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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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Abstract
Abstract
Background
Gastric cancer (GC) is the common cause of cancer-related deaths worldwide and inflammation represents the early phases in the GC.
Objective
To review the tumor necrosis factor (TNF)-α-308 G>A (GG, GA, and AA) in GC by meta-analysis studies for any differences in TNF-α-308 G>A gene polymorphisms.
Methods
Case–control studies published from 2003 to 2017 were identified by searching PubMed, EMASE, and the Internet with the English language. The analysis published on TNF-α-308 G>A polymorphism was analyzed and a limited number of articles were included in the present study. TNF-α-308 G>A from 4,157 patients and 5,185 healthy controls was evaluated. Studies were evaluated using Cochrane Q-test and publication bias was evaluated by constructing funnel plots.
Results
Overall, TNF-α-308 GA genotype showed significant association [P < 0.0001, odds ratio (OR), 95% confidence interval (CI) = 0.82 (0.74–0.91)]. However, meta-analysis of TNF-α-308 genotypes (GG, GA, AA, and GA + AA) between GC patients and controls showed nonsignificant association with GC [P > 0.05, recessive model: OR = 1.38, 95% CI: 1.15–1.66; 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]. Analysis stratified by ethnicity showed same results in Asian and Caucasian populations.
Conclusions
Results revealed nonsignificant association of TNF-α-308 genotypes (GG, GA, AA, and GA + AA) and GC. TNF-α-308GA genotype showed significant association whereas homozygous genotype AA did not show association with GC risk.
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Osadchuk AM, Davydkin IL, Gricenko TA, Osadchuk MA. [General and particular issues of etiopathogenesis of peptic ulcer and gastric cancer: current status of the problem]. TERAPEVT ARKH 2020; 92:97-103. [PMID: 32598726 DOI: 10.26442/00403660.2020.02.000485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Indexed: 12/16/2022]
Abstract
The development of peptic ulcer (PU) and gastric cancer (GC) is the result of the interaction of various internal and external factors. Moreover, if the role ofHelicobacter pylori(H. pylori) in the development of diseases of the stomach is fully established, the significance of many other factors continues to be discussed. Serious controversy is caused by the participation of various strains ofH. pyloriin the development of PU and GC. First of all, these are Vac- and Cag-positive strains ofH. pylori. The role of genetic human polymorphism in the development of this pathology is debatable. Especially the interleukin genes and necrotizing tumor factor alpha. The role of environmental factors in the formation of PU and GC is not fully understood. So, the role of alcohol, occupational hazards and drugs in the development of these diseases continues to be discussed. Further study of risk factors for various diseases of the stomach will optimize their prevention and treatment. The review presents a modern view of individual issues in the pathogenesis of PU and GC.
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Affiliation(s)
| | | | | | - M A Osadchuk
- Sechenov First Moscow State Medical University (Sechenov University)
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Hirbod-Mobarakeh A, Shabani M, Keshavarz-Fathi M, Delavari F, Amirzargar AA, Nikbin B, Kutikhin A, Rezaei N. Immunogenetics of Cancer. CANCER IMMUNOLOGY 2020:417-478. [DOI: 10.1007/978-3-030-30845-2_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chen TH, Huang JJ, Kung WS, Lee SS, Sun HY, Chuang HY. The Association of Serum TNF-α Levels and Blood Multi-Elements Modified by TNF-α Gene Polymorphisms in Metal Industrial Workers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16214079. [PMID: 31652851 PMCID: PMC6862333 DOI: 10.3390/ijerph16214079] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 12/27/2022]
Abstract
Health of the metal industrial workers should be a noteworthy issue due to the hazard of chronic exposure to metals or toxic elements. The interactions among multiple elements are sophisticated and may differ from person to person. Tumor necrosis factor-α (TNF-α) gene polymorphisms were supposed to be involved with the interactions because TNF-α plays an important role in inflammation, a mechanism by which toxic elements cause threats to human health. This research aimed to analyze the influence of TNF-α gene polymorphisms and multi-elements on serum TNF-α level. Blood multi-elements concentrations (lead, cadmium, arsenic, selenium, cobalt, copper, and zinc), serum TNF-α level, and TNF-α single nucleotide polymorphisms (SNPs), including −238G > A (rs361525), −308G > A (rs1800629), −857C > T (rs1799724), −863C > A (rs1800630), and −1031T > C (rs1799964), were measured in 462 metal industrial workers. We applied mixed-effect models to analyze the interactions among multi-elements and TNF-α SNPs. Blood concentration of all elements were positively associated with serum TNF-α level, and the effects may be modified by TNF-α gene polymorphisms. Our study revealed that TNF-α −308A/A and −1031C/C may be susceptible genotypes, and thus we suggest that those workers should take preventive measures against metal toxicity.
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Affiliation(s)
- Tzu-Hua Chen
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Department of Family Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan.
- Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan .
| | - Joh-Jong Huang
- Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan .
| | - Wei-Shyang Kung
- Department of Pediatrics, National Cheng Kung University Hospital, Tainan 70101, Taiwan.
| | - Su-Shin Lee
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Hung-Yu Sun
- Department of Family Medicine, Changhua Christian Hospital, Changhua 50006, Taiwan.
| | - Hung-Yi Chuang
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Department of Environmental and Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
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Pucułek M, Machlowska J, Wierzbicki R, Baj J, Maciejewski R, Sitarz R. Helicobacter pylori associated factors in the development of gastric cancer with special reference to the early-onset subtype. Oncotarget 2018; 9:31146-31162. [PMID: 30123433 PMCID: PMC6089554 DOI: 10.18632/oncotarget.25757] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023] Open
Abstract
Nowadays, gastric cancer is one of the most common neoplasms and the fourth cause of cancer-related death on the world. Regarding the age at the diagnosis it is divided into early-onset gastric carcinoma (45 years or younger) and conventional gastric cancer (older than 45). Gastric carcinomas are rarely observed in young population and rely mostly on genetic factors, therefore provide the unique model to study genetic and environmental alternations. The latest research on early-onset gastric cancer are trying to explain molecular and genetic basis, because young patients are less exposed to environmental factors predisposing to cancer. In the general population, Helicobacter pylori, has been particularly associated with intestinal subtype of gastric cancers. The significant association of Helicobacter pylori infection in young patients with gastric cancers suggests that the bacterium has an etiologic role in both diffuse and intestinal subtypes of early-onset gastric cancers. In this paper we would like to ascertain the possible role of Helicobacter pylori infection in the development of gastric carcinoma in young patients. The review summarizes recent literature on early-onset gastric cancers with special reference to Helicobacter pylori infection.
