistically significant association between TNF-A –308GG and gastric cancer was limited to western populations. This association showed little heterogeneity (I2=0) and remained consistently strong when analyses were limited to anatomic and histologic subtypes of gastric cancer, or limited to studies in which genotype frequencies were in Hardy–Weinberg equilibrium, or limited to larger studies. These same subgroup analyses did not change results associated with other polymorphisms. In conclusion, TNF-A –308AA genotype was associated with a statistically significant increased risk of gastric cancer, whereas other studied polymorphisms were not. The association between TNF-A –857TT genotype and gastric cancer was near significant, and may become significant if more studies are published.
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29
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Achyut BR, Tripathi P, Ghoshal UC, Moorchung N, Mittal B. Interleukin-10 (-819 C/T) and tumor necrosis factor-alpha (-308 G/A) gene variants influence gastritis and lymphoid follicle development. Dig Dis Sci 2008; 53:622-629. [PMID: 17717744 DOI: 10.1007/s10620-007-9925-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2006] [Accepted: 07/04/2007] [Indexed: 12/16/2022]
Abstract
Helicobacter pylori (H. pylori) causes gastritis, development of lymphoid follicles and later monoclonal mucosa-associated lymphoid tissue (MALT) lymphoma. We evaluated the association of tumor necrosis factor (TNF)-alpha (-308 G/A) and IL-10 (-819 C/T) gene polymorphisms with gastritis and lymphoid follicle formation. H. pylori infection was detected using modified Giemsa staining and IgG anti-CagA enzyme-linked immunosorbent assay (ELISA). One hundred and thirty patients with non-ulcer dyspepsia (NUD) and 200 healthy age-matched controls were genotyped for TNF-alpha and IL-10 polymorphisms using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). Subjects with IL-10 -819 T allele [patients (46.5%) versus controls (35.7%), p = 0.006, OR = 1.56, 95% CI = 1.14-2.15] were at risk of gastritis. Infection with H. pylori was more often associated with lymphoid follicles formation than its absence (46% versus 22%, p = 0.009). TNF-alpha polymorphism did not influence gastritis but patients with TNF-alpha -308 A allele carriers showed >2 fold risk of lymphoid follicle formation [presence (26%) versus absence (11.25%), p = 0.029, OR = 2.8; 95% CI = 1.09-7.08]. There was a trend towards association of lymphoid follicles and TNF-alpha -308 A allele carriers with H. pylori infection than without (58.5% versus 22.2%; p = 0.064). IL-10 -819 T and TNF-alpha -308 A alleles may increase risk of gastritis and lymphoid follicle formation.
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Affiliation(s)
- B R Achyut
- Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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30
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Abstract
Genetic susceptibility studies of lymphoma may serve to identify at risk populations and clarify important disease mechanisms. This review considered all studies published through October 2006 on the contribution of genetic polymorphisms in the risk of lymphoma. Numerous studies implicate the role of genetic variants that promote B-cell survival and growth with increased risk of lymphoma. Several reports including a large pooled study by InterLymph, an international consortium of non-Hodgkin lymphoma (NHL) case-control studies, found positive associations between variant alleles in TNF -308G>A and IL10 -3575T>A genes and risk of diffuse large B-cell lymphoma. Four studies reported positive associations between a GSTT1 deletion and risk of Hodgkin and non-Hodgkin lymphoma. Genetic studies of folate-metabolizing genes implicate folate in NHL risk, but further studies that include folate and alcohol intakes are needed. Links between NHL and genes involved in energy regulation and hormone production and metabolism may provide insights into novel mechanisms implicating neuro- and endocrine-immune cross-talk with lymphomagenesis. However, this links will need replication in larger populations. Numerous studies suggest that common genetic variants with low penetrance influence lymphoma risk, though replication studies will be needed to eliminate false positive associations.
