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Whitmire JM, Windham IH, Makobongo MO, Westland MD, Tran SC, Piñol J, Hui Y, Raheem Alkarkoushi R, Pich OQ, McGee DJ, Piazuelo MB, Melton-Celsa A, Testerman TL, Cover TL, Merrell DS. A unique Helicobacter pylori strain to study gastric cancer development. Microbiol Spectr 2025; 13:e0216324. [PMID: 39641575 PMCID: PMC11705839 DOI: 10.1128/spectrum.02163-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 10/20/2024] [Indexed: 12/07/2024] Open
Abstract
Helicobacter pylori colonizes a majority of the human population worldwide and can trigger development of a variety of gastric diseases. Since the bacterium is classified as a carcinogen, elucidation of the characteristics of H. pylori that influence gastric carcinogenesis is a high priority. To this end, the Mongolian gerbil infection model has proven to be an important tool to study gastric cancer progression. However, only a small number of H. pylori strains have been evaluated in the gerbil model. Thus, to identify additional strains able to colonize and induce disease in this model, several H. pylori strains were used to infect Mongolian gerbils, and stomachs were harvested at multiple timepoints to assess colonization and gastric pathology. The USU101 strain reproducibly colonized Mongolian gerbils and induced gastric inflammation in the majority of the animals 1 month after infection. Adenocarcinoma or dysplasia was observed in the majority of gerbils by 2 months post-infection. To define the contribution of key virulence factors to this process, isogenic strains lacking cagA or vacA, along with restorant strains containing a wild-type (WT) copy of the genes, were studied. The ΔcagA USU101 strain colonized gerbils at levels similar to WT, but did not induce comparable levels of inflammation or disease. In contrast, the ΔvacA USU101 strain did not colonize gerbils, and the stomach pathology resembled that of the mock-infected animals. The restorant USU101 strains expressed the CagA and VacA proteins in vitro, and in vivo experiments with Mongolian gerbils showed a restoration of colonization levels and inflammation scores comparable to those observed in WT USU101. Our studies indicate that the USU101 strain is a valuable tool to study H. pylori-induced disease.IMPORTANCEGastric cancer is the fifth leading cause of cancer-related death globally; the majority of gastric cancers are associated with Helicobacter pylori infection. Infection of Mongolian gerbils with H. pylori has been shown to result in induction of gastric cancer, but few H. pylori strains have been studied in this model; this limits our ability to fully understand gastric cancer pathogenesis in humans because H. pylori strains are notoriously heterogenous. Our studies reveal that USU101 represents a unique H. pylori strain that can be added to our repertoire of strains to study gastric cancer development in the Mongolian gerbil model.
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Affiliation(s)
| | - Ian H. Windham
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Morris O. Makobongo
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
- University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | | | | | - Jaume Piñol
- Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
- Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
| | - Yvonne Hui
- University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | | | - Oscar Q. Pich
- Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
- Laboratori de Recerca en Microbiologia i Malalties Infeccioses, Hospital Universitari Parc Taulí, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
| | - David J. McGee
- Department of Microbiology and Immunology, LSU Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | | | - Angela Melton-Celsa
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Traci L. Testerman
- University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Timothy L. Cover
- Vanderbilt University, Nashville, Tennessee, USA
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - D. Scott Merrell
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, USA
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Gu J, He F, Clifford GM, Li M, Fan Z, Li X, Wang S, Wei W. A systematic review and meta-analysis on the relative and attributable risk of Helicobacter pylori infection and cardia and non-cardia gastric cancer. Expert Rev Mol Diagn 2023; 23:1251-1261. [PMID: 37905778 DOI: 10.1080/14737159.2023.2277377] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/03/2023] [Indexed: 11/02/2023]
Abstract
INTRODUCTION This study aimed to update the association between Helicobacter pylori (H. pylori) infection and gastric cancer (GC). METHODS We searched PubMed, Embase, and Cochrane Library from 1990 to December 2021 to identify prospective studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were summarized to validate the relationship between H. pylori infection and GC. RESULTS Including 27 studies, findings indicated a strong link between H. pylori and non-cardia gastric cancer (NCGC) in both Europe/North America (OR=5.37, 95%CI:4.39-6.57) and Asia (OR = 2.50, 95%CI:1.89-3.32), and a positive association with cardia gastric cancer (CGC) in Asia (OR = 1.74, 95%CI:1.38-2.19), but an inverse association in European/American populations (OR = 0.64, 95%CI: 0.51 to 0.79). Furthermore, the strength of association was greater in studies that detected H. pylori by immunoblotting versus ELISA, and also in studies testing for H. pylori detection further back in time prior to cancer diagnosis (Ptrend<0.05). Approximately 79% of NCGC in Asia and 87% in Europe/North America, along with 62% of CGC in Asia, could be attributable to H. pylori infection. CONCLUSIONS The meta-analysis supports the significant attributable risk of H. pylori infection for GC and underscores the potential impact of targeting H. pylori in GC prevention programs. PROSPERO REGISTRATION CRD42021274120.
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Affiliation(s)
- Jianhua Gu
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Feifan He
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Gary M Clifford
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Minjuan Li
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiyuan Fan
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinqing Li
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shaoming Wang
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenqiang Wei
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Astaxanthin Inhibits Matrix Metalloproteinase Expression by Suppressing PI3K/AKT/mTOR Activation in Helicobacter pylori-Infected Gastric Epithelial Cells. Nutrients 2022; 14:nu14163427. [PMID: 36014933 PMCID: PMC9412703 DOI: 10.3390/nu14163427] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) increases production of reactive oxygen species (ROS) and activates signaling pathways associated with gastric cell invasion, which are mediated by matrix metalloproteinases (MMPs). We previously demonstrated that H. pylori activated mitogen-activated protein kinase (MAPK) and increased expression of MMP-10 in gastric epithelial cells. MMPs degrade the extracellular matrix, enhancing tumor invasion and cancer progression. The signaling pathway of phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is associated with MMP expression. ROS activates PIK3/AKT/mTOR signaling in cancer. Astaxanthin, a xanthophyll carotenoid, shows antioxidant activity by reducing ROS levels in gastric epithelial cells infected with H. pylori. This study aimed to determine whether astaxanthin inhibits MMP expression, cell invasion, and migration by reducing the PI3K/AKT/mTOR signaling in H. pylori-infected gastric epithelial AGS cells. H. pylori induced PIK3/AKT/mTOR and NF-κB activation, decreased IκBα, and induced MMP (MMP-7 and -10) expression, the invasive phenotype, and migration in AGS cells. Astaxanthin suppressed these H. pylori-induced alterations in AGS cells. Specific inhibitors of PI3K, AKT, and mTOR reversed the H. pylori-stimulated NF-κB activation and decreased IκBα levels in the cells. In conclusion, astaxanthin suppressed MMP expression, cell invasion, and migration via inhibition of PI3K/AKT/mTOR/NF-κB signaling in H. pylori-stimulated gastric epithelial AGS cells.
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Helicobacter pylori in Native Americans in Northern Arizona. Diseases 2022; 10:diseases10020019. [PMID: 35466189 PMCID: PMC9036257 DOI: 10.3390/diseases10020019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/11/2022] [Accepted: 03/13/2022] [Indexed: 02/04/2023] Open
Abstract
Background: In Arizona Helicobacter pylori prevalence of infection among Navajo adults is about 62% and gastric cancer incidence rate is 3–4 times higher than that of the non-Hispanic White population. Aim: The aim of this study was to estimate the prevalence of specific H. pylori virulence factors (cagA and vacA) among Navajo patients undergoing and their association with gastric disease. Methods: Virulence genes, cagA and vacA, in H. pylori were investigated in gastric biopsies from 96 Navajo patients over age 18 who were undergoing esophagogastroduodenoscopy. Biopsies from the antrum and fundus were used for molecular characterization to determine cagA type and number of EPIYA motifs and presence of alleles in the signal (s) and medium (m) regions of the vacA gene. Results: H. pylori infection was found in 22.9% of the biopsy samples. The cagA gene amplified in 57.6% of samples and showed a predominant “Western cagA” type, with the EPIYA-ABC motif (45.4%), most prevalent. The vacA allele s1bm1 was the most prevalent (54.5%). Conclusions: H. pylori genotypes were predominantly cagA Western-type and ABC EPIYA motifs. The vacA s1bm1 genotype was the most prevalent and seemed to be associated with gastritis. American Indian/Alaska Native populations are at higher risk for gastric cancer. It is important to identify genotypes of H. pylori and virulence factors involved in the high prevalence of H. pylori and associated disease among the Navajo population.
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Suyapoh W, Tirnitz-Parker JEE, Tangkawattana S, Suttiprapa S, Sripa B. Biliary Migration, Colonization, and Pathogenesis of O. viverrini Co-Infected with CagA+ Helicobacter pylori. Pathogens 2021; 10:pathogens10091089. [PMID: 34578122 PMCID: PMC8469007 DOI: 10.3390/pathogens10091089] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/04/2021] [Accepted: 08/23/2021] [Indexed: 12/21/2022] Open
Abstract
Co-infection with the cagA strain of Helicobacter pylori exacerbates the pathology of human liver fluke Opisthorchis viverrini (OV) infection leading to cholangiocarcinoma. However, underlying mechanisms remain unclear. We report a significant increase in cagA-positive and cagA-negative H. pylori in the stomach, blood, bile, and in the OV worms of co-infected Syrian golden hamsters at one hour, three hours, and one month, post-infection, compared to hamsters infected with either OV or H. pylori alone. Except in the worms, H. pylori numbers declined at three months post-infection, particularly in the bile fluid of co-infected animals. Both strains of H. pylori were immunohistochemically detected in the tegument of the worm, as well as in the bile duct epithelium when co-infected with O. viverrine, but not in H. pylori infection alone. Interestingly, only the cagA-positive strain was detected in the gut of the worm. Co-infection between cagA-positive H. pylori and O. viverrini resulted in a more severe biliary pathology and decreased E-cadherin expression in vivo and in vitro than those of the cagA-negative strain. These data suggest that O. viverrini acts as a carrier of cagA-positive H. pylori and co-migrates to the bile ducts, whereas O. viverrini facilitates H. pylori colonization and enhances the biliary pathogenesis and carcinogenesis.