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Affiliation(s)
| | | | - Ryszard Wierzbicki
- Department of Surgery with Trauma, Orthopaedic and Urological Subunit, Independent Public Health Care Center of the Ministry of Interior and Administration in Lublin, Poland
- Department of Surgical Oncology, Medical University of Lublin, Poland
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, Poland
| | | | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, Poland
- Department of Surgery with Trauma, Orthopaedic and Urological Subunit, Independent Public Health Care Center of the Ministry of Interior and Administration in Lublin, Poland
- Department of Surgery, St. John's Cancer Center, Lublin, Poland
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Arachchi PS, Weerasekera MM, Senevirathna B, Weerasekera D, Fernando N, Gunasekara CP. Association of tumor necrosis factor alpha gene polymorphisms with Helicobacter pylori infection in dyspeptic patients in Sri Lanka. Microbiol Immunol 2018; 62:429-435. [PMID: 29704402 DOI: 10.1111/1348-0421.12597] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/27/2018] [Accepted: 04/26/2018] [Indexed: 11/29/2022]
Abstract
Single nucleotide polymorphisms present on the promoter sequence of the TNF-α gene may affect production of TNF-α, a pro-inflammatory cytokine, during immune responses. The presence of TNF-α polymorphisms is also reportedly associated with more severe manifestations of Helicobacter pylori infection. However, the frequency of TNF-α polymorphisms and the associated disease severity vary between different patient groups. In this study, gastric biopsies and blood specimens were collected from 138 patients with dyspepsia undergoing routine upper gastrointestinal endoscopy. Our institution's Ethics Review Committee approved the study and written informed consent was obtained from all participants. The presence of H. pylori was confirmed histologically in all patients. The frequency of TNF-α polymorphisms in the study cohort was investigated using PCR-restriction fragment length polymorphism and expression of serum TNF-α quantitated using a commercial ELISA assay. The proportions of selected TNF-α polymorphisms (TNF-α -238, -308 and -863) were similar in H. pylori-positive and -negative patients. Homozygous mutations of TNF-α polymorphisms were rarely detected in the study group. There was a significant difference in TNF-α concentrations between patients with mild chronic gastritis and TNF-α -308 GG genotype and patients with moderate to severe chronic gastritis (P = 0.008). It was not possible to identify an association between these genotypes and disease severity because of the low frequency of heterozygous and homozygous mutated genes in Sri Lankan patients with dyspepsia.
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Affiliation(s)
- Piyumali Sandareka Arachchi
- Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - Manjula Manoji Weerasekera
- Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - Bimalka Senevirathna
- Department of Pathology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - Deepaka Weerasekera
- Department of Surgery, Faculty of Medical Sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - Neluka Fernando
- Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
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Angel J, DiGiovanni J. Genetic Determinants of Cancer Susceptibility. COMPREHENSIVE TOXICOLOGY 2018:330-360. [DOI: 10.1016/b978-0-12-801238-3.65251-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Banday MZ, Balkhi HM, Hamid Z, Sameer AS, Chowdri NA, Haq E. Tumor necrosis factor-α (TNF-α)-308G/A promoter polymorphism in colorectal cancer in ethnic Kashmiri population - A case control study in a detailed perspective. Meta Gene 2016; 9:128-36. [PMID: 27331018 PMCID: PMC4908285 DOI: 10.1016/j.mgene.2016.06.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 06/01/2016] [Indexed: 12/31/2022] Open
Abstract
Background Inflammation constitutes one of the important components of colorectal cancer (CRC) pathogenesis. Tumor necrosis factor-α (TNF-α), a cytokine and an important inflammatory mediator plays a pivotal role in the malignant cellular proliferation, angiogenesis, tissue invasion and metastasis in CRC. The studies on association of various polymorphisms in human TNF-α gene including TNF-α-308G/A single nucleotide polymorphism (SNP) are limited, mixed and inconclusive. Materials and methods The aim of this study was to analyze the association of TNF-α-308G/A promoter SNP with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TNF-α-308G/A genotypes on different risk factors of CRC in ethnic population of Kashmir, India through a case–control setup. The genotype frequencies of TNF-α-308G/A promoter SNP were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The associations between the TNF-α-308G/A SNP and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. Further, the associations between this SNP and various clinico-pathological parameters, demographic variables and environmental factors within the case group subjects with regard to CRC risk were also evaluated. Results The association between the TNF-α-308G/A SNP and the modulation of risk of CRC was not found to be significant (p value = 0.156). The effect of less common TNF-α-308A allele on the risk of colorectal cancer was also not found to be significant (p value = 0.175). The variant genotype (AA) was nonexistent in the study population. Further, we found no significant effect modulation of CRC risk by wild and heterozygous TNF-α-308G/A SNP genotypes in presence of different possible risk factors (p > 0.05). We also found no significant association of TNF-α-308G/A SNP with the subsets of various characteristics of the case group subjects under study (p > 0.05). Conclusions This study indicates that there is no significant association between the TNF-α-308G/A promoter SNP and the risk of developing CRC in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with bigger sample size and should involve other ethnically defined populations with high CRC risk.
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Affiliation(s)
- Mujeeb Zafar Banday
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Henah Mehraj Balkhi
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Zeenat Hamid
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Aga Syed Sameer
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Nissar A. Chowdri
- Department of Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India
| | - Ehtishamul Haq
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
- Corresponding author.