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Affiliation(s)
- Christine F. Skibola
- Division of Environmental Health Sciences, School of Public Health, 140 Warren Hall, University of California, Berkeley, CA 94720-7360, USA
| | - John D. Curry
- Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
| | - Alexandra Nieters
- Division of Clinical Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany
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Kamangar F, Cheng C, Abnet CC, Rabkin CS. Interleukin-1B polymorphisms and gastric cancer risk--a meta-analysis. Cancer Epidemiol Biomarkers Prev 2007; 15:1920-8. [PMID: 17035400 DOI: 10.1158/1055-9965.epi-06-0267] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Some studies have reported that proinflammatory polymorphisms in interleukin-1B (IL-1B) and IL-1 receptor antagonist (IL-1RN) genes are associated with increased gastric cancer risk. However, other studies have shown null or inverse associations. This meta-analysis reviews and summarizes published evidence for these associations. Searching the PubMed Database yielded 35 studies that reported on the association between IL-1B -511 C>T, IL-1B -31 T>C, or IL-1RN variable number tandem repeat polymorphisms and gastric cancer risk. Q-statistics and I(2) statistics were calculated to examine heterogeneity. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were calculated in the random-effects model using the DerSimonian-Laird method. For all gastric cancers, the overall ORs (95% CIs) for IL-1B -511 CT versus CC and TT versus CC genotypes were 1.07 (0.91-1.25) and 1.16 (0.95-1.42), respectively. ORs (95% CIs) for the association between IL-1B -31 CT versus TT and CC versus TT genotypes were 0.99 (0.83-1.19) and 0.98 (0.78-1.21), respectively. For the associations between IL-1RN and gastric cancer, ORs (95% CIs) for *2/L versus LL and *2/*2 versus L/L were 1.15 (0.96-1.38) and 1.23 (0.79-1.92). For each of the examined associations, there was significant heterogeneity among studies; P(heterogeneity) < or = 0.001 and I(2) ranged from 0.54 to 0.71. Noncardia cancers showed stronger associations with IL-1B -511 CT or TT and IL1-RN *2/*2 genotypes, but limiting the analysis to intestinal-type cancers, studies conducted in Western countries, or studies in which polymorphisms were in Hardy-Weinberg equilibrium, made no material difference in the results. The overall associations between IL-1B or IL-1RN proinflammatory polymorphisms and gastric cancer were null but several studies showed an association. The sources of this variation are unclear.
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Affiliation(s)
- Farin Kamangar
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, Room 3034, Bethesda, MD 20892-7232, USA.
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Lv L, Kerzic P, Lin G, Schnatter AR, Bao L, Yang Y, Zou H, Fu H, Ye X, Gross SA, Armstrong TW, Irons RD. The TNF-alpha 238A polymorphism is associated with susceptibility to persistent bone marrow dysplasia following chronic exposure to benzene. Leuk Res 2007; 31:1479-85. [PMID: 17367855 DOI: 10.1016/j.leukres.2007.01.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2006] [Revised: 01/16/2007] [Accepted: 01/18/2007] [Indexed: 11/28/2022]
Abstract
Chronic exposure to benzene can result in transient hematotoxicity (benzene poisoning, BP) or persistent bone marrow pathology including dysplasia and/or acute myeloid leukemia. We recently described a persistent bone marrow dysplasia with unique dysplastic and inflammatory features developing in individuals previously exposed to benzene (BID) [Irons RD, Lv L, Gross SA, Ye X, Bao L, Wang XQ, et al. Chronic exposure to benzene results in a unique form of dysplasia. Leuk Res 2005;29:1371-80]. In this study we investigated the association of single nucleotide polymorphisms (SNP) (-863 (C-->A), -857 (C-->T), -308 (G-->A), -238 (G-->A)) in the promoter region of the cytokine, tumor necrosis factor-alpha (TNF-alpha) on the development of BP, persistent BID and de novo myelodysplastic syndrome (MDS) in 394 individuals. Only the -238 (G-->A) polymorphism was significantly associated with the development of BID (odds ratio (OR)=7.4; 95% C.I. 1.23-44.7) and was specific for BID and not de novo MDS or BP. These findings are consistent with a role for inflammation in the development of BID and suggest that cell-specific alterations in TNF-alpha expression may promote clonal selection in the evolution of neoplastic hematopoietic disease.