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Affiliation(s)
- Watcharapol Suyapoh
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand;
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (S.T.); (S.S.)
| | - Janina E. E. Tirnitz-Parker
- Liver Disease and Regeneration Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, Australia;
| | - Sirikachorn Tangkawattana
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (S.T.); (S.S.)
- Faculty of Veterinary Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Sutas Suttiprapa
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (S.T.); (S.S.)
- Tropical Medicine Graduate Program, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Banchob Sripa
- WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (S.T.); (S.S.)
- Tropical Disease Research Center, Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
- Correspondence: ; Tel.: +66-62-6080860; Fax: +66-43-363319
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Park Y, Ki M. Population Attributable Fraction of Helicobacter pylori Infection-Related Gastric Cancer in Korea: A Meta-Analysis. Cancer Res Treat 2021; 53:744-753. [PMID: 33321562 PMCID: PMC8291171 DOI: 10.4143/crt.2020.610] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 12/14/2020] [Indexed: 12/11/2022] Open
Abstract
PURPOSE This study aimed to determine the proportion of gastric cancer attributable to Helicobactor pylori in the Korean population. Infection with H. pylori has been recognized as the most significant risk factor for gastric cancer. In Korea, gastric cancer is the most common cancer that accounted for 13.3% of all cancers in 2016. In particular, men are most commonly diagnosed with gastric cancer; the age-standardized incidence rate in men is 49.6 per 100,000, which is more than twice the incidence in women. MATERIALS AND METHODS The population attributable fraction (PAF) was calculated as a function of the relative risk (RR) of gastric cancer associated with H. pylori infections. To estimate PAF of gastric cancer due to H. pylori, the prevalence of H. pylori infections was extrapolated for the year of 1990 and a pooled RR was obtained by conducting a meta-analysis of studies recently published in Korea. RESULTS The estimated prevalence of H. pylori was 76.4% in men and 71.9% in women. The RRs (95% confidence interval) pooled from case-control studies using a random effects model was 1.69 (1.29-2.22) for overall gastric cancer and 2.17 (1.04-4.55) for non-cardia gastric cancer. Using the RR for overall gastric cancer, the estimated PAFs due to H. pylori were 34.5% in men and 33.2% in women. CONCLUSION The occurrence of gastric cancer in Koreans may be affected by other risk factors in addition to H. pylori infection, which may contribute to increasing baseline risk for gastric cancer.
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Affiliation(s)
- Yoon Park
- Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
| | - Moran Ki
- Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea
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Holmes L, Rios J, Berice B, Benson J, Bafford N, Parson K, Halloran D. Predictive Effect of Helicobacter pylori in Gastric Carcinoma Development: Systematic Review and Quantitative Evidence Synthesis. MEDICINES (BASEL, SWITZERLAND) 2021; 8:medicines8010001. [PMID: 33466356 PMCID: PMC7824775 DOI: 10.3390/medicines8010001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori (H. pylori) is a bacterial pathogen implicated in gastritis, gastric ulceration, and gastric carcinoma. This study aimed to synthesize literature in providing evidence on the causative role of H. pylori in gastric carcinoma development. This study is based on assessing public literature using an applied meta-analysis, namely, quantitative evidence synthesis (QES). The analytic procedure uses DerSimonian-Laird, including assessing heterogeneity. The QES also utilizes meta-regression and the environmental effect associated with H. pylori in gastric cancer development. Eighteen studies are included in the QES. There is increased prevalence of H. pylori exposure among the cases. The heterogeneity between the CES and individual effect sizes is also significant. Despite controlling for the confoundings, there is increased exposure to H. pylori among the gastric cancer cases, regardless of the differences in the geographic location. H. pylori in this synthesized literature illustrates the contributory role of this microbe in gastric carcinoma. Additionally, regardless of geographic locale, namely, South Korea or Spain, H. pylori is implicated in gastric cancer development.
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Affiliation(s)
- Laurens Holmes
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Correspondence: ; Tel.: +1-(302)-298-7741
| | - Jasmine Rios
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
- History of Science and Medicine Department, Yale University, New Haven, CT 06511, USA
| | - Betyna Berice
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
- Master of Public Health, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA
| | - Jacqueline Benson
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
- Master of Public Health Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nastocia Bafford
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
| | - Kadedrah Parson
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
| | - Daniel Halloran
- Nemours Healthcare System for Children, Wilmington, DE 19803, USA; (J.R.); (B.B.); (J.B.); (N.B.); (K.P.); (D.H.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
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Banerjee S, Alwine JC, Wei Z, Tian T, Shih N, Sperling C, Guzzo T, Feldman MD, Robertson ES. Microbiome signatures in prostate cancer. Carcinogenesis 2020; 40:749-764. [PMID: 30794288 DOI: 10.1093/carcin/bgz008] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 11/21/2018] [Accepted: 02/01/2019] [Indexed: 12/20/2022] Open
Abstract
We have established a microbiome signature for prostate cancer using an array-based metagenomic and capture-sequencing approach. A diverse microbiome signature (viral, bacterial, fungal and parasitic) was observed in the prostate cancer samples compared with benign prostate hyperplasia controls. Hierarchical clustering analysis identified three distinct prostate cancer-specific microbiome signatures. The three signatures correlated with different grades, stages and scores of the cancer. Thus, microbiome signature analysis potentially provides clinical diagnosis and outcome predictions. The array data were validated by PCR and targeted next-generation sequencing (NGS). Specific NGS data suggested that certain viral genomic sequences were inserted into the host somatic chromosomes of the prostate cancer samples. A randomly selected group of these was validated by direct PCR and sequencing. In addition, PCR validation of Helicobacter showed that Helicobacter cagA sequences integrated within specific chromosomes of prostate tumor cells. The viral and Helicobacter integrations are predicted to affect the expression of several cellular genes associated with oncogenic processes.
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Affiliation(s)
- Sagarika Banerjee
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - James C Alwine
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Tian Tian
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Natalie Shih
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Colin Sperling
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thomas Guzzo
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael D Feldman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Erle S Robertson
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA
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Jang J, Ma SH, Ko KP, Choi BY, Yoo KY, Park SK. Hepatocyte Growth Factor in Blood and Gastric Cancer Risk: A Nested Case-Control Study. Cancer Epidemiol Biomarkers Prev 2019; 29:470-476. [PMID: 31740519 DOI: 10.1158/1055-9965.epi-19-0436] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/17/2019] [Accepted: 11/12/2019] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Potential of hepatocyte growth factor (HGF)-stimulating signaling pathways related to cytotoxin-associated gene A (CagA) to predict gastric cancer development has not been fully investigated. METHODS We conducted a nested case-control study consisting of 238 gastric cancer cases and 238 matched controls within the Korean Multicenter Cancer Cohort. Plasma HGF concentrations were measured with a human HGF ELISA. Odds ratios (OR) and 95% confidence intervals (CI) for gastric cancer development according to HGF level were calculated using conditional logistic regression model. RESULTS Sequential elevation of gastric cancer risk according to HGF level increase was observed (OR, 10.99; 95% CI, 4.91-24.62) for highest quartile HGF (≥364 pg/mL) versus lowest quartile HGF (<167 pg/mL). A significantly increased gastric cancer risk associated with high HGF level measured even 6 or more years prior to cancer diagnosis was also found. The group with both high risk of HGF and CagA-related genetic variants was associated with highest gastric cancer risk compared with the group with both low risk of HGF and genetic variants (P interaction = 0.05). Model performance using HGF and CagA-related genetic variants to discriminate gastric cancer was fair [area under the curve of receiver operating characteristic (AUC-ROC), 0.71; 95% CI, 0.64-0.78] and significantly higher than that of model not including those biomarkers. CONCLUSIONS Our results suggest HGF as a potential biomarker to predict gastric cancer development. IMPACT These findings suggest HGF as a useful biomarker to predict gastric cancer risk. Further research to assess gastric cancer risk based on useful biomarkers, including HGF, may contribute to primary prevention of gastric cancer.
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Affiliation(s)
- Jieun Jang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
| | - Seung Hyun Ma
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Kwang-Pil Ko
- Department of Preventive Medicine, Gachon University College of Medicine, Incheon, Korea
| | - Bo Yul Choi
- Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,The Armed Forces Capital Hospital, Seongnam, Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea. .,Cancer Research Institute, Seoul National University, Seoul, Korea.,Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
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The Prevalence of Helicobacter Pylori babA, homB, aspA, and sabA Genes and Its Relationship with Clinical Outcomes in Turkey. Can J Gastroenterol Hepatol 2019; 2019:1271872. [PMID: 31312620 PMCID: PMC6595381 DOI: 10.1155/2019/1271872] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS The cag A and vac A genes of Helicobacter pylori (H. pylori) are closely associated with the pathogenicity of bacteria. However, the significance of H. pylori babA, homB, aspA, and sabA genes is not clear in phenotypic characteristics of virulence. This study aimed to investigate the frequency and importance of these genes in patients with H. pylori positive peptic ulcer (PU). MATERIALS AND METHODS Patients with a PU or nonulcer dyspepsia (NUD) based on the upper gastrointestinal (UGI) endoscopy findings were included in the study. Biopsy samples from antrum and corpus were cultured into Columbia agar. H pylori were characterized by urease, catalase, oxidase test, and gram staining. Genomic DNA was extracted and stored. The babA, homB, aspA, and sabA genes were determined by using polymerase chain reaction analysis. RESULTS A total 214 patients were included (99 PU and 115 NUD) and H. pylori could be isolated in 82 patients (36 PU and 46 NUD). The frequency of the babA (25% vs. 15.2%, p=0.25), homB (2.7% vs. 4.3%, p=1), aspA (69.4% vs. 73.9%, p=0.2), and sabA (2.7% vs. 10.8%, p=0.88) genotypes was not different between PU and NUD patients. There were some correlations between the presences of these genes. CONCLUSION This study managed to determine babA, homB, aspA, and sabA genes of H. pylori by PCR. However, the frequency of these factors was not different in patients with PU and NUD. There is no role of babA, homB, aspA, and sabA genes for the development of peptic ulcer in Turkish population.