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Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-2474. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
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Zabaglia LM, Ferraz MA, Pereira WN, Orcini WA, de Labio RW, Neto AC, Wisnieski F, de Oliveira JG, de Arruda Cardoso Smith M, Payão SLM, Rasmussen LT. Lack of association among TNF-α gene expression, -308 polymorphism (G > A) and virulence markers of Helicobacter pylori. J Venom Anim Toxins Incl Trop Dis 2015; 21:54. [PMID: 26719751 PMCID: PMC4696262 DOI: 10.1186/s40409-015-0054-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 12/21/2015] [Indexed: 12/18/2022] Open
Abstract
Background Tumor necrosis factor plays a critical role in the pathogenesis of gastric diseases such as gastric cancer, and an abnormal inflammatory response has frequently been observed in dyspeptic patients. Helicobacter pylori infection can induce a gastric mucosal inflammatory response that may be influenced by -308 (G > A) polymorphisms and gene expression of the TNF-α gene. Methods One hundred and thirty-four gastric biopsy samples were collected from patients of both genders (61♂ and 73♀, mean age 40.3 ± 24.2 years) with gastric symptoms. The -308 (G > A) polymorphism of TNF-α was characterized using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The expression level was measured using real-time PCR, and relative quantification (RQ) was calculated using the comparative CT method (2-ΔΔCT). Results The analysis revealed an increase in TNF-α gene expression in patients with gastritis; on the other hand, no statistical differences were observed in patients with gastric cancer. In addition, no association was found among -308 polymorphism genotypes, virulence markers, or TNF-α gene expression. Conclusions Helicobacter pylori induces a large increase in TNF-α expression in patients with gastritis, regardless of tissue inflammation, but after the tissue becomes neoplastic, the presence of bacteria did not influence expression. These results suggest that the TNF-α pathway may play an important role in the progression from gastritis to gastric cancer
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Affiliation(s)
- Luanna Munhoz Zabaglia
- Universidade Sagrado Coração, Rua Irmã Arminda 10-50, Jardim Brasil, CEP 17011-160 Bauru, SP Brazil
| | - Mariane Avante Ferraz
- Universidade Sagrado Coração, Rua Irmã Arminda 10-50, Jardim Brasil, CEP 17011-160 Bauru, SP Brazil
| | - Weendelly Nayara Pereira
- Universidade Sagrado Coração, Rua Irmã Arminda 10-50, Jardim Brasil, CEP 17011-160 Bauru, SP Brazil
| | - Wilson Aparecido Orcini
- Universidade Sagrado Coração, Rua Irmã Arminda 10-50, Jardim Brasil, CEP 17011-160 Bauru, SP Brazil
| | | | | | - Fernanda Wisnieski
- Universidade Federal de São Paulo, Rua Sena Madureira, 1500, 04021-001 São Paulo, SP Brazil
| | | | | | - Spencer Luiz Marques Payão
- Universidade Sagrado Coração, Rua Irmã Arminda 10-50, Jardim Brasil, CEP 17011-160 Bauru, SP Brazil ; Faculdade de Medicina de Marília, Rua Lourival Freire 240, 17519-050 Marília, SP Brazil
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Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α(-193) (G/A). Mediators Inflamm 2015; 2015:143941. [PMID: 26504356 PMCID: PMC4609487 DOI: 10.1155/2015/143941] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Revised: 03/03/2015] [Accepted: 03/06/2015] [Indexed: 12/18/2022] Open
Abstract
Polymorphisms in tumor necrosis factor alpha (TNF-α) gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A) and TNF-α−238 (G/A) single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238) in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis. The TNF-α−238 (G/A) genotype was significantly associated with a high risk of gastritis and gastric cancer (GC) (P = 0.001 and P = 0.002, resp.). Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A) genotype and high risk of ulcer was significant (P = 0.03). These results suggest that the TNF-α−193 (G/A) allele has a protective function against gastric cancer by developing ulcer.
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Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer. Tumour Biol 2015; 36:9159-70. [PMID: 26088449 DOI: 10.1007/s13277-015-3593-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 05/19/2015] [Indexed: 12/20/2022] Open
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Hirbod-Mobarakeh A, Amirzargar AA, Nikbin B, Nicknam MH, Kutikhin A, Rezaei N. Immunogenetics of Cancer. CANCER IMMUNOLOGY 2015:295-341. [DOI: 10.1007/978-3-662-44006-3_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ferreira RM, Machado JC, Figueiredo C. Clinical relevance of Helicobacter pylori vacA and cagA genotypes in gastric carcinoma. Best Pract Res Clin Gastroenterol 2014; 28:1003-15. [PMID: 25439067 DOI: 10.1016/j.bpg.2014.09.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/21/2014] [Accepted: 09/15/2014] [Indexed: 02/08/2023]
Abstract
Helicobacter pylori infection is the major etiological factor of gastric carcinoma. This disease is the result of a long, multistep, and multifactorial process, which occurs only in a small proportion of patients infected with H. pylori. Gastric carcinoma development is influenced by host genetic susceptibility factors, environmental factors, and H. pylori virulence. H. pylori is genetically highly variable, and variability that affects H. pylori virulence factors may be useful to identify strains with different degrees of pathogenicity. This review will focus on VacA and CagA that have polymorphic regions that impact their functional properties. The characterization of H. pylori vacA and cagA-associated could be useful for identifying patients at highest risk of disease, who could be offered H. pylori eradication therapy and who could be included in programs of more intensive surveillance in an attempt to reduce gastric carcinoma incidence.
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Affiliation(s)
- Rui M Ferreira
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal
| | - José C Machado
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Ceu Figueiredo
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine of the University of Porto, Porto, Portugal.
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16
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Xu R, Peng C, Xiao S, Zhuang W. IFRD1 polymorphisms and gastric cancer risk in a Chinese population. Med Oncol 2014; 31:135. [PMID: 25073439 DOI: 10.1007/s12032-014-0135-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 07/11/2014] [Indexed: 02/05/2023]
Abstract
The association between gene polymorphisms of IFRD1 and gastric cancer is not clear. The aim of this study was to investigate the association between IFRD1 polymorphisms and gastric cancer in Chinese population. Fifty-three consecutive patients with the diagnosis of gastric cancer were defined as the case group, and another 50 healthy donors were denoted as the control group. About 4 ml of peripheral blood was collected from each donor for extracting DNA. Finally, IFRD1 rs7818, rs3807213, and rs6968084 SNPs were detected with polymerase chain reaction. C/C genotype distribution frequencies of rs6968084 and rs7817 in gastric cancer patients were similar with the controls (OR 0.192, 95 % CI 0.513-2.769, P = 0.683 and OR 2.075, 95 % CI 0.744-5.792, P = 0.16, respectively). Patients with gastric cancer had a significantly higher frequency of rs3807213 C allele and rs3807213 C/C genotype than controls. (OR 4.028, 95 % CI 1.513-10.72, P = 0.004) (OR 3.759, 95 % CI 1.521-9.294, P = 0.003). This study suggests that the SNPs of IFRD1 rs7818 and rs6968084 have nothing to do with the gastric cancer susceptibility. The allele gene C and genotype C/C of rs3807213 SNP are involved in susceptibility to gastric cancer, but there were no relations when subgroup stratified all the three SNPs according to pathological stages.