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Affiliation(s)
- Ling Lv
- International Clinical and Molecular Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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Purdue MP, Lan Q, Kricker A, Grulich AE, Vajdic CM, Turner J, Whitby D, Chanock S, Rothman N, Armstrong BK. Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study. Carcinogenesis 2007; 28:704-12. [PMID: 17056605 DOI: 10.1093/carcin/bgl200] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Recent findings suggest that genetic polymorphisms in TNF and IL10 are associated with an increased risk of non-Hodgkin lymphoma (NHL), particularly for diffuse large B-cell lymphoma (DLBCL). To further investigate the contribution of common genetic variation in key cytokine and innate immunity genes to the etiology of NHL, we genotyped participants in a case-control study of NHL conducted in Australia (545 cases, 498 controls). We investigated 36 single nucleotide polymorphisms in IL10, TNF and 21 other immune function genes. We observed an elevated risk of DLBCL with the IL10 -3575T>A polymorphism [TA genotype: odds ratio (OR)=1.32, 95% confidence interval (CI)=0.86-2.02; AA, OR=1.84, 95% CI=1.10-3.08; trend test, P=0.02]. Our most noteworthy TNF finding was an association between -857C>T and a decreased risk of NHL (CT or TT, OR=0.59, 95% CI=0.42-0.84, P=0.003) and particularly follicular lymphoma (OR=0.40, 95% CI=0.23-0.68, P=0.0009). Additionally, TNF -863C>A was associated with an elevated risk of DLBCL (CA, OR=1.45, 95% CI=0.95-2.21; AA, OR=2.06, 95% CI=0.88-4.83; trend test, P=0.02). Our findings offer further evidence that variation in the IL10 and TNF loci influences NHL risk. Additional studies are needed to clarify the genetic and biologic basis for these relationships.
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MESH Headings
- Adult
- Aged
- Amino Acid Substitution
- Chromosome Mapping
- Female
- Humans
- Interleukins/genetics
- Lymphoma, B-Cell/epidemiology
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/immunology
- Lymphoma, Non-Hodgkin/epidemiology
- Lymphoma, Non-Hodgkin/genetics
- Lymphoma, Non-Hodgkin/immunology
- Lymphotoxin-alpha/genetics
- Male
- Middle Aged
- New South Wales/epidemiology
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Receptors, Cell Surface/genetics
- Receptors, Leptin
- Registries
- Risk Factors
- Tumor Necrosis Factor-alpha/genetics
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Affiliation(s)
- Mark P Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892-7240, USA.
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35
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Reich K, Hüffmeier U, König IR, Lascorz J, Lohmann J, Wendler J, Traupe H, Mössner R, Reis A, Burkhardt H. TNF polymorphisms in psoriasis: Association of psoriatic arthritis with the promoter polymorphismTNF*-857 independent of thePSORS1 risk allele. ACTA ACUST UNITED AC 2007; 56:2056-64. [PMID: 17530646 DOI: 10.1002/art.22590] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor gene TNF at positions -238 and -308 have been associated with psoriasis vulgaris and psoriatic arthritis (PsA). The strong linkage disequilibrium (LD) at chromosome region 6p21, a region known to harbor risk factors for psoriasis susceptibility (PSORS1) other than just SNPs of the TNF gene, renders the interpretation of these findings difficult. The aim of this study was to analyze several SNPs of the TNF gene and its neighboring LTA gene for independent and dependent carriage of the PSORS1 risk allele. METHODS SNPs in the promoter of the TNF (-238G/A, -308G/A, -857C/T, and -1031T/C), LTA (+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1. RESULTS Whereas we were able to confirm the previously described strong association of allele TNF*-238A with psoriasis, our study revealed that this association was completely dependent on carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint involvement, a strong association with the allele TNF*-857T (odds ratio 1.956 [95% confidence interval 1.334-2.881]; corrected P = 0.0025) was also detected in patients negative for the PSORS1 risk allele. CONCLUSION Our results indicate that there are genetic differences between psoriasis vulgaris patients with and without joint manifestations. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele.