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Nolen LD, Bruden D, Miernyk K, McMahon BJ, Sacco F, Varner W, Mezzetti T, Hurlburt D, Tiesinga J, Bruce MG. H. pylori-associated pathologic findings among Alaska native patients. Int J Circumpolar Health 2018; 77:1510715. [PMID: 30157723 PMCID: PMC6116699 DOI: 10.1080/22423982.2018.1510715] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 07/27/2018] [Accepted: 08/02/2018] [Indexed: 12/17/2022] Open
Abstract
Helicobacter pylori infection is common among Alaska native (AN) people, however scant gastric histopathologic data is available for this population. This study aimed to characterise gastric histopathology and H. pylori infection among AN people. We enrolled AN adults undergoing upper endoscopy. Gastric biopsy samples were evaluated for pathologic changes, the presence of H. pylori, and the presence of cag pathogenicity island-positive bacteria. Of 432 persons; two persons were diagnosed with gastric adenocarcinoma, two with MALT lymphoma, 40 (10%) with ulcers, and 51 (12%) with intestinal metaplasia. Fifty-five per cent of H. pylori-positive persons had cag pathogenicity island positive bacteria. The gastric antrum had the highest prevalence of acute and chronic moderate-severe gastritis. H. pylori-positive persons were 16 and four times more likely to have moderate-severe acute gastritis and chronic gastritis (p < 0.01), respectively. An intact cag pathogenicity island positive was correlated with moderate-severe acute antral gastritis (53% vs. 31%, p = 0.0003). H. pylori-positive persons were more likely to have moderate-severe acute and chronic gastritis compared to H. pylori-negative persons. Gastritis and intestinal metaplasia were most frequently found in the gastric antrum. Intact cag pathogenicity island positive was correlated with acute antral gastritis and intestinal metaplasia.
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Affiliation(s)
- Leisha Diane Nolen
- Arctic Investigations Program, DPEI/NCEZID, Centers for Disease Control and Prevention, Anchorage, AK, USA
| | - Dana Bruden
- Arctic Investigations Program, DPEI/NCEZID, Centers for Disease Control and Prevention, Anchorage, AK, USA
| | - Karen Miernyk
- Arctic Investigations Program, DPEI/NCEZID, Centers for Disease Control and Prevention, Anchorage, AK, USA
| | - Brian J. McMahon
- Arctic Investigations Program, DPEI/NCEZID, Centers for Disease Control and Prevention, Anchorage, AK, USA
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
| | - Frank Sacco
- Department of Surgery, The Alaska Native Medical Center, Anchorage, AK, USA
| | - Wayne Varner
- Department of Pathology and Clinical Laboratory, The Alaska Native Medical Center, Anchorage, AK, USA
| | - Tom Mezzetti
- Department of Pathology and Clinical Laboratory, The Alaska Native Medical Center, Anchorage, AK, USA
| | - Debby Hurlburt
- Arctic Investigations Program, DPEI/NCEZID, Centers for Disease Control and Prevention, Anchorage, AK, USA
| | - James Tiesinga
- Department of Pathology and Clinical Laboratory, The Alaska Native Medical Center, Anchorage, AK, USA
| | - Michael G. Bruce
- Arctic Investigations Program, DPEI/NCEZID, Centers for Disease Control and Prevention, Anchorage, AK, USA
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12
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Pormohammad A, Mohtavinejad N, Gholizadeh P, Dabiri H, Salimi Chirani A, Hashemi A, Nasiri MJ. Global estimate of gastric cancer in Helicobacter pylori-infected population: A systematic review and meta-analysis. J Cell Physiol 2018; 234:1208-1218. [PMID: 30132888 DOI: 10.1002/jcp.27114] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 07/02/2018] [Indexed: 12/11/2022]
Abstract
There is information regarding the rates of gastric cancer (GC) in different populations and the important role of Helicobacter pylori in GC development; however, no comprehensive study has yet been performed to investigate the prevalence of GC in H. pylori-infected patients. PubMed, Embase, and Cochrane Library through January 1, 2000 were searched without language restrictions. Quality of included studies was assessed with a critical appraisal checklist recommended by the Joanna Briggs Institute. All of the analyses were conducted using Comprehensive Meta-Analysis Software Version 2.0 and Stata 14.0. Forty-four studies from 17 countries were included. The pooled frequency of GC was 17.4% (95% confidence interval: 16.4-18.5) in H. pylori-infected population. The frequency of GC among H. pylori-infected population varied markedly across countries. The highest rate of GC was observed in H. pylori-infected individuals from Asian countries. The frequency of GC was relatively high in H. pylori-infected population in the world. However, the eradication of H. pylori might be a promising strategy for GC prevention, especially in high-risk populations such as Asian countries.
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Affiliation(s)
- Ali Pormohammad
- Student Research Committee, Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naser Mohtavinejad
- Department of Radio Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Pourya Gholizadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Dabiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Salimi Chirani
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Hashemi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Ko KP, Shin A, Cho S, Park SK, Yoo KY. Environmental contributions to gastrointestinal and liver cancer in the Asia-Pacific region. J Gastroenterol Hepatol 2018; 33:111-120. [PMID: 28960448 DOI: 10.1111/jgh.14005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 01/06/2023]
Abstract
In the Asia-Pacific region, gastric, colorectal, and hepatocellular (liver) cancer show substantial regional variation in incidence consistent with the presence of important environmental factors. For gastric cancer, global incidence is concentrated in Asia with substantially higher rates in East Asia than in South-East Asia and Australia. The differences in incidence rates for gastric cancer in the Asia-Pacific region may be due, in part, to differences in the prevalence of Helicobacter pylori infection and the prevalence of H. pylori virulence factors. Smoking is also correlated with gastric cancer risk and is responsible for the highest population attributable fraction among men in East Asia. Colorectal cancer has increased rapidly in incidence to become the third most common digestive cancer in Asia. According to cohort studies in Asia, smoking, alcohol use, obesity, and physical inactivity increase the risk of colorectal cancer. Unlike West Asia, East Asia and Australia have high incidence rates for colorectal cancer that correlates to a high Human Development Index and a high prevalence of alcohol consumption and obesity. Liver cancer is the second most common digestive cancer in Asia. The high incidence of liver cancer in East Asia and South-East Asia is concordant with the high prevalence of hepatitis B virus and hepatitis C virus infection. Other important risk factors include alcohol use, smoking, and diabetes. The identification of the earlier and other environmental factors (currently under investigation) is central to the development and implementation of effective cancer control programs for the region.
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Affiliation(s)
- Kwang-Pil Ko
- Department of Preventive Medicine, Gachon University, Incheon, Korea
| | - Aesun Shin
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sooyoung Cho
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Korean Armed Forces Capital Hospital, Seongnam, Korea
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14
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Performance of a Multiplex Serological Helicobacter pylori Assay on a Novel Microfluidic Assay Platform. Proteomes 2017; 5:proteomes5040024. [PMID: 28972560 PMCID: PMC5748559 DOI: 10.3390/proteomes5040024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 09/19/2017] [Accepted: 09/29/2017] [Indexed: 01/25/2023] Open
Abstract
Infection with Helicobacter pylori (H. pylori) occurs in 50% of the world population, and is associated with the development of ulcer and gastric cancer. Serological diagnostic tests indicate an H. pylori infection by detecting antibodies directed against H. pylori proteins. In addition to line blots, multiplex assay platforms provide smart solutions for the simultaneous analysis of antibody responses towards several H. pylori proteins. We used seven H. pylori proteins (FliD, gGT, GroEL, HpaA, CagA, VacA, and HP0231) and an H. pylori lysate for the development of a multiplex serological assay on a novel microfluidic platform. The reaction limited binding regime in the microfluidic channels allows for a short incubation time of 35 min. The developed assay showed very high sensitivity (99%) and specificity (100%). Besides sensitivity and specificity, the technical validation (intra-assay CV = 3.7 ± 1.2% and inter-assay CV = 5.5 ± 1.2%) demonstrates that our assay is also a robust tool for the analysis of the H. pylori-specific antibody response. The integration of the virulence factors CagA and VacA allow for the assessment of the risk for gastric cancer development. The short assay time and the performance of the platform shows the potential for implementation of such assays in a clinical setting.
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15
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Bae JM, Kim EH. Helicobacter pylori Infection and Risk of Gastric Cancer in Korea: A Quantitative Systematic Review. J Prev Med Public Health 2017; 49:197-204. [PMID: 27499162 PMCID: PMC4977768 DOI: 10.3961/jpmph.16.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/07/2016] [Indexed: 12/14/2022] Open
Abstract
Objectives: In the context of the global decrease in mortality due to gastric cancer, previous studies have reported that the effect of chronic Helicobacter pylori (H. pylori) infection on the incidence of gastric cancer varies among regions. This systematic review was conducted to investigate H. pylori as a risk factor for gastric cancer in Korea, where the incidence of gastric cancer is among the highest in the world. Methods: A search strategy was established to identify articles published in Korean as well as in English. Ultimately, we included observational studies conducted among Korean patients that designed with an age-matched and sex-matched control group that reported the odds ratio associated with H. pylori. Gastric cancer cases were subdivided into overall (OGC), cardia (CGC), non-cardia (NGC), early (EGC), advanced, intestinal (IGC), and diffuse forms of gastric cancer. Summary odds ratios (SORs) with 95% confidence intervals (CIs) were calculated in the meta-analysis using a random-effect model. Results: Eleven case-control studies were ultimately selected. H. pylori was associated with an SOR of 1.81 (95% CI, 1.29 to 2.54) for OGC. Additionally, statistically significant risks were observed for CGC, NGC, EGC, and IGC. Conclusions: Chronic H. pylori infection was found to raise the risk of gastric cancer among Koreans, with the highest risk observed for CGC and EGC (SOR=2.88 for both). Follow-up clinical epidemiologic studies are needed to assess the effects of current treatments aimed at eradicating H. pylori infections.