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Affiliation(s)
- Rui Xu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 37 Guo Xue Rd., Chengdu, 610041, Sichuan Province, China
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Association between TNF-α gene 308G>A polymorphism and lung cancer risk: a meta-analysis. Tumour Biol 2014; 35:9693-9. [PMID: 24969564 DOI: 10.1007/s13277-014-2265-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 06/19/2014] [Indexed: 12/21/2022] Open
Abstract
Many studies have investigated the association between tumor necrosis factor alpha (TNF-α) gene 308G/A polymorphism and lung cancer risk, but the results were inconsistent. We thus comprehensively searched the PubMed, EMBASE, and BIOSIS Previews databases and extracted data from all eligible articles to estimate the association between TNF-α gene 308G/A polymorphism and lung cancer risk. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. Twelve case-control studies in 11 articles involving 2,436 cases and 2,573 controls were included in the meta-analysis to assess the association between TNF-α gene 308G>A polymorphism and susceptibility to lung cancer. Overall, TNF-α gene 308G>A polymorphism was significantly associated with an increased risk of lung cancer for A vs. G (OR = 1.13, 95 % CI 1.00 ~ 1.27, P = 0.04). Subgroup analysis by ethnicity showed that there was a significant association between TNF-α gene 308G>A polymorphism and increased risk of lung cancer in Asians, but not in Caucasians. In subgroup analysis by tumor type, there were significant associations between TNF-α gene 308G>A polymorphism and increased risk of lung cancer in small cell lung cancer (SCLC) for AA+AG vs. GG, in non-small cell lung cancer (NSCLC) for A vs. G, AA vs. GG, and AA+AG vs. GG. No association between the genotypes and different stages of lung cancer was detected. The meta-analysis suggests that TNF-α gene 308G>A polymorphism is associated with an increased risk of lung cancer, particularly among Asians, both for SCLC and NSCLC, considering tumor type.
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Genetic susceptibility and gastric cancer risk: the importance of meta-analyses as a statistical tool. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:421-6. [PMID: 24661935 DOI: 10.1016/j.gastrohep.2014.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 01/21/2014] [Accepted: 01/29/2014] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is a complex disease and a worldwide health burden due to its high prevalence and poor prognosis. A deeper knowledge of the factors involved in the development and progression of GC could help to identify subpopulations at risk that therefore require surveillance or early treatment strategies. Current research is based on the study of genetic variants that confer a higher risk of GC and their interactions with environmental exposure. Recently, meta-analysis has emerged as an important statistical method involving pooling of data from individual association studies to increase statistical power and obtain more conclusive results. Given the importance of chronic inflammation in the process of gastric carcinogenesis, the present article reviews the most recent meta-analyses of the contribution of cytokine gene polymorphisms to GC risk.
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Beyaert R, Beaugerie L, Van Assche G, Brochez L, Renauld JC, Viguier M, Cocquyt V, Jerusalem G, Machiels JP, Prenen H, Masson P, Louis E, De Keyser F. Cancer risk in immune-mediated inflammatory diseases (IMID). Mol Cancer 2013; 12:98. [PMID: 23987103 PMCID: PMC3765952 DOI: 10.1186/1476-4598-12-98] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 08/22/2013] [Indexed: 02/07/2023] Open
Abstract
Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.
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Affiliation(s)
- Rudi Beyaert
- Department of Rheumatology, Ghent University, 0K12, De Pintelaan 185, Ghent B-9000, Belgium.
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Waters JP, Pober JS, Bradley JR. Tumour necrosis factor and cancer. J Pathol 2013; 230:241-8. [PMID: 23460481 DOI: 10.1002/path.4188] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Revised: 02/15/2013] [Accepted: 02/23/2013] [Indexed: 02/06/2023]
Abstract
Tumour necrosis factor (TNF) was originally described as a circulating factor that can induce haemorrhagic necrosis of tumours. It is now clear that TNF has many different functions in cancer biology. In addition to causing the death of cancer cells, TNF can activate cancer cell survival and proliferation pathways, trigger inflammatory cell infiltration of tumours and promote angiogenesis and tumour cell migration and invasion. These effects can be explained by the diverse cellular responses TNF can initiate through distinct signal transduction pathways, opening the way for more selective targeting of TNF signalling in cancer therapy.
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Affiliation(s)
- John P Waters
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
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de Oliveira JG, Rossi AFT, Nizato DM, Miyasaki K, Silva AE. Profiles of gene polymorphisms in cytokines and Toll-like receptors with higher risk for gastric cancer. Dig Dis Sci 2013; 58:978-88. [PMID: 23086128 DOI: 10.1007/s10620-012-2460-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 10/08/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk. AIMS The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample. METHODS We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP. RESULTS Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis, with an OR increased 2.95-fold to 50.4-fold, highlighting the combinations IL-1RN2/TNF-A-857T/IL-8-845C, IL-1RN2/IL-8-845C/TLR2del, IL-1RN2/IL-10-592A/TLR4 + 896G, IL-10-592A/TLR2del/TLR4 + 896G, and IL-1RN2/TNFA-857T/IL8-845C/TLR2del. CONCLUSIONS Our findings evidenced that the combined effect of polymorphisms in genes involved in the inflammatory process may potentiate the risk of gastric cancer, thus emphasizing the importance of evaluating multiple polymorphisms together.
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Affiliation(s)
- Juliana Garcia de Oliveira
- Department of Biology, São Paulo State University (UNESP), Rua Cristovão Colombo, 2265, São José do Rio Preto, 15054-000 SP, Brazil.