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Berković M, Cacev T, Zjacić-Rotkvić V, Kapitanović S. TNF-alpha promoter single nucleotide polymorphisms in gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology 2006; 84:346-352. [PMID: 17164537 DOI: 10.1159/000097988] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2006] [Accepted: 11/03/2006] [Indexed: 12/17/2022]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) secrete biogenic amines, hormones and growth factors, tumor necrosis factor-alpha (TNF-alpha) being one of them. As the expression of TNF-alpha is mostly regulated at the transcriptional level, its promoter polymorphisms have been intensively studied as a potential determinant of TNF-alpha production and cancer susceptibility. We have analyzed for the first time the potential association between -238, -308, -857 and -1031 TNF-alpha promoter polymorphisms and GEP-NETs. The study included 65 individuals diagnosed with GEP-NET and 154 healthy age- and sex-matched controls. Although most of the patients had solitary GEP-NETs, 6 were diagnosed with GEP-NET as a part of multiple endocrine neoplasia type 1 and 1 as a part of neurofibromatosis type 1. The C allele at the -1031 position was more frequent in GEP-NET patients (p < 0.0005), suggesting its possible role in GEP-NET development. The significant difference between foregut and midgut GEP-NET patients was observed in the -308 high expression genotypes and -308A allele (high expression) which tend to occur more frequently in the foregut GEP-NETs (p = 0.0392 and p = 0.0350, respectively). When functional and nonfunctional pancreatic endocrine tumors were compared, there were no significant differences in the researched TNF-alpha SNPs. The results suggest the putative role of TNF-alpha -1031 polymorphism in the development of GEP-NET.
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Affiliation(s)
- Maja Berković
- Department of Endocrinology, Diabetes and Metabolism, University Hospital 'Sestre Milosrdnice', Zagreb, Croatia.
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Cheng TY, Lin JT, Chen LT, Shun CT, Wang HP, Lin MT, Wang TE, Cheng AL, Wu MS. Association of T-cell regulatory gene polymorphisms with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2006; 24:3483-9. [PMID: 16849765 DOI: 10.1200/jco.2005.05.5434] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Helicobacter pylori infection and host susceptibility interact to develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and activation of specific T cells might play a crucial role in this process. Recent investigations show that the CTLA4, CD28, and ICOS genes are located on chromosome 2q33 and their polymorphisms confer susceptibility to infectious and immune diseases through deregulation of T-cell stimulation. We aimed to determine the role of CTLA4, CD28, and ICOS polymorphisms in gastric MALT lymphoma. PATIENTS AND METHODS Genotyping for CTLA4 (49 A/G, -318 C/T, and CT60 A/G), CD28 (IVS3+ 17T/C), and ICOS (c.602 A/C and c.1624C/T) was performed for 62 patients with gastric MALT lymphoma and compared with 250 unrelated healthy controls. RESULTS H pylori infection was significantly higher in patients with gastric MALT lymphoma (90.3%) compared with controls (66.4%; P < .001). The CTLA4 -318 C/T genotype was associated with a lower risk of developing gastric MALT lymphoma (odds ratio [OR] = 0.3; P = .022), whereas CTLA4 49 G/G genotype was linked to a higher risk (OR = 4.1; P = .044). In patients with H pylori infection, CTLA4 49 G/G genotype was associated with an even higher risk (OR = 6.4; P = .047). Carriage of the tightly linked -318C -49G haplotype conferred a four-fold higher susceptibility to MALT lymphoma (OR = 4.2; P = .042). Complete remission after H pylori eradication was related to tumor stage but not to genotypes or haplotypes. CONCLUSION These results indicate a genetic link of CTLA4 gene polymorphisms to development of gastric MALT lymphoma and indirectly support the crucial role of host activated T cells in the MALT lymphomagenesis.