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Affiliation(s)
- Jong-Myon Bae
- Department of Preventive Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Eun Hee Kim
- Department of Preventive Medicine, Jeju National University School of Medicine, Jeju, Korea
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16
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Helicobacter pylori outer membrane protein, HomC, shows geographic dependent polymorphism that is influenced by the Bab family. J Microbiol 2016; 54:846-852. [DOI: 10.1007/s12275-016-6434-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/19/2016] [Accepted: 09/20/2016] [Indexed: 02/07/2023]
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17
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Waldum HL, Kleveland PM, Sørdal ØF. Helicobacter pylori and gastric acid: an intimate and reciprocal relationship. Therap Adv Gastroenterol 2016; 9:836-844. [PMID: 27803738 PMCID: PMC5076771 DOI: 10.1177/1756283x16663395] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Helicobacter pylori (Hp) is the main cause of gastritis, peptic ulcer disease and gastric cancer. There are still unanswered questions related to the interaction between Hp and man, like what determines the susceptibility for the initial infection and the mechanisms for the carcinogenic effect. The initial infection seems to require a temporal gastric hypoacidity. For Hp to survive in the gastric mucous layer, some acidity is necessary. Hp itself is probably not directly carcinogenic. Only when inducing oxyntic mucosal inflammation and atrophy with hypoacidity, Hp predisposes for gastric cancer. Gastrin most likely plays a central role in the Hp pathogenesis of duodenal ulcer and gastric cancer.
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Affiliation(s)
- Helge L. Waldum
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Per M. Kleveland
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Øystein F. Sørdal
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
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18
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Vinagre IDF, Queiroz ALD, Silva Júnior MRD, Vinagre RMDF, Martins LC. HELICOBACTER PYLORI INFECTION IN PATIENTS WITH DIFFERENT GASTROINTESTINAL DISEASES FROM NORTHERN BRAZIL. ARQUIVOS DE GASTROENTEROLOGIA 2016; 52:266-71. [PMID: 26840466 DOI: 10.1590/s0004-28032015000400004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 06/18/2015] [Indexed: 01/23/2023]
Abstract
BACKGROUND The mechanisms whereby Helicobacter pylori produces different pathological manifestations in the stomach and duodenum are not fully understood. Considering the geographic diversity in the prevalence of virulence factors of this microorganism and their association with the development of different diseases, the search for pathogenicity markers such as CagA and VacA alleles by molecular techniques has intensified. OBJECTIVES To investigate the presence of H. pylori infection and the frequency of different genotypes of this bacterium in patients with gastrointestinal diseases from Northern Brazil, and to establish their association with the histopathological findings. METHODS In a prospective study, samples were collected from 554 patients with different gastrointestinal diseases (gastritis, duodenal ulcer, gastric ulcer, and gastric cancer) seen at a referral hospital attending the entire State of Pará, located in the metropolitan region of Belém. Data such as gender and age obtained with an epidemiological questionnaire were analyzed. The presence of H. pylori and the bacterial genotype were investigated by PCR. Gastric biopsies were assessed histologically. RESULTS The prevalence of H. pylori infection was 91%. Infection was more frequent among patients with gastric ulcer and gastric cancer. In these groups, there was a predominance of men and older patients when compared to the other two groups studied. The predominant bacterial genotype was s1m1cagA+, which was more frequent among patients with gastric ulcer, duodenal ulcer and gastric cancer. A significant association was observed between s1m1cagA+ strains and a higher degree of inflammation, neutrophil activity and development of intestinal metaplasia. CONCLUSION The present study demonstrates a high incidence of H. pylori infection in the patients analyzed, especially among those with gastric ulcer and gastric cancer. Virulent s1m1cagA+ strains predominated and were associated with more severe lesions.
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19
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Ma SH, Jung W, Weiderpass E, Jang J, Hwang Y, Ahn C, Ko KP, Chang SH, Shin HR, Yoo KY, Park SK. Impact of alcohol drinking on gastric cancer development according to Helicobacter pylori infection status. Br J Cancer 2015; 113:1381-8. [PMID: 26379079 PMCID: PMC4815794 DOI: 10.1038/bjc.2015.333] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 08/05/2015] [Accepted: 08/12/2015] [Indexed: 12/26/2022] Open
Abstract
Background: Helicobacter pylori are major carcinogen of gastric cancer, but the associations among gastric cancer, H. pylori infection status, and alcohol consumption are not fully described. This study aimed to clarify how H. pylori infection status affects the association between alcohol consumption and gastric cancer risk. Methods: We selected 949 case–cohort participants from the 18 863 Korean Multi-center Cancer Cohort (KMCC) populations. Gastric cancer incidence inside and outside of the subcohort were 12 and 254 cases, respectively. Seropositivities for CagA, VacA, and H. pylori infection were determined by performing immunoblot assays. Weighted Cox regression models were used to calculate hazard ratios and 95% confidence intervals (CIs). Results: Relative to non-drinking, heavy drinking (⩾7 times a week), and binge drinking (⩾55 g alcohol intake per occasion) showed a 3.48-fold (95% CI, 1.13–10.73) and 3.27-fold (95% CI, 1.01–10.56) higher risk in subjects not previously infected by H. pylori. There was no significant association between drinking pattern and gastric cancer risk in H. pylori IgG seropositive subjects. An increased risk for gastric cancer in heavy- and binge-drinking subjects were also present in subjects not infected by CagA- or VacA-secreting H. pylori. Conclusions: Heavy and binge alcohol consumption is an important risk factor related to an increasing incidence of gastric cancer in a population not infected by H. pylori.
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Affiliation(s)
- Seung-Hyun Ma
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Woohyun Jung
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Elisabete Weiderpass
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.,Cancer Registry of Norway, Oslo, Norway.,Department of Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Jieun Jang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea
| | - Yunji Hwang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea.,Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea
| | - Chunghyun Ahn
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea
| | - Kwang-Pil Ko
- Department of Preventive Medicine, Gachon University College of Medicine, Incheon, Korea
| | - Soung-Hoon Chang
- Department of Preventive Medicine, Konkuk University, Chungju, Korea
| | - Hai-Rim Shin
- Non-communicable Disease and Health Promotion, Western Pacific Regional Office, World Health Organization, Manila, Philippines
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Cancer Research Institute, Seoul National University, Seoul, Korea.,Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea
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20
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Kim A, Servetas SL, Kang J, Kim J, Jang S, Cha HJ, Lee WJ, Kim J, Romero-Gallo J, Peek RM, Merrell DS, Cha JH. Helicobacter pylori bab Paralog Distribution and Association with cagA, vacA, and homA/B Genotypes in American and South Korean Clinical Isolates. PLoS One 2015; 10:e0137078. [PMID: 26317221 PMCID: PMC4552749 DOI: 10.1371/journal.pone.0137078] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 08/13/2015] [Indexed: 12/19/2022] Open
Abstract
Helicobacter pylori genetic variation is a crucial component of colonization and persistence within the inhospitable niche of the gastric mucosa. As such, numerous H. pylori genes have been shown to vary in terms of presence and genomic location within this pathogen. Among the variable factors, the Bab family of outer membrane proteins (OMPs) has been shown to differ within subsets of strains. To better understand genetic variation among the bab genes and to determine whether this variation differed among isolates obtained from different geographic locations, we characterized the distribution of the Bab family members in 80 American H. pylori clinical isolates (AH) and 80 South Korean H. pylori clinical isolates (KH). Overall, we identified 23 different bab genotypes (19 in AH and 11 in KH), but only 5 occurred in greater than 5 isolates. Regardless of strain origin, a strain in which locus A and locus B were both occupied by a bab gene was the most common (85%); locus C was only occupied in those isolates that carried bab paralog at locus A and B. While the babA/babB/- genotype predominated in the KH (78.8%), no single genotype could account for greater than 40% in the AH collection. In addition to basic genotyping, we also identified associations between bab genotype and well known virulence factors cagA and vacA. Specifically, significant associations between babA at locus A and the cagA EPIYA-ABD motif (P<0.0001) and the vacA s1/i1/m1 allele (P<0.0001) were identified. Log-linear modeling further revealed a three-way association between bab carried at locus A, vacA, and number of OMPs from the HOM family (P<0.002). En masse this study provides a detailed characterization of the bab genotypes from two distinct populations. Our analysis suggests greater variability in the AH, perhaps due to adaptation to a more diverse host population. Furthermore, when considering the presence or absence of both the bab and homA/B paralogs at their given loci and the vacA genotype, an association was observed. Our results highlight the multifactorial nature of H. pylori mediated disease and the importance of considering how the specific combinations of H. pylori virulence genes and their multiple interactions with the host will collectively impact disease progression.
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Affiliation(s)
- Aeryun Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Stephanie L. Servetas
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland, 20814, United States of America
| | - Jieun Kang
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jinmoon Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Ho Jin Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Wan Jin Lee
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - June Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Judith Romero-Gallo
- Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee, 37240, United States of America
| | - Richard M. Peek
- Departments of Cancer Biology and Medicine, Vanderbilt University, Nashville, Tennessee, 37240, United States of America
| | - D. Scott Merrell
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, Maryland, 20814, United States of America
- * E-mail: (DSM); (JHC)
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
- * E-mail: (DSM); (JHC)
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21
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Song M, Lee HW, Kang D. Epidemiology and screening of gastric cancer in Korea. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2015. [DOI: 10.5124/jkma.2015.58.3.183] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Minkyo Song
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hwi-Won Lee
- 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
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22
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Homan M, Šterbenc A, Kocjan BJ, Luzar B, Zidar N, Orel R, Poljak M. Prevalence of the Helicobacter pylori babA2 gene and correlation with the degree of gastritis in infected Slovenian children. Antonie Van Leeuwenhoek 2014; 106:637-645. [PMID: 25055876 DOI: 10.1007/s10482-014-0234-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 07/07/2014] [Indexed: 12/16/2022]
Abstract
The aims of our study were to determine the prevalence of the babA2 gene within Helicobacter pylori strains circulating in the Slovenian pediatric population, to further clarify its significance in causing inflammation of gastric mucosa in children and to verify whether cagA, vacA, iceA and babA genes work independently or synergistically in causing gastritis. A total of 163 H. pylori isolates obtained from the same number of children were tested for the presence of cagA, vacA and iceA genes using previously established methods, while the babA2 gene was determined using novel polymerase chain reaction assay targeting a 139-bp fragment of the central region of babA2. The babA2 gene was detected in 47.9% of H. pylori samples. The presence of the babA2 gene was strongly associated with cagA, vacA s1 and vacA m1 genotype. The babA2 status correlated positively with bacterial density score, activity of inflammation and chronic inflammation of gastric mucosa. No significant correlation was found between the babA2 status and the presence of atrophy or intestinal metaplasia. In addition, the activity of gastric inflammation and density score were significantly associated with the coexpression of the cagA, vacA s1, vacA m1 and babA2 genes. The study, which included the largest number of pediatric H. pylori samples to date, confirmed that babA2 gene plays an important role in the pathogenesis of H. pylori gastritis in children. Furthermore, our results suggest that babA2, cagA and vacA s1 and m1 gene products may work synergistically in worsening the inflammation of gastric mucosa.