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Hong Y, Ge Z, Jing C, Shi J, Dong X, Zhou F, Wang M, Zhang Z, Gong W. Functional promoter -308G>A variant in tumor necrosis factor α gene is associated with risk and progression of gastric cancer in a Chinese population. PLoS One 2013; 8:e50856. [PMID: 23326309 PMCID: PMC3542372 DOI: 10.1371/journal.pone.0050856] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2012] [Accepted: 10/29/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Tumor necrosis factor-α (TNF-α) plays a crucial role in the development and progression of gastric cancer. A functional polymorphism, -308 G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. In the present study, we sought to investigate whether this polymorphism has effects on the risk and progression of gastric cancer in a Chinese population. METHODS We genotyped the TNFA -308 G>A polymorphism using the TaqMan method in a two-stage case-control study comprising a total of 1686 gastric cancer patients and 1895 cancer-free subjects. The logistic regression was used to assess the genetic associations with occurrence and progression of gastric cancer. RESULTS We found a significant association between the variant genotypes and increased risk of gastric cancer [P = 0.034, odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.01-1.67, GA/AA vs. GG]. Similar results were observed in the follow-up replication study. When combined the data from the two studies, we found a more significant association (P = 0.001, OR = 1.34, 95%CI = 1.13-1.59), especially for older subjects (>65 years). Furthermore, the patients carrying the variant genotypes had a significantly greater prevalence of T4 stage of disease (P = 0.001, OR = 2.19, 95%CI = 1.39-3.47) and distant metastasis (P = 0.013, OR = 1.61, 95%CI = 1.10-2.35). CONCLUSIONS Our results suggest that the functional promoter -308 G>A polymorphism in TNFA influence the susceptibility and progression of gastric cancer in the Chinese population.
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Affiliation(s)
- Yan Hong
- Department of Surgery, Yixing People's Hospital, Yixing, China
| | - Zhijun Ge
- Department of Surgery, Yixing People's Hospital, Yixing, China
| | - Changrui Jing
- Department of Plastic Surgery, Wuxi No.2 People's Hospital, Wuxi, China
| | - Jun Shi
- Department of Surgery, Yixing People's Hospital, Yixing, China
| | - Xiao Dong
- Department of Surgery, Yixing Cancer Hospital, Yixing, China
| | - Fengying Zhou
- Department of Breast Surgery, Wuxi Maternal and Child Health Hospital, Wuxi, China
| | - Meilin Wang
- Department of Molecular and Genetic Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhengdong Zhang
- Department of Molecular and Genetic Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weida Gong
- Department of Surgery, Yixing People's Hospital, Yixing, China
- Department of Surgery, Yixing Cancer Hospital, Yixing, China
- Cancer Center, Nanjing Medical University, Nanjing, China
- * E-mail:
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Yang Z, Lv Y, Lv Y, Wang Y. Meta-Analysis Shows Strong Positive Association of the TNF-α Gene with Tumor Stage in Bladder Cancer. Urol Int 2012; 89:337-41. [DOI: 10.1159/000341701] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 07/09/2012] [Indexed: 01/08/2023]
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Zorzetto V, Maddalo G, Basso D, Farinati F. Immunotherapy for gastric premalignant lesions and cancer. Immunotherapy 2012; 4:587-99. [PMID: 22788127 DOI: 10.2217/imt.12.50] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Kim EH, Hong KS, Hong H, Hahm KB. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis. Cancers (Basel) 2011; 3:3018-28. [PMID: 24212943 PMCID: PMC3759184 DOI: 10.3390/cancers3033018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Revised: 07/12/2011] [Accepted: 07/19/2011] [Indexed: 02/06/2023] Open
Abstract
Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.
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Affiliation(s)
- Eun-Hee Kim
- Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea; E-Mails: (E.-H.K.); (K.-S.H.); (H.H.)
| | - Kyung-Sook Hong
- Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea; E-Mails: (E.-H.K.); (K.-S.H.); (H.H.)
| | - Hua Hong
- Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea; E-Mails: (E.-H.K.); (K.-S.H.); (H.H.)
| | - Ki Baik Hahm
- Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea; E-Mails: (E.-H.K.); (K.-S.H.); (H.H.)
- Department of Gastroenterology, Gachon Graduate School of Medicine, Gil Hospital, Incheon 406-840, Korea
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +82-32-899-6055; Fax: +82-32-899-6054
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Shi Z, Du C. Tumor necrosis factor alpha 308 G/A polymorphism and hepatocellular carcinoma risk in a Chinese population. Genet Test Mol Biomarkers 2011; 15:569-72. [PMID: 21401328 DOI: 10.1089/gtmb.2011.0008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. Tumor necrosis factor alpha (TNF-α) is a cytokine that may act as an endogenous tumor promoter. The association between TNF-α 308 G/A polymorphism and HCC risk remains unclear. AIM The aim of this study was to investigate the association between TNF-α 308 G/A polymorphism and HCC risk in a Chinese population. METHODS The study population consisted of 88 patients with documented HCC and 88 healthy controls. The gene polymorphism of TNF-α was analyzed by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS HCC patients had a significantly lower frequency GG (odds ratio=0.36; 95% confidence interval=0.13, 0.94; p=0.04) and G allele (odds ratio=0.58; 95% confidence interval=0.37, 0.90; p=0.01) than healthy controls. When stratifying for tumor size and cirrhosis, no statistically significant results were found. CONCLUSION This study suggested that TNF-α -308GG and G allele were associated with a modest decrease in the risk of HCC in Chinese population.
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Affiliation(s)
- Zhengrong Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Janjigian YY, Tang LH, Coit DG, Kelsen DP, Francone TD, Weiser MR, Jhanwar SC, Shah MA. MET expression and amplification in patients with localized gastric cancer. Cancer Epidemiol Biomarkers Prev 2011; 20:1021-7. [PMID: 21393565 DOI: 10.1158/1055-9965.epi-10-1080] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND MET, the receptor for hepatocyte growth factor, has been proposed as a therapeutic target in gastric cancer. This study assessed the incidence of MET expression and gene amplification in tumors of Western patients with gastric cancer. METHODS Tumor specimens from patients enrolled on a preoperative chemotherapy study (NCI 5700) were examined for the presence of MET gene amplification by FISH, MET mRNA expression by quantitative PCR, MET overexpression by immunohistochemistry (IHC), and for evidence of MET pathway activation by phospho-MET (p-MET) IHC. RESULTS Although high levels of MET protein and mRNA were commonly encountered (in 63% and 50% of resected tumor specimens, respectively), none of these tumors had MET gene amplification by FISH, and only 6.6% had evidence of MET tyrosine kinase activity by p-MET IHC. CONCLUSIONS In this cohort of patients with localized gastric cancer, the presence of high MET protein and RNA expression does not correlate with MET gene amplification or pathway activation, as evidenced by the absence of amplification by FISH and negative p-MET IHC analysis. IMPACT This article shows a lack of MET amplification and pathway activation in a cohort of 38 patients with localized gastric cancer, suggesting that MET-driven gastric cancers are relatively rare in Western patients.