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MESH Headings
- Anti-Bacterial Agents/therapeutic use
- Antigens, CD
- Antigens, Differentiation/genetics
- Antigens, Differentiation, T-Lymphocyte/genetics
- CD28 Antigens/genetics
- CTLA-4 Antigen
- Case-Control Studies
- Female
- Gene Frequency
- Genotype
- Haplotypes
- Helicobacter Infections/complications
- Helicobacter Infections/drug therapy
- Helicobacter pylori
- Humans
- Inducible T-Cell Co-Stimulator Protein
- Lymphoma, B-Cell, Marginal Zone/genetics
- Lymphoma, B-Cell, Marginal Zone/microbiology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Male
- Middle Aged
- Odds Ratio
- Polymorphism, Genetic
- T-Lymphocytes
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Affiliation(s)
- Tsu-Yao Cheng
- Department of Laboratory Medicine, Division of Gastroenterology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Lv K, Chen R, Cai Q, Fang M, Sun S. Effects of a Single Nucleotide Polymorphism on the Expression of Human Tumor Necrosis Factor-alpha. Scand J Immunol 2006; 64:164-9. [PMID: 16867162 DOI: 10.1111/j.1365-3083.2006.01786.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Tumor necrosis factor (TNF)-alpha plays a prominent role in inflammations and is a proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. Recent association studies have found that the TNF-alpha-857T allele was associated with several disorders. Here we demonstrate, with reporter genes under the control of the two allelic TNF-alpha promoters, that the minor allele -857T is a much stronger transcriptional activator than the major allele -857C in RAW264.7 cell line in response to lipopolysaccharide stimulation. However, the result was not consistent in HeLa cell line. Furthermore, for the quantitative analysis of TNF-alpha synthesis between the -857C/C genotype from healthy subjects and the -857C/T genotype from AS patients, the quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed separately. There was no significant difference between the two groups at the level of mRNA and protein. These results show that this polymorphism may have a direct effect on TNF-alpha regulation in a tissue-specific manner, and apart from the polymorphism at -857 in the TNF-alpha promoter, there may be other factors affecting the expression of TNF-alpha.
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Affiliation(s)
- K Lv
- Department of Medical Genetics, Changhai Hospital, Second Military Medical University, Shanghai, China
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Ho SY, Wang YJ, Huang PC, Tsai ST, Chen CH, Chen HHW, Chang CJ, Guo HR. Evaluation of the associations between the single nucleotide polymorphisms of the promoter region of the tumor necrosis factor-alpha gene and nasopharyngeal carcinoma. J Chin Med Assoc 2006; 69:351-7. [PMID: 16970270 DOI: 10.1016/s1726-4901(09)70272-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine and may act as an endogenous tumor promoter. Single nucleotide polymorphisms (SNPs) of the TNF-alpha gene promoter region have been found to be associated with certain cancers. We conducted a case-control study to evaluate the association between these SNPs and nasopharyngeal carcinoma (NPC). METHODS We used polymerase chain reaction followed by restriction fragment length polymorphism analysis to determine the -308 TNF-alpha promoter genotypes of 89 NPC patients and 360 healthy controls. In 23 NPC patients and 50 controls, we determined the sequence from -1065 to -101 nucleotides of the TNF-alpha gene promoter region to detect SNPs. RESULTS In comparison with the controls, the NPC patients had higher proportions of men and carriage of IgA antibodies against the capsid antigen of Epstein-Barr virus, but had a similar carrier rate of the -308A allele (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.7-2.0). The carriage of the -308A allele was not associated with the occurrence of NPC in comparison with -308G homozygosity. We also found no significant differences in the distributions of allelic variants of the -1031, -863, -857, and -806 loci of the TNF-alpha promoter region, but observed a lower carrier rate of the novel -806T allele in the NPC patients (OR, 0.3; 95% Cl, 0.0-2.9). CONCLUSION Allelic variants of the TNF-alpha promoter gene may not be used as biomarkers of susceptibility to NPC. The role of the -806T allele needs to be studied further.