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Affiliation(s)
- Matjaž Homan
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Ljubljana, Slovenia,
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23
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Zhao Z, Li Y, Liu S, Fu W. Serum Helicobacter pylori CagA antibody may not be used as a tumor marker for diagnosing gastric cancer in east Asian countries. Tumour Biol 2014; 35:12217-24. [PMID: 25168369 DOI: 10.1007/s13277-014-2530-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 08/20/2014] [Indexed: 12/21/2022] Open
Abstract
Gastric cancer (GC) is a highly malignant cancer with increasing incidence and mortality worldwide. Serum Helicobacter pylori CagA antibody has been widely reported to play an important role in diagnosing GC. However, published data on this subject are inconclusive. Therefore, we performed a meta-analysis to evaluate the sensitivity and specificity of serum H. pylori CagA antibody in the diagnosis of GC. We conducted a comprehensive search to identify eligible related studies, in which the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curves could be determined. A total of 12 studies including 1,524 cases and 3,324 controls who fulfilled all of the inclusion criteria were included for analysis. The summary estimates for serum H. pylori CagA antibody in the diagnosis of GC in these studies were pooled sensitivity 0.71 (95 % CI 0.69-0.73), specificity 0.40 (95 % CI 0.39-0.42), DOR 2.11 (95 % CI 1.55-2.8), and the area under the curve was 0.636. Our meta-analysis showed that serum H. pylori CagA antibody should not be used for detecting GC.
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Affiliation(s)
- Zhicheng Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
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High natural variability bacteria identification and typing: Helicobacter pylori analysis based on peptide mass fingerprinting. J Proteomics 2014; 98:112-22. [DOI: 10.1016/j.jprot.2013.11.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 11/04/2013] [Accepted: 11/22/2013] [Indexed: 01/18/2023]
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Abstract
Since its discovery in 1982, the global importance of Helicobacter pylori-induced disease, particularly in developing countries, remains high. The use of rodent models, particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen, and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive.
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Affiliation(s)
- James G. Fox
- Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York
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Pich OQ, Merrell DS. The ferric uptake regulator of Helicobacter pylori: a critical player in the battle for iron and colonization of the stomach. Future Microbiol 2013; 8:725-38. [PMID: 23701330 DOI: 10.2217/fmb.13.43] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Helicobacter pylori is arguably one of the most successful pathogens; it colonizes the stomachs of more than half of the human population. Colonization and persistence in such an inhospitable niche requires the presence of exquisite adaptive mechanisms. One of the proteins that contributes significantly to the remarkable adaptability of H. pylori is the ferric uptake regulator (Fur), which functions as a master regulator of gene expression. In addition to genes directly related to iron homeostasis, Fur controls expression of several enzymes that play a central role in metabolism and energy production. The absence of Fur leads to severe H. pylori colonization defects and, accordingly, several Fur-regulated genes have been shown to be essential for colonization. Moreover, proteins encoded by Fur-regulated genes have a strong impact on redox homeostasis in the stomach and are major determinants of inflammation. In this review, we discuss the main roles of Fur in the biology of H. pylori and highlight the importance of this regulatory protein in the infectious process.
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Affiliation(s)
- Oscar Q Pich
- Department of Microbiology & Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
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Bessède E, Staedel C, Acuña Amador LA, Nguyen PH, Chambonnier L, Hatakeyama M, Belleannée G, Mégraud F, Varon C. Helicobacter pylori generates cells with cancer stem cell properties via epithelial-mesenchymal transition-like changes. Oncogene 2013; 33:4123-31. [PMID: 24096479 DOI: 10.1038/onc.2013.380] [Citation(s) in RCA: 148] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 07/22/2013] [Accepted: 07/30/2013] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori infection is the major risk factor for gastric adenocarcinoma. The link with gastric adenocarcinoma is partly due to the H. pylori CagA oncoprotein. CagA is responsible for a particular cell phenotype in vitro, the 'hummingbird' phenotype, that corresponds to an elongation of the cells, mimicking an epithelial-mesenchymal transition (EMT). EMT participates in the carcinogenesis process, and is involved in the generation of cancer stem cells (CSCs). However, its involvement in gastric carcinogenesis has yet not been studied. Therefore, the aim of this study was to determine the role of H. pylori in EMT and in the emergence of gastric CSCs. For this purpose, gastric epithelial cells were cocultured with a cagA-positive H. pylori strain or its isogenic-deleted mutants or were transfected with CagA expression vectors. Study of the expression of epithelial and mesenchymal markers showed that H. pylori, via CagA, is responsible for an EMT phenotype associated with an increase in mesenchymal markers as well as CD44 expression, a known gastric CSC marker. Moreover, infection led to an increased ability to migrate, to invade and to form tumorspheres. Cell sorting experiments showed that only the CD44(high) cells induced by H. pylori infection displayed the mesenchymal phenotype and CSC properties in vitro, and had higher tumorigenic properties than CD44(low) cells in xenografted mice. Immunohistochemistry analyses on human and mouse gastric mucosa tissue samples confirmed a high expression of CD44 and mesenchymal markers in H. pylori-infected cases, and in gastric dysplasia and carcinoma. All of these data suggest that H. pylori, via CagA, unveils CSC-like properties by induction of EMT-like changes in gastric epithelial cells.
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Affiliation(s)
- E Bessède
- 1] Université de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France [2] INSERM, U853, Bordeaux, France
| | - C Staedel
- 1] 'RNA: Natural and Artificial Regulation' (ARNA) Laboratory, Université de Bordeaux, Bordeaux, France [2] INSERM, U869, Bordeaux, France
| | - L A Acuña Amador
- 1] Université de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France [2] INSERM, U853, Bordeaux, France
| | - P H Nguyen
- 1] Université de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France [2] INSERM, U853, Bordeaux, France
| | - L Chambonnier
- 1] Université de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France [2] INSERM, U853, Bordeaux, France
| | - M Hatakeyama
- Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - G Belleannée
- Pathology Department, Haut Leveque Hospital, University Hospital Center, Bordeaux, France
| | - F Mégraud
- 1] Université de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France [2] INSERM, U853, Bordeaux, France
| | - C Varon
- 1] Université de Bordeaux, Laboratoire de Bactériologie, Bordeaux, France [2] INSERM, U853, Bordeaux, France
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VINAGRE RMDF, VILAR-e-SILVA A, FECURY AA, MARTINS LC. ROLE OF HELICOBACTER PYLORI INFECTION AND LIFESTYLE HABITS IN THE DEVELOPMENT OF GASTRODUODENAL DISEASES IN A POPULATION FROM THE BRAZILIAN AMAZON. ARQUIVOS DE GASTROENTEROLOGIA 2013; 50:170-4. [DOI: 10.1590/s0004-28032013000200030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 04/24/2013] [Indexed: 02/04/2023]
Abstract
Context Although more than half of the world's population is colonized with Helicobacter pylori, it remains unknown why this organism is able to produce severe disease in some hosts and be innocuous in others. The clinical outcome of infection is determined by several factors, including differences in the host response to bacterial stimulation, specific virulence factors of the organism and environmental influences, or a combination of these factors. Objectives This study compared the prevalence of H. pylori infection and risk factors (infection with CagA+ strains, excessive alcohol consumption, smoking, and inadequate eating habits) between patients with different gastrointestinal disorders and associated these risk factors with the histopathological findings. Methods In a prospective study, samples were collected from 442 patients and a standardized questionnaire regarding lifestyle habits (excessive alcohol consumption, smoking, and eating habits) was applied. The presence of H. pylori and of the cagA gene was investigated by polymerase chain reaction (PCR). Gastric biopsies were obtained for histological assessment. Results The frequency of alcohol consumption, smoking, inadequate diet and infection with CagA+ H. pylori was higher among patients with peptic ulcer and adenocarcinoma when compared to those with gastritis. Gastric inflammation was more pronounced in patients infected with CagA+ strains. Conclusion We conclude that infection with CagA+ H. pylori strains, excessive alcohol consumption, smoking and inadequate eating habits increase the risk of developing peptic ulcer and gastric carcinoma.
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Zhang YW, Eom SY, Yim DH, Song YJ, Yun HY, Park JS, Youn SJ, Kim BS, Kim YD, Kim H. Evaluation of the relationship between dietary factors, CagA-positive Helicobacter pylori infection, and RUNX3 promoter hypermethylation in gastric cancer tissue. World J Gastroenterol 2013; 19:1778-1787. [PMID: 23555166 PMCID: PMC3607754 DOI: 10.3748/wjg.v19.i11.1778] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 11/14/2012] [Accepted: 01/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the relationship among Helicobacter pylori (H. pylori) infection, CagA status, and dietary factors with RUNX3 promoter hypermethylation.
METHODS: Gastric cancer tissue samples were collected from 184 South Korean patients. All patients were interviewed following a semi-quantitative food frequency questionnaire. The average frequencies of intake and portion sizes of 89 common food items were documented, and total intakes of calories, nutrients, vitamins, and minerals were calculated for each subject. DNA was extracted from gastric cancer tissue samples, and amplification of the HSP60 gene was performed to detect H. pylori infection. Nested polymerase chain reaction (PCR) was used to detect the presence of the CagA gene. RUNX3 gene expression was measured by reverse transcription-PCR, and RUNX3 methylation status was evaluated by methylation-specific PCR. The odds ratios (ORs) and 95%CI associated with RUNX3 promoter hypermethylation status were estimated for each of the food groups, lifestyle factors, and the interaction between dietary and lifestyle factors with CagA status of H. pylori infection.