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Affiliation(s)
- Yelena Y Janjigian
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY 10065, USA.
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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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Chen B, Cao L, Zhou Y, Yang P, Wan HW, Jia GQ, Liu L, Wu XT. Glutathione S-transferase T1 (GSTT1) gene polymorphism and gastric cancer susceptibility: a meta-analysis of epidemiologic studies. Dig Dis Sci 2010; 55:1831-8. [PMID: 19960261 DOI: 10.1007/s10620-009-1000-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2009] [Accepted: 09/17/2009] [Indexed: 02/05/2023]
Abstract
PURPOSE Studies investigating the association between genetic polymorphism of glutathione S-transferase T1 (GSTT1) and gastric cancer risk have reported conflicting results. Therefore, we conducted this meta-analysis to provide more precise evidence. METHODS We searched the databases Medline, PubMed, Embase, and China National Knowledge Infrastructure up to July 30, 2009. Thirty-six studies with 4,357 gastric cancer cases and 9,796 controls were selected. Odds ratio (OR) and 95% confidence intervals (CI) were calculated based on fixed- and random-effects models. RESULTS The combined results based on all studies showed there was a significant link between GSTT1 null genotype and gastric cancer risk (OR = 1.14, 95%CI = 1.01-1.28). In subgroup analysis stratified on the basis of ethnic group, we also observed positive association between GSTT1 polymorphism and gastric cancer risk among Caucasians (non-Europeans + non-Americans), but not among East Asians. When stratifying by control source, the overall ORs for population- and hospital-based studies were 1.09 (95%CI = 0.94-1.28) and 1.17 (95%CI = 1.03-1.34), respectively. Subjects with both GSTM1 and GSTT1 negative genotypes had increased gastric cancer risk compared with those who had nonnull genotypes of both GST genes. Subgroup analyses for Helicobacter pylori infection and smoking habit did not reveal any significant association between GSTT1 polymorphism and gastric cancer development. CONCLUSIONS This meta-analysis suggests that GSTT1 gene polymorphism may be not associated with increased gastric cancer risk among Europeans, Americans, and East Asians. More large-scale studies based on the same racial group are needed.
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Affiliation(s)
- Bo Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Yoon JH, Song JH, Kang YH, Park YK, Zhang C, Nam SW, Lee JY, Park WS. TNF-α and TNF-β polymorphisms with susceptibility to gastric cancer in a Korean population. Mol Cell Toxicol 2010; 6:161-167. [DOI: 10.1007/s13273-010-0023-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram. Ann Surg 2010; 251:640-6. [PMID: 20224369 DOI: 10.1097/sla.0b013e3181d3d29b] [Citation(s) in RCA: 283] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To compare disease-specific survival (DSS) between the US and Korea following R0 resection for gastric carcinoma (GC). SUMMARY BACKGROUND DATA Many studies have described decreased 5-year survival after curative gastrectomy for GC in the West compared with the East. Although clinicopathological presentations of GC are known to vary widely between Eastern and Western countries, including histology, tumor location, and stage at presentation, it remains unclear whether these factors account for differences in survival. METHODS All patients undergoing curative intent resections (R0) for GC (1995-2005) were evaluated in 2 independent, single-institution prospectively maintained databases from the US (711 patients) and Korea (1646 patients). Patients receiving neoadjuvant chemotherapy were excluded from this analysis. Patient, surgical and pathologic variables were compared. DSS was determined via multivariate analysis using prognostic variables from an internationally validated GC nomogram that estimates the probability of 5- and 9-year survival. RESULTS Age and body mass index were significantly higher in US patients. Location of tumors was more often proximal in the United States (39% vs. 9%, P < 0.0001) and distal in Korea (54% vs. 33%, P < 0.0001). Korean patients had more early stage tumors (42% vs. 28% stage Ia, P < 0.0001) with a higher number of lymph nodes identified (97% vs. 79%, >or=15 lymph nodes, P < 0.0001). The 5-year DSS was higher in Korea than in the United States. After multivariate analysis, applying factors used in the nomogram, DSS of Korean GC patients remained significantly better than that of US patients (HR = 1.3, 95% CI; 1.0-1.6, P = 0.008). CONCLUSIONS This study demonstrates better survival for GC patients in Korea compared with the US as determined by multivariate analysis with a validated gastric cancer nomogram. Multiple possibilities can explain this difference.
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Partida-Rodríguez O, Torres J, Flores-Luna L, Camorlinga M, Nieves-Ramírez M, Lazcano E, Perez-Rodríguez M. Polymorphisms in TNF and HSP-70 show a significant association with gastric cancer and duodenal ulcer. Int J Cancer 2010; 126:1861-1868. [PMID: 19626584 DOI: 10.1002/ijc.24773] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Tumour Necrosis Factor (TNF) and Heat Shock Protein 70 (HSP70) are important molecules in inflammatory, infectious and tumoral processes. The genes codifying these molecules are polymorphic and certain alleles have been associated with susceptibility to disease. Gastric cancer is associated with an Helicobacter pylori-induced chronic inflammatory response. The aim of this work was to analyze whether polymorphisms in inflammation-related genes are associated with the development of gastric cancer. We studied 447 Mexican adult patients including 228 with non-atrophic gastritis, 98 with intestinal metaplasia, 63 with gastric cancer and 58 with duodenal ulcer, and 132 asymptomatic individuals as well. DNA from peripheral white blood cells was typed for the Single Nucleotide Polymorphisms (SNPs) -308 of TNF-alpha, +252 of TNF-beta, +190 of HSP70-1, +1267 of HSP70-2 and +2437 of HSP70-HOM. Compared with the asymptomatic group, we found a significant association of TNF-beta*A and HSP70-1*C alleles with gastric cancer (OR 5.69 and 3.76, respectively) and HSP70-1*C with duodenal ulcer (OR 3.08). Genotype TNF-beta G/G showed a significant gene-dose effect with gastric cancer (OR 0.09); whereas HSP70-1 C/G showed significant association with both, gastric cancer (OR 13.31) and duodenal ulcer (OR 16.19). Polymorphisms in TNF and HSP70 showed a significant severity-dose-response as risk markers from preneoplastic lesions to gastric cancer in Mexican population, probably because of their association with an intense and sustained inflammatory response.