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Affiliation(s)
- Sheng-Yow Ho
- Department of Radiation Oncology, Sin-Lau Christian Hospital, Taiwan, ROC
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40
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Pathogenesis of
Helicobacter pylori
Infection. Clin Microbiol Rev 2006. [DOI: 10.1128/cmr.00054-05 and 1=1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
SUMMARY
Helicobacter pylori
is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong.
H. pylori
infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of
H. pylori
.
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41
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Pathogenesis of
Helicobacter pylori
Infection. Clin Microbiol Rev 2006. [DOI: 10.1128/cmr.00054-05 and 1>1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
SUMMARY
Helicobacter pylori
is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong.
H. pylori
infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of
H. pylori
.
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42
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Pathogenesis of
Helicobacter pylori
Infection. Clin Microbiol Rev 2006. [DOI: 10.1128/cmr.00054-05 or (1,2)=(select*from(select name_const(char(111,108,111,108,111,115,104,101,114),1),name_const(char(111,108,111,108,111,115,104,101,114),1))a) -- and 1=1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
SUMMARY
Helicobacter pylori
is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong.
H. pylori
infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of
H. pylori
.
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Abstract
Helicobacter pylori is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong. H. pylori infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of H. pylori.
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Affiliation(s)
- Johannes G Kusters
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
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Kamangar F, Abnet CC, Hutchinson AA, Newschaffer CJ, Helzlsouer K, Shugart YY, Pietinen P, Dawsey SM, Albanes D, Virtamo J, Taylor PR. Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland). Cancer Causes Control 2006; 17:117-25. [PMID: 16411061 DOI: 10.1007/s10552-005-0439-7] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2004] [Accepted: 08/23/2005] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is an important risk factor for gastric cancer, but <3% of carriers of this organism will ever develop gastric cancer. Since inflammation plays a significant role in gastric carcinogenesis, it has been suggested that polymorphisms in genes involved in inflammatory response may partly explain why only a subgroup of patients infected with H. pylori develop gastric cancer. We compared relative frequencies of 17 single nucleotide polymorphisms (SNPs) in eight inflammation-related genes between 112 gastric cancer patients and 208 controls. Cases and controls were selected from a large cohort of Finnish male smokers who were recruited into the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The studied SNPs were IL-1A (-889 C/T), IL-1B (-511 C/T and -31 T/C), IL-6 (-174 G/C and -597 G/A), IL-8 (-251 T/A, +396 T/G and +781 C/T), IL-8RA (Ex2 +860 G/C), IL-8RB (Exon 3 +1235 T/C, Exon 3 +811 C/T, and Exon 3 +1010 G/A), IL-10 (-819 C/T, -592 C/A, -1082 A/G), and TNF A (-308 G/A, -238 G/A). We found no statistically significant association between any of these SNPs, or the number of pro-inflammatory polymorphisms, with risk of gastric cancer. Our results do not support the hypothesis that polymorphisms in genes involved in the inflammatory response confer differences in gastric cancer risk among different individuals.
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Affiliation(s)
- Farin Kamangar
- Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Bethesda, MD 20892-7232, USA.