RESULTS: Overall, 164 patients (89.1%) were positive for H. pylori DNA, with the CagA gene detected in 59 (36%) of these H. pylori-positive samples. In all, 106 (57.6%) patients with gastric cancer demonstrated CpG island hypermethylation at the RUNX3 promoter. RUNX3 expression was undetectable in 52 (43.7%) of the 119 gastric cancer tissues sampled. A high consumption of eggs may increase the risk of RUNX3 methylation in gastric cancer patients, having a mean OR of 2.15 (range, 1.14-4.08). A significantly increased OR of 4.28 (range, 1.19-15.49) was observed with a high consumption of nuts in patients with CagA-positive H. pylori infection. High intakes of carbohydrate, vitamin B1, and vitamin E may decrease the risk of RUNX3 methylation in gastric cancer tissue, particularly in CagA- or H. pylori-negative infection, with OR of 0.41 (0.19-0.90), 0.42 (0.20-0.89), and 0.29 (0.13-0.62), respectively. A high consumption of fruits may protect against RUNX3 methylation.
CONCLUSION: These results suggest that the CagA status of H. pylori infection may be a modifier of dietary effects on RUNX3 methylation in gastric cancer tissue.
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Park SK, Yang JJ, Oh S, Cho LY, Ma SH, Shin A, Ko KP, Park T, Yoo KY, Kang D. Innate immunity and non-Hodgkin's lymphoma (NHL) related genes in a nested case-control study for gastric cancer risk. PLoS One 2012; 7:e45274. [PMID: 23028900 PMCID: PMC3448653 DOI: 10.1371/journal.pone.0045274] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 08/14/2012] [Indexed: 12/21/2022] Open
Abstract
Objective Genetic variants regulating the host immune system may contribute to the susceptibility for the development of gastric cancer. Little is known about the role of the innate immunity- and non-Hodgkin’s lymphoma (NHL)-related genes for gastric cancer risk. This nested case-control study was conducted to identify candidate genes for gastric cancer risk for future studies. Methods In the Discovery phase, 3,072 SNPs in 203 innate immunity- and 264 NHL-related genes using the Illumine GoldenGateTM OPA Panel were analyzed in 42 matched case-control sets selected from the Korean Multi-center Cancer Cohort (KMCC). Six significant SNPs in four innate immunity (DEFA6, DEFB1, JAK3, and ACAA1) and 11 SNPs in nine NHL-related genes (INSL3, CHMP7, BCL2L11, TNFRSF8, RAD50, CASP7, CHUK, CD79B, and CLDN9) with a permutated p-value <0.01 were re-genotyped in the Replication phase among 386 cases and 348 controls. Odds ratios (ORs) for gastric cancer risk were estimated adjusting for age, smoking status, and H. pylori and CagA sero-positivity. Summarized ORs in the total study population (428 cases and 390 controls) are presented using pooled- and meta-analyses. Results Four SNPs had no heterogeneity across the phases: in the meta-analysis, DEFA6 rs13275170 and DEFB1 rs2738169 had both a 1.3-fold increased odds ratio (OR) for gastric cancer (95% CIs = 1.1–1.6; and 1.1–1.5, respectively). INSL3 rs10421916 and rs11088680 had both a 0.8-fold decreased OR for gastric cancer (95% CIs = 0.7–0.97; and 0.7–0.9, respectively). Conclusions Our findings suggest that certain variants in the innate immunity and NHL-related genes affect the gastric cancer risk, perhaps by modulating infection-inflammation-immunity mechanisms that remain to be defined.
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Affiliation(s)
- Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
| | - Jae Jeong Yang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sohee Oh
- Department of Statistics, College of Natural Science, Seoul National University, Seoul, Korea
| | - Lisa Y. Cho
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seung Hyun Ma
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Aesun Shin
- National Cancer Control Research Institute, National Cancer Center, Goyang, Korea
| | - Kwang-Pil Ko
- Department of Preventive Medicine, Graduate School of Medicine, Gachon University, Incheon, Korea
| | - Taesung Park
- Department of Statistics, College of Natural Science, Seoul National University, Seoul, 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
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
- * E-mail:
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Zhang C, Xu S, Xu D. Risk assessment of gastric cancer caused by Helicobacter pylori using CagA sequence markers. PLoS One 2012; 7:e36844. [PMID: 22615823 PMCID: PMC3352932 DOI: 10.1371/journal.pone.0036844] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2011] [Accepted: 04/11/2012] [Indexed: 02/07/2023] Open
Abstract
Background As a marker of Helicobacter pylori, Cytotoxin-associated gene A (cagA) has been revealed to be the major virulence factor causing gastroduodenal diseases. However, the molecular mechanisms that underlie the development of different gastroduodenal diseases caused by cagA-positive H. pylori infection remain unknown. Current studies are limited to the evaluation of the correlation between diseases and the number of Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in the CagA strain. To further understand the relationship between CagA sequence and its virulence to gastric cancer, we proposed a systematic entropy-based approach to identify the cancer-related residues in the intervening regions of CagA and employed a supervised machine learning method for cancer and non-cancer cases classification. Methodology An entropy-based calculation was used to detect key residues of CagA intervening sequences as the gastric cancer biomarker. For each residue, both combinatorial entropy and background entropy were calculated, and the entropy difference was used as the criterion for feature residue selection. The feature values were then fed into Support Vector Machines (SVM) with the Radial Basis Function (RBF) kernel, and two parameters were tuned to obtain the optimal F value by using grid search. Two other popular sequence classification methods, the BLAST and HMMER, were also applied to the same data for comparison. Conclusion Our method achieved 76% and 71% classification accuracy for Western and East Asian subtypes, respectively, which performed significantly better than BLAST and HMMER. This research indicates that small variations of amino acids in those important residues might lead to the virulence variance of CagA strains resulting in different gastroduodenal diseases. This study provides not only a useful tool to predict the correlation between the novel CagA strain and diseases, but also a general new framework for detecting biological sequence biomarkers in population studies.
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Affiliation(s)
- Chao Zhang
- Department of Computer Science, University of Missouri, Columbia, Missouri, United States of America
- C.S. Bond Life Science Center, University of Missouri, Columbia, Missouri, United States of America
| | - Shunfu Xu
- C.S. Bond Life Science Center, University of Missouri, Columbia, Missouri, United States of America
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- * E-mail: (SX); (DX)
| | - Dong Xu
- Department of Computer Science, University of Missouri, Columbia, Missouri, United States of America
- C.S. Bond Life Science Center, University of Missouri, Columbia, Missouri, United States of America
- * E-mail: (SX); (DX)
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Clinical Significance of Gastric Cancer Surveillance in Renal Transplant Recipients. World J Surg 2012; 36:1806-10. [DOI: 10.1007/s00268-012-1605-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Yang JJ, Cho LY, Ko KP, Shin A, Ma SH, Choi BY, Han DS, Song KS, Kim YS, Lee JY, Han BG, Chang SH, Shin HR, Kang D, Yoo KY, Park SK. Genetic susceptibility on CagA-interacting molecules and gene-environment interaction with phytoestrogens: a putative risk factor for gastric cancer. PLoS One 2012; 7:e31020. [PMID: 22383989 PMCID: PMC3286459 DOI: 10.1371/journal.pone.0031020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 12/29/2011] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk. METHODS In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay. RESULTS SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05). CONCLUSIONS Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.
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Affiliation(s)
- Jae Jeong Yang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Lisa Y. Cho
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Kwang-Pil Ko
- Department of Preventive Medicine, Gachon University of Medicine and Science, Incheon, Korea
| | - Aesun Shin
- Cancer Epidemiology Branch, National Cancer Center, Goyang-si, Korea
| | - Seung Hyun Ma
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Bo Youl Choi
- Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Kyu Sang Song
- Department of Pathology, Chungnam National University College of Medicine, Daejeon, Korea
| | - Yong Sung Kim
- Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Jong-Young Lee
- Center for Genome Science, Korea National Institute of Health, Osong, Korea
| | - Bok Ghee Han
- Center for Genome Science, Korea National Institute of Health, Osong, Korea
| | - Soung-Hoon Chang
- Department of Preventive Medicine, Konkuk University, Chungju, Korea
| | - Hai-Rim Shin
- Cancer Epidemiology Branch, National Cancer Center, Goyang-si, Korea
- Non Communicable Diseases and Health Promotion, World Health Organization, Western Pacific Regional Office, Manila, Philippines
| | - Daehee Kang
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
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The geographic origin of Helicobacter pylori influences the association of the homB gene with gastric cancer. J Clin Microbiol 2012; 50:1082-5. [PMID: 22205793 DOI: 10.1128/jcm.06293-11] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We found that South Korean Helicobacter pylori isolates predominantly carry homB at locus B and that there is no association between the homB allele and the cagA allele or the development of gastric cancer within this population. Uniquely, several East Asian strains carried multiple copies of the hom genes.
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Shin A, Kim J, Park S. Gastric cancer epidemiology in Korea. J Gastric Cancer 2011; 11:135-40. [PMID: 22076217 PMCID: PMC3204471 DOI: 10.5230/jgc.2011.11.3.135] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 08/10/2011] [Accepted: 08/16/2011] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer has been the most commonly diagnosed cancer in Korea although the age-standardized mortality and incidence has decreased gradually during last two decades. Helicobacter pylori infection and cigarette smoking are well-established risk factors, and the role of dietary factors, such as salted foods, fresh vegetables and fruits, soy foods, and processed or grilled meats on gastric carcinogenesis has been suggested. In this review, we review national and international gastric cancer statistics, studies on environmental risk factors conducted in the Korean population, and gastric cancer screening activities.