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Affiliation(s)
| | - Javier Torres
- Infectious Diseases Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
| | | | - Margarita Camorlinga
- Infectious Diseases Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
| | - Miriam Nieves-Ramírez
- Immunology Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
| | - Eduardo Lazcano
- Instituto Nacional de Salud Pública, Cuernavaca, Morelos CP 62100, Mexico
| | - Martha Perez-Rodríguez
- Immunology Research Unity, Pediatric Hospital, CMN S-XXI, IMSS, Mexico City CP 06720, Mexico
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Peleteiro B, Lunet N, Carrilho C, Durães C, Machado JC, La Vecchia C, Barros H. Association between cytokine gene polymorphisms and gastric precancerous lesions: systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19:762-76. [PMID: 20200422 DOI: 10.1158/1055-9965.epi-09-0917] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Polymorphisms within interleukin-1 (IL1) and tumor necrosis factor alpha (TNFA) gene clusters are associated with an increased risk of gastric cancer. However, their role in gastric precancerous lesions remains poorly understood. Our objective was to perform a meta-analysis of studies addressing the association between IL1B-511, IL1RN variable number of tandem repeat, and TNFA-308 gene polymorphisms and gastric precancerous lesions, including original data from Portugal and Mozambique. Published studies on the association between these cytokine gene polymorphisms and gastric precancerous lesions were identified by systematic review, and estimates of the association were combined using random-effects meta-analysis taking into account new data obtained from Portuguese volunteer shipyard workers (n = 215) and Mozambican dyspeptic patients (n = 96) who underwent endoscopic and pathologic evaluation following the same protocol. Odds ratio (OR) estimates for intestinal metaplasia were 2.83 [95% confidence interval (95% CI), 1.15-6.96] for the IL1RN*22 genotype, 1.86 (95% CI, 1.03-3.36) for IL1B-511 T carriers, and 0.59 (95% CI, 0.12-3.04) for the TNFA-308*AA genotype in the Portuguese sample. All Mozambican subjects with intestinal metaplasia were T carriers for IL1B-511 and none had the 2 allele for IL1RN. In meta-analysis, IL1RN*22 genotype was associated with an increased risk of gastric precancerous lesions (22 versus LL: OR, 2.27; 95% CI, 1.40-3.70; I(2) = 26.4%; 12 studies). No such association was found for the IL1B-511 (TT versus CC: OR, 1.34; 95% CI, 0.87-2.07; I(2) = 65.7%; 13 studies) or TNFA-308 genotypes (AA versus GG: OR, 0.93; 95% CI, 0.35-2.43; I(2) = 0.0%; 7 studies). The IL1RN*22 genotype seems to consistently increase the risk of gastric precancerous lesions, supporting a role for this polymorphism in the early stages of gastric carcinogenesis.
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Affiliation(s)
- Bárbara Peleteiro
- Serviço de Higiene e Epidemiologia, Faculdade de Medicina da Universidade do Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
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Angel J, Abel E, DiGiovanni J. Genetic Determinants of Cancer Susceptibility. COMPREHENSIVE TOXICOLOGY 2010:371-400. [DOI: 10.1016/b978-0-08-046884-6.01419-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Milne AN, Carneiro F, O'Morain C, Offerhaus GJA. Nature meets nurture: molecular genetics of gastric cancer. Hum Genet 2009; 126:615-628. [PMID: 19657673 PMCID: PMC2771140 DOI: 10.1007/s00439-009-0722-x] [Citation(s) in RCA: 173] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2009] [Accepted: 07/16/2009] [Indexed: 12/14/2022]
Abstract
The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest findings as well as to look at the larger picture in terms of how to tackle the problem of solving this multi-piece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inflammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diffuse gastric cancer is highlighted, and finally the ever growing discipline of SNP analysis (including IL1B) is discussed.
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Affiliation(s)
- Anya N Milne
- Pathology Department H04.2.25, University Medical Centre Utrecht, Postbus 85500, 3508GA Utrecht, The Netherlands.
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Trombone APF, Cardoso CR, Repeke CE, Ferreira Jr SB, Martins Jr W, Campanelli AP, Avila-Campos MJ, Trevilatto PC, Silva JS, Garlet GP. Tumor necrosis factor-alpha −308G/A single nucleotide polymorphism and red-complex periodontopathogens are independently associated with increased levels of tumor necrosis factor-α in diseased periodontal tissues. J Periodontal Res 2009; 44:598-608. [DOI: 10.1111/j.1600-0765.2008.01166.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest findings as well as to look at the larger picture in terms of how to tackle the problem of solving this multi-piece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inflammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diffuse gastric cancer is highlighted, and finally the ever growing discipline of SNP analysis (including IL1B) is discussed.
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Yang JJ, Ko KP, Cho LY, Shin A, Gwack J, Chang SH, Shin HR, Yoo KY, Kang D, Park SK. The role of TNF genetic variants and the interaction with cigarette smoking for gastric cancer risk: a nested case-control study. BMC Cancer 2009; 9:238. [PMID: 19615068 PMCID: PMC2725140 DOI: 10.1186/1471-2407-9-238] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Accepted: 07/17/2009] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the role of TNF genetic variants and the combined effect between TNF gene and cigarette smoking in the development of gastric cancer in the Korean population. METHODS We selected 84 incident gastric cancer cases and 336 matched controls nested within the Korean Multi-Center Cancer Cohort. Six SNPs on the TNF gene, TNF-alpha-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C, and TNF-beta 252 A/G were genotyped. The ORs (95% CIs) were calculated using unconditional logistic regression model to detect each SNP and haplotype-pair effects for gastric cancer. The combined effects between the TNF gene and smoking on gastric cancer risk were also evaluated. Multi dimensionality reduction (MDR) analyses were performed to explore the potential TNF gene-gene interactions. RESULTS TNF-alpha-857 C/T containing the T allele was significantly associated with an increased risk of gastric cancer and a linear trend effect was observed in the additive model (OR = 1.6, 95% CI 1.0-2.5 for CT genotype; OR = 2.6, 95% CI 1.0-6.4 for TT genotype). All haplotype-pairs that contained TCT or CCC of TNF-alpha-1031 T/C, TNF-alpha-863 C/A, and TNF-alpha-857 C/T were associated with a significantly higher risk for gastric cancer only among smokers. In the MDR analysis, regardless of smoking status, TNF-alpha-857 C/T was included in the first list of SNPs with a significant main effect. CONCLUSION TNF-alpha-857 C/T polymorphism may play an independent role in gastric carcinogenesis and the risk for gastric cancer by TNF genetic effect is pronounced by cigarette smoking.