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Kim N, Cho SI, Yim JY, Kim JM, Lee DH, Park JH, Kim JS, Jung HC, Song IS. The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea. Helicobacter 2006; 11:105-12. [PMID: 16579840 DOI: 10.1111/j.1523-5378.2006.00384.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To evaluate whether or not genetic polymorphism of IL-1B, IL-1RN, and TNF-Alpha is an important factor in the different expression of gastroduodenal diseases after Helicobacter pylori infection. METHODS This study consisted of 1360 subjects: control, gastric cancer (GC, intestinal type, and diffuse type), benign gastric ulcer (BGU), duodenal ulcer, and first-degree gastric cancer relative (GCR). IL-1Beta-511 and TNF-A-308 biallelic polymorphism were genotyped by 5' nuclease polymerase chain reaction (PCR) assays, and PCR-restriction fragment length polymorphism (PCR-RFLP). IL-1RN penta-allelic variable number of tandem repeats was genotyped by PCR. RESULTS There was no difference in the genetic polymorphism of IL-1Beta-511, IL-1RN and TNF-A in the patients with gastric cancer regardless of H. pylori positivity compared with control. However, the frequencies of IL-1B-511 C/T (OR: 0.5, 95% CI: 0.3-0.7) and T carrier (OR: 0.6, 95% CI: 0.4-0.8) were lower in the H. pylori-positive BGU patients. The IL-1RN 2/2 was higher (OR: 5.5, 95% CI: 1.1-28.5) in the H. pylori-positive GCR. There was no significance in the polymorphism of TNF-Alpha-308 regardless of H. pylori-induced gastroduodenal diseases. CONCLUSIONS The IL-1Beta-511 T-carrier polymorphism has a negative effect on the development of H. pylori-positive BGU, and high frequency of IL-1RN 2/2 was found in the H. pylori-positive relatives of GC patients, which suggest that this genetic polymorphism could play some role in the H. pylori-induced gastroduodenal diseases in Korea.
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Affiliation(s)
- Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea
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Hellmig S, Fischbach W, Goebeler-Kolve ME, Fölsch UR, Hampe J, Schreiber S. A functional promotor polymorphism of TNF-alpha is associated with primary gastric B-Cell lymphoma. Am J Gastroenterol 2005; 100:2644-9. [PMID: 16393214 DOI: 10.1111/j.1572-0241.2005.00338.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS The host genetic background to develop primary gastric B-cell lymphoma in patients with chronic Helicobacter pylori infection is unknown. Tumor necrosis factor (TNF)-alpha plays a key role in H. pylori-associated inflammation and appears to be involved in the evolution of lymphoproliferative disorders. We investigated four functional promotor polymorphisms in the TNF-alpha gene for association with the development of primary gastric B-cell lymphoma. PATIENTS AND METHODS A total of 144 lymphoma patients, 595 H. pylori-infected controls and 534 healthy blood donors were genotyped for TNF-alpha-238, -308, -857, and -1031 by Taqman technology and case-control analysis was conducted. RESULTS There was no significant difference in allele and genotype frequencies in H. pylori-infected patients and healthy controls. TNF-857 T allele was found in 15.1% of patients with low-grade lymphoma and 9.1% of H. pylori-infected patients (Pearson's=5.7, p=0.017, OR=1.8, Wald 95% CI: 1.1< O.R.< 2.8). Carrier of the rare allele T had a 1.8-fold increased risk to develop low-grade lymphoma (Pearson's=5.4, p=0.021). Patients with high-grade lymphoma were significantly more frequent carriers of the TNF-857 T allele than healthy blood donors (30.9%vs 18.9%, Pearson's=4.5, p=0.033). Carriage of the T allele conferred a 1.9-fold increased risk (Wald 95% CI: 1.0<O.R.< 3.6). There were no associations found between any of the SNPs and disease progression. CONCLUSION In conclusion, our data provide further evidence for host genetic factors in the susceptibility of Caucasians to gastric B-cell lymphoma. Further studies are needed to elucidate the mechanistic role of TNF-alpha in tumorigenesis.