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Affiliation(s)
- Aesun Shin
- Cancer Epidemiology Branch, National Cancer Center, Goyang, Korea
| | - Jeongseon Kim
- Cancer Epidemiology Branch, National Cancer Center, Goyang, Korea
| | - Sohee Park
- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, Korea
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Wang XQ, Yan H, Terry PD, Wang JS, Cheng L, Wu WA, Hu SK. Interactions between CagA and smoking in gastric cancer. World J Gastroenterol 2011; 17:3330-4. [PMID: 21876621 PMCID: PMC3160537 DOI: 10.3748/wjg.v17.i28.3330] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 02/15/2011] [Accepted: 02/22/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the interactions between cytotoxin-associated gene (CagA) positive Helicobacter pylori infection and smoking in non-cardiac gastric cancer.
METHODS: A case-control study (257 cases and 514 frequency-matched controls) was conducted from September 2008 to July 2010 in Xi’an, China. Cases were newly diagnosed, histologically confirmed non-cardiac cancer. Controls were randomly selected from similar communities to the cases and were further matched by sex and age (± 5 years). A face-to-face interview was performed by the investigators for each participant. Data were obtained using a standardized questionnaire that included questions regarding known or suspected lifestyle and environmental risk factors of gastric cancer. A 5 mL sample of fasting venous blood was taken. CagA infection was serologically detected by enzyme-linked immunosorbent assays.
RESULTS: Smoking and CagA infection were statistically significant risk factors of non-cardiac cancer. CagA was categorized in tertiles, and the odds ratio (OR) was 12.4 (95% CI: 6.1-20.3, P = 0.003) for CagA after being adjusted for confounding factors when the high-exposure category was compared with the low-exposure category. Smokers had an OR of 5.4 compared with subjects who never smoked (95% CI: 2.3-9.0, P = 0.002). The OR of non-cardiac cancer was 3.5 (95% CI: 1.8-5.3) for non-smokers with CagA infection, 3.5 (95% CI: 1.9-5.1) for smokers without CagA infection, and 8.7 (95% CI: 5.1-11.9) for smokers with CagA infection compared with subjects without these risk factors. After adjusting for confounding factors, the corresponding ORs of non-cardiac cancer were 3.2 (95% CI: 1.5-6.8), 2.7 (95% CI: 1.3-4.9) and 19.5 (95% CI: 10.3-42.2), respectively. There was a multiplicative interaction between smoking and CagA, with a synergistic factor of 2.257 (Z = 2.315, P = 0.021).
CONCLUSION: These findings support a meaningful interaction between CagA and smoking for the risk of gastric cancer which may have implications for its early detection.
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Helicobacter pylori homB, but not cagA, is associated with gastric cancer in Iran. J Clin Microbiol 2011; 49:3191-7. [PMID: 21734027 DOI: 10.1128/jcm.00947-11] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
While several distinct virulence factors of Helicobacter pylori have been shown to be associated with different clinical outcomes, there is still much to learn about the role of different bacterial factors in gastric carcinogenesis. This study looked at the distribution of the cagA, homA, and homB genes in strains isolated from patients suffering from gastroduodenal diseases in Iran and assessed if there was any association between disease state and the presence of the aforementioned virulence factors. Genomic DNA from 138 H. pylori strains was isolated and genotyped via PCR. Strains were obtained from dyspeptic patients (35 from gastritis patients, 62 from peptic ulcer patients, and 41 from gastric cancer patients) at the Teaching Touba Clinic and Imam Hospital of the Mazandaran University of Medical Sciences in Sari, Iran. The overall prevalence rates of cagA, homA, and homB were 58%, 54%, and 43%, respectively. Stratification of patients showed a significant difference in the prevalence of H. pylori virulence genes across the disease states. The frequency of homB was statistically significantly higher in gastric cancer patients (78%) than in patients suffering from peptic ulcers (20%) or gastritis (43%) (P < 0.0001). The presence of homB was also associated with the presence of cagA (r = 0.243). These data suggest that in this population the presence of homB may be a predictor of more virulent strains of H. pylori and influence the severity of disease manifestation.
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Shiota S, Matsunari O, Watada M, Yamaoka Y. Serum Helicobacter pylori CagA antibody as a biomarker for gastric cancer in east-Asian countries. Future Microbiol 2011; 5:1885-93. [PMID: 21155667 DOI: 10.2217/fmb.10.135] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIMS In east-Asian countries, while almost all Helicobacter pylori strains possess the cytotokine-associated gene A (CagA) gene, serum CagA antibody is not detected in some infected subjects. We aimed to clarify the association between anti-CagA antibody and gastric cancer in east-Asian countries. MATERIALS AND METHODS We performed a meta-analysis of case-control studies with age- and sex-matched controls, which provided raw data in east-Asian countries. RESULTS Ten studies with a total of 4325 patients were identified in the search. Some reports from Japan, Korea and China showed a positive association between the presence of anti-CagA antibody and gastric cancer; however, the results differed in their various backgrounds. The disparate findings appeared to result from the use of different methods or from variations in the antigens used to detect the anti-CagA antibody. CagA seropositivity was associated with an increased risk of developing gastric cancer. CONCLUSION Anti-CagA antibody can be used as a biomarker for gastric cancer even in east-Asian countries.
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Affiliation(s)
- Seiji Shiota
- Department of Environmental & Preventative Medicine, Oita University Faculty of Medicine, Hasama-machi, Yufu-City, Oita, Japan
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Jones KR, Whitmire JM, Merrell DS. A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease. Front Microbiol 2010; 1:115. [PMID: 21687723 PMCID: PMC3109773 DOI: 10.3389/fmicb.2010.00115] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2010] [Accepted: 09/27/2010] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori is a pathogenic bacterium that colonizes more than 50% of the world's population, which leads to a tremendous medical burden. H. pylori infection is associated with such varied diseases as gastritis, peptic ulcers, and two forms of gastric cancer: gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. This association represents a novel paradigm for cancer development; H. pylori is currently the only bacterium to be recognized as a carcinogen. Therefore, a significant amount of research has been conducted to identify the bacterial factors and the deregulated host cell pathways that are responsible for the progression to more severe disease states. Two of the virulence factors that have been implicated in this process are cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), which are cytotoxins that are injected and secreted by H. pylori, respectively. Both of these virulence factors are polymorphic and affect a multitude of host cellular pathways. These combined facts could easily contribute to differences in disease severity across the population as various CagA and VacA alleles differentially target some pathways. Herein we highlight the diverse types of cellular pathways and processes targeted by these important toxins.
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Affiliation(s)
- Kathleen R Jones
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences Bethesda, MD, USA
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Polymorphisms in the intermediate region of VacA impact Helicobacter pylori-induced disease development. J Clin Microbiol 2010; 49:101-10. [PMID: 21084502 DOI: 10.1128/jcm.01782-10] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is the etiological agent of diseases such as gastritis, gastric and duodenal ulcers, and two types of gastric cancers. While some insight has been gained into the etiology of these diverse manifestations, by and large, the reason that some individuals develop more severe disease remains elusive. Recent studies have focused on the roles of H. pylori toxins CagA and VacA on the disease process and have suggested that both toxins are intimately involved. Moreover, CagA and VacA are polymorphic within different H. pylori strains, and particular polymorphisms seem to show a correlation with the development of particular disease states. Among VacA polymorphisms, the intermediate region has recently been proposed to play a major role in disease outcome. In this article, we describe a detailed sequence analysis of the polymorphic intermediate region of vacA from strains obtained from a large South Korean population. We show that polymorphisms found at amino acid position 196 are associated with more severe disease manifestations. Additionally, polymorphisms found at amino acid position 231 are linked to disease in strains that carry the non-EPIYA-ABD allele of CagA. Collectively, these data help explain the impact of the VacA intermediate region on disease and lead to the hypothesis that there are allele-driven interactions between VacA and CagA.
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Ko KP, Park SK, Park B, Yang JJ, Cho LY, Kang C, Kim CS, Gwack J, Shin A, Kim Y, Kim J, Yang HK, Kang D, Chang SH, Shin HR, Yoo KY. Isoflavones from phytoestrogens and gastric cancer risk: a nested case-control study within the Korean Multicenter Cancer Cohort. Cancer Epidemiol Biomarkers Prev 2010; 19:1292-300. [PMID: 20447921 DOI: 10.1158/1055-9965.epi-09-1004] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The role of soybean products in gastric cancer risk is not clear in epidemiologic studies due to measurement error from dietary intake questionnaires and due to different degrees of bias according to study design. To examine the association between soybean products and gastric cancer risk, we measured phytoestrogen biological markers in a nested case-control study. METHODS The study population was composed of 131 cases and 393 matched controls within the Korean Multicenter Cancer Cohort. The concentrations of the four biomarkers in the plasma samples were measured using time-resolved fluoroimmunoassay. Conditional and unconditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence intervals (CI). RESULTS Median plasma concentrations of genistein (229 nmol/L for controls, 181.8 nmol/L for cases; P=0.07) and daidzein (131.2 nmol/L for controls, 80.5 nmol/L for cases; P=0.04) in cases were lower than in controls, whereas equol concentrations were similar. Compared with the reference group, gastric cancer risk decreased in the highest groups for genistein (OR, 0.54; 95% CI, 0.31-0.93) and daidzein (OR, 0.21; 95% CI, 0.08-0.58). Higher equol concentrations were associated with a decreased risk for gastric cancer (OR, 0.50; 95% CI, 0.27-0.90). The combination of the highest concentrations for each isoflavone category was associated with a 0.09-fold decreased risk for gastric cancer compared with the combination of the lowest concentrations for each category. There was no association between plasma lignan concentrations and gastric cancer. CONCLUSIONS High serum concentrations of isoflavones were associated with a decreased risk for gastric cancer. IMPACT These results suggest a beneficial effect of high soybean product intake for gastric cancer risk.