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Affiliation(s)
- Jae Jeong Yang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Pil Ko
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Division of Epidemiology and Health Index, Center for Genome Science, Korea Center for Disease Control and Prevention, Seoul, Korea
| | - Lisa Y Cho
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Aesun Shin
- National Cancer Control Research Institute, National Cancer Center, Goyang, Korea
| | - Jin Gwack
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Soung-Hoon Chang
- Department of Preventive Medicine, Konkuk University, Chungju, Korea
| | - Hai-Rim Shin
- National Cancer Control Research Institute, National Cancer Center, Goyang, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Daehee Kang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Seoul National University Cancer Research Institute, Seoul, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Seoul National University Cancer Research Institute, Seoul, Korea
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Gao L, Nieters A, Brenner H. Cell proliferation-related genetic polymorphisms and gastric cancer risk: systematic review and meta-analysis. Eur J Hum Genet 2009; 17:1658-67. [PMID: 19536170 DOI: 10.1038/ejhg.2009.102] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Apart from Helicobacter pylori infection and lifestyle factors, host genetic susceptibility has been suggested to contribute to individual variation in gastric cancer risk as well. Aiming to evaluate the associations between host cell proliferation-related genetic polymorphisms and gastric cancer susceptibility, we reviewed the related studies published until 15 September 2008 and quantitatively summarized the associations of the most widely studied polymorphisms (TP53 Arg72Pro, L-myc EcoRI) using meta-analysis. Fifty-five eligible studies were included in this review. Twenty-three polymorphisms significantly related to gastric cancer risk in at least one study were identified. Polymorphisms determining higher levels of growth factors, which are important for tissue repair, were recently observed to be associated with reduced risk of gastric cancer. In the meta-analysis, TP53 72Pro was associated with increased risk of diffuse gastric cancer among Asians (OR, 1.44; 95% CI, 1.04-1.99), but decreased risk of intestinal gastric cancer among Caucasians (OR, 0.56; 95% CI, 0.36-0.89). This review suggests that cell proliferation-related genetic polymorphisms could be candidate biomarkers of gastric cancer risk, but current evidence for the use for risk stratification is still very limited. Modestly significant associations in meta-analyses stratified by population or type of gastric cancer may be observed by chance because of the limited number of studies and small sample size. Larger studies are warranted to clarify the effect of cell proliferation-related genetic polymorphisms on gastric carcinogenesis.
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Affiliation(s)
- Lei Gao
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
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Canedo P, Durães C, Pereira F, Regalo G, Lunet N, Barros H, Carneiro F, Seruca R, Rocha J, Machado JC. Tumor necrosis factor alpha extended haplotypes and risk of gastric carcinoma. Cancer Epidemiol Biomarkers Prev 2008; 17:2416-20. [PMID: 18768512 DOI: 10.1158/1055-9965.epi-08-0413] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The tumor necrosis factor alpha (TNFA)-308*A allele has been found to confer an increased risk of gastric carcinoma. Inconsistency in risk estimates across populations lead us to hypothesize about the presence of an alternative causal locus in the same chromosomal region. A suitable approach is to determine the tumor necrosis factor haplotypic structure in order to clarify whether the association between the *A allele and the increased risk of gastric carcinoma is etiologic or secondary to linkage disequilibrium. Firstly, we assessed the association between the TNFA-308G>A polymorphism and the risk of gastric carcinoma in a population from Northern Portugal (508 gastric carcinoma patients, 713 controls); secondly, we genotyped five microsatellite loci (TNFa, b, c, d, e) flanking the TNFA-308G>A locus to establish the haplotypic structure associated with this single-nucleotide polymorphism in cases (122 patients) and controls (169 individuals). We found a significant association between the *A allele and increased risk of gastric carcinoma (odds ratio, 1.7; 95% confidence interval, 1.3-2.2) confirming previous results in our population. Regarding the *A allele-associated haplotypes, the most relevant difference was found for the H1A haplotype present in 33.1% of the cases and 12.5% of the controls. We also observed haplotypes associated with the *A allele that were found only in cases or controls. A population differentiation test showed that the gastric carcinoma and the control groups were significantly different for the *A allele haplotypic structure. This suggests that the association between the TNFA-308G>A polymorphism and increased risk of gastric carcinoma is dependent on linkage disequilibrium with an as yet unidentified locus.
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Affiliation(s)
- Paulo Canedo
- IPATIMUP-Institute of Molecular Pathology and Immunology, Porto, Portugal
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Vasto S, Carruba G, Lio D, Colonna-Romano G, Di Bona D, Candore G, Caruso C. Inflammation, ageing and cancer. Mech Ageing Dev 2008; 130:40-5. [PMID: 18671998 DOI: 10.1016/j.mad.2008.06.003] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2008] [Revised: 06/04/2008] [Accepted: 06/30/2008] [Indexed: 12/22/2022]
Abstract
Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. In this review, we have briefly mentioned inflammatory mediators involved in cancer although we decided to choose the ones which show a strict association with ageing and longevity. Inflammation is necessary to manage with damaging agents and is crucial for survival. But, in our opinion, the pro-inflammatory status of ageing might be one of the mechanisms which relate cancer to ageing. The most appropriate inflammatory genes have been selected to survive and to reproduce. Paradoxically, inflammatory age-related diseases (including cancer) are the marks of the same evolutionistic trait. Centenarians are characterized by a higher frequency of genetic markers associated with better control of inflammation. The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective effect towards the development of those age-related pathologies having a strong inflammatory pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background with a peculiar resistance to cancer which is also an anti-inflammatory profile.
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Affiliation(s)
- Sonya Vasto
- Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy
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