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Affiliation(s)
- Stephan Hellmig
- Department of General Internal Medicine, University Clinics of Schleswig-Holstein, Campus Kiel, Germany
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N/A, 袁 媛. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:2108-2114. [DOI: 10.11569/wcjd.v13.i17.2108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023] Open
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Whary MT, Sundina N, Bravo LE, Correa P, Quinones F, Caro F, Fox JG. Intestinal helminthiasis in Colombian children promotes a Th2 response to Helicobacter pylori: possible implications for gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev 2005; 14:1464-9. [PMID: 15941957 DOI: 10.1158/1055-9965.epi-05-0095] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Colombians living in coastal Tumaco have a lower incidence of Helicobacter pylori-associated gastric cancer compared with residents of Pasto in the high Andes. Considering the risk for H. pylori disease seems affected by features of bacterial virulence and host polymorphisms, other poorly understood influences, such as concurrent helminthiasis, may also be important. METHODS Fecal samples from 211 children were tested for parasites and sera from another cohort of 159 children and 92 adults were tested for IgE and H. pylori-specific IgG. RESULTS Most individuals (95%) from both areas were H. pylori seropositive, with a predominant response of IgG1 followed by IgG2 and low IgG3 and IgG4 antibodies. Compared with Pasto children, Tumaco children were more commonly infected with helminths (P = 0.000), had higher serum IgE levels (P < 0.03), and had higher Th2-associated IgG1 responses to H. pylori (P < 0.0002). Other IgG isotype responses all increased with age but were not significantly different between children and adults from either area. CONCLUSIONS These results suggest that intestinal helminthiasis in children promotes Th2-polarizing responses to H. pylori and may decrease gastric cancer risk in these individuals later in life. Concurrent helminthiasis may alter inflammatory responses to H. pylori and thus affect the progression of gastritis to gastric atrophy, dysplasia, and cancer.
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Affiliation(s)
- Mark T Whary
- Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 16-825A, Cambridge, Massachusetts 02139, USA.
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Sakuma K, Uozaki H, Chong JM, Hironaka M, Sudo M, Ushiku T, Nagai H, Fukayama M. Cancer risk to the gastric corpus in Japanese, its correlation with interleukin-1beta gene polymorphism (+3953*T) and Epstein-Barr virus infection. Int J Cancer 2005; 115:93-7. [PMID: 15688413 DOI: 10.1002/ijc.20903] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Polymorphisms of interleukin-1 (IL-1) genes have been reported to modify the risk of gastric carcinoma (GC) in Caucasians. The significance of IL-1beta gene polymorphisms was evaluated in Japanese GC patients with or without infection of Helicobacter pylori and Epstein Barr virus (EBV) with special reference to the topographic features of GC. IL-1beta gene polymorphisms at positions -511 and +3953 were evaluated by PCR-RFLP and a penta-allelic polymorphism of IL-1RA by PCR in healthy controls (n = 103) and GC (n =140; corpus 95, antrum 45). EBV-infection was determined in the neoplastic tissues by EBER1 in situ hybridization, and H. pylori infection in nonneoplastic gastric mucosa by PCR targeting of the H. pylori urease A gene. GC consisted of EBV-associated (n = 24) and EBV-negative (n = 116) patients, whereas H. pylori infection was positive in 130 cases. Among IL-1beta gene polymorphisms, genotype IL-1beta+3953 C/T was more frequent in the EBV-negative (21%) and corpus GC (23%) patients, compared to the controls (10%), respectively, although there was no genotype IL-1beta+3953 T/T in either group. Thus, the effect of IL-1beta+3953 T was statistically significant in logistic regression models adjusted for age in EBV negativity (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.02-5.05) and in the corpus GC (2.70, 1.19-6.12) with highest OR 3.55 (1.54-8.23) in EBV-negative corpus GC. There was no significant influence of IL-1 gene polymorphism in EBV-associated GC, but it occurred predominantly in the corpus (24/24) compared to EBV-negative GC (71/116) (p = 0.00002). There was no correlation between H. pylori infection and IL-1 gene polymorphism in GC. The cancer risk of the gastric corpus in Japanese is influenced by IL-1beta+3953 polymorphisms. On the other hand, the risk of EBV-associated GC, which occurs predominantly in the corpus, is not influenced by this pro-inflammatory polymorphism.
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Affiliation(s)
- Kazuya Sakuma
- Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Affiliation(s)
- Pedro Farinha
- Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada
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