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Affiliation(s)
- Kwang-Pil Ko
- Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehangno, Chongno-gu, Seoul 110-799, Korea
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Epidemiological link between gastric disease and polymorphisms in VacA and CagA. J Clin Microbiol 2009; 48:559-67. [PMID: 19955279 DOI: 10.1128/jcm.01501-09] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Gastritis, peptic ulcer disease, and gastric cancer are a few of the diverse disease manifestations that have been shown to be associated with infection by Helicobacter pylori. Why some individuals develop more severe forms of disease remains largely unknown. In this study, 225 South Korean strains were genotyped for vacA and then analyzed to determine if particular genotypes varied across disease state, sex, or cagA allele. Of these strains, 206 strains carried an s1/i1/m1 allele, 11 strains carried an s1/i1/m2 allele, and 8 strains carried an s1/i2/m2 allele. By using Fisher's exact test, a statistical association between variations in the cagA and vacA alleles was identified (P = 0.0007), and by using log linear modeling, this variation was shown to affect the severity of disease outcome (P = 0.027). Additionally, we present evidence that variation within the middle region of VacA contributes significantly to the distribution of vacA alleles across gender (P = 0.008) as well as the association with disease outcome (P = 0.011). In this South Korean population, the majority of H. pylori strains carry the vacA s1/i1/m1 allele and the CagA EPIYA-ABD allele. These facts may contribute to the high incidence of gastric maladies, including gastric cancer.
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Shin DW, Yun YH, Choi IJ, Koh E, Park SM. Cost-effectiveness of eradication of Helicobacter pylori in gastric cancer survivors after endoscopic resection of early gastric cancer. Helicobacter 2009; 14:536-44. [PMID: 19889071 DOI: 10.1111/j.1523-5378.2009.00721.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Clinical effectiveness of Helicobacter pylori eradication in gastric cancer survivors after endoscopic resection of early gastric cancer (EGC) was recently established in a randomized controlled trial. We aimed to establish long-term cost-effectiveness in gastric cancer survivors after endoscopic resection of EGC. MATERIALS AND METHODS A Markov model was constructed to compare the costs and outcomes of the two intervention strategies: (1) eradicate H. pylori after complete resection of EGC by endoscopy (2) do not eradicate. Estimates for variables in the model were obtained by extensive review of published reports. Analyses were made from the Korean public healthcare provider's perspective. RESULTS Base-case analysis indicated H. pylori eradication costs less (US$ 29,780 vs. US$ 30,594) than no eradication, and save more lives (mean life expectancy from eradication: 13.60 years vs. 13.55 years). One-way and three-way sensitivity analyses showed the robustness of the cost-effectiveness results. CONCLUSION In this selective population with very high risk of developing gastric cancer, H. pylori eradication should be considered for reimbursement with priority to prevent subsequent cancer and also reduce health care cost.
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Affiliation(s)
- Dong Wook Shin
- National Cancer Control Research Institute & Hospital, National Cancer Center, Goyang, Korea
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Suzuki H, Iwasaki E, Hibi T. Helicobacter pylori and gastric cancer. Gastric Cancer 2009; 12:79-87. [PMID: 19562461 DOI: 10.1007/s10120-009-0507-x] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Accepted: 03/25/2009] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori is now well known as an important pathogen related to the development of gastric cancer. However, some clinicians still doubt the causal association of H. pylori with the development of gastric cancer. To summarize the recent clinical data on the link between H. pylori and gastric cancer, we reviewed related articles published over the past 3 years, after the award of the Nobel Prize for Physiology or Medicine to Drs. J.R. Warren and B.J. Marshall for the first culture and isolation of H. pylori and the investigation of their relevance to peptic ulcer disease. This updated summary of the relationship between H. pylori and gastric cancer highlights the strong link between the organism and the development of gastric cancer, and suggests eradication of this bacterial infection as a possible prophylactic measure against the development of this lethal malignancy. At present, clinicians and researchers in the field emphasize the strong need for H. pylori eradication from the human stomach.
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Affiliation(s)
- Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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45
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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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Oh DY, Choi KS, Shin HR, Bang YJ. Public awareness of gastric cancer risk factors and disease screening in a high risk region: a population-based study. Cancer Res Treat 2009; 41:59-66. [PMID: 19707502 DOI: 10.4143/crt.2009.41.2.59] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2009] [Accepted: 05/12/2009] [Indexed: 01/17/2023] Open
Abstract
PURPOSE This study involved a population-based survey to provide evidence of public awareness of risk factors of gastric cancer and to investigate attitudes for the screening of gastric cancer in the South Korean population. MATERIALS AND METHODS Using a nationwide random selection method, 2014 subjects were enrolled in the study between 5 September 2006 and 25 September 2006. RESULTS In terms of the awareness of risk factors, awareness was scored as the percentage of the probability of developing gastric cancer when a subject had a particular risk factor. For the risk factors, stress ranked highest with a score of 73.5%, followed by chronic gastritis (score of 72.1%), gastric ulcer (score of 71.2%) and a previous gastrectomy history (score of 68.7%). Other factors included a diet of charred foods (score of 67.3%), alcohol use (score of 65.3%), salty diet (score of 65.1%), history of smoking (score of 64.3%) and Helicobacter pylori infection (score of 57.5%). Subjects believed that 60.4% of all gastric cancers were preventable by lifestyle modification and the subjects believed that regular screening could prevent 72.1% of all gastric cancers. However, 54% of subjects did not receive regular screening and the most common reason for not undergoing screening was a lack of symptoms. CONCLUSION Public education about the risk factors of gastric cancer and of lifestyle modifications and the importance of regular screening regardless of the presence of symptoms should be emphasized to reduce gastric cancer mortality in South Korea.
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Affiliation(s)
- Do-Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
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Epstein-Barr virus antibody level and gastric cancer risk in Korea: a nested case-control study. Br J Cancer 2009; 101:526-9. [PMID: 19550421 PMCID: PMC2720236 DOI: 10.1038/sj.bjc.6605146] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background: Few cohort studies have investigated Epstein–Barr virus (EBV) infection before the occurrence of gastric cancer. Methods: Among 14 440 cohort participants, 100 incident gastric cancer cases were individually matched to two controls. Epstein–Barr virus antibodies IgG and IgA against viral capsid antigen (VCA), EBV nuclear antigen (EBNA) antibody IgG, and early antigen (EA) antibody IgG were measured using enzyme immunoassays (EIAs). Results: The highest titres of VCA IgG (odds ratio (OR): 1.37, 95% confidence interval (CI): 0.62–3.06) or EBNA IgG (OR: 0.87, 95% CI: 0.51–1.46) were not associated with gastric cancer risk. Conclusion: Higher levels of VCA IgG or EBNA IgG were not associated with increased risk of gastric adenocarcinoma in Koreans.
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48
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Ko KP, Park SK, Cho LY, Gwack J, Yang JJ, Shin A, Kim CS, Kim Y, Kang D, Chang SH, Shin HR, Yoo KY. Soybean product intake modifies the association between interleukin-10 genetic polymorphisms and gastric cancer risk. J Nutr 2009; 139:1008-12. [PMID: 19321591 DOI: 10.3945/jn.108.101865] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In this study, our aim was to investigate the association of inflammation-related genetic polymorphisms and gastric cancer risk and to examine whether the combined effect of soybean product intake modified cancer risk. Eighty-four incident gastric cancer cases and 336 matched controls were selected from the Korean Multi-Center Cancer Cohort. We selected 14 single nucleotide polymorphisms (SNP) from 5 genes [interleukin (IL)-1beta, IL-2, IL-4, IL-8, and IL-10] and used unconditional logistic regression model to calculate the odds ratios (OR) and 95% CI adjusting for H. pylori seropositivity, smoking, age, sex, enrollment year, and residential area. The risk for gastric cancer in relation to genetic polymorphisms and haplotypes were assessed according to soybean product intake levels. Although no single SNP effect was found, the combined effect between IL-10 gene variants of -592 GG/GA, -819 TC/CC, or -1082 AG/GG and low intake of soybean products had an increased risk for gastric cancer compared with the group with no risk gene variants and a high intake of soybean products (OR [95% CI] = 2.82 [1.04-7.62], 2.75 [1.02-7.44], and 4.34 [1.51-12.5], respectively). Among the low-soybean product intake group, IL-10 CCG haplotype had an increased risk of gastric cancer (OR = 3.38 [1.40-8.13]) relative to the ATA haplotype. Our results suggest that the association between IL-10 genetic polymorphisms and gastric cancer risk was modified by soybean product intake.
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Affiliation(s)
- Kwang-Pil Ko
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
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Gao L, Weck MN, Michel A, Pawlita M, Brenner H. Association between chronic atrophic gastritis and serum antibodies to 15 Helicobacter pylori proteins measured by multiplex serology. Cancer Res 2009; 69:2973-80. [PMID: 19318564 DOI: 10.1158/0008-5472.can-08-3477] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Infection with Helicobacter pylori is a major risk factor for chronic atrophic gastritis (CAG), a precursor lesion of intestinal gastric cancer. The pathogenicity of the bacterium is thought to play an important role in determining the extent and severity of clinical outcome. We aimed to assess the associations between CAG and the serostatus of antibodies to 15 H. pylori proteins. The analyses were based on 534 cases with serologically defined CAG and 1,068 age-matched and sex-matched controls participating in a population-based study conducted in Saarland, Germany among 9,953 men and women ages 50 to 74 years. A newly developed H. pylori multiplex serology method was used to detect antibodies specific to 15 H. pylori antigens. Significant associations were observed between seropositivity for all 15 specific antibodies and the presence of CAG. Exclusion of severe cases, who might have lost the infection in the course of CAG progression, substantially increased the observed associations. In H. pylori-seropositive subjects, cytotoxin-associated gene A (CagA), vacuolating toxin (VacA), helicobacter cysteine-rich protein C (HcpC), and the chaperonin GroEL were identified as independent virulence factors for CAG with adjusted odds ratios (95% confidence interval) of 3.52 (2.01-6.10), 3.19 (1.44-7.05), 4.03 (1.53-10.65), and 2.65 (1.06-6.62), respectively; the simultaneous presence of all four independent virulence factors was associated with an 18-fold risk of CAG. In conclusion, HcpC and GroEL were identified as new independent virulence factors, and in combination with the established virulence factors, CagA and VacA, were strongly associated with CAG.
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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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Chung JW, Lee GH, Choi KS, Kim DH, Jung KW, Song HJ, Choi KD, Jung HY, Kim JH, Yook JH, Kim BS, Jang SJ. Unchanging trend of esophagogastric junction adenocarcinoma in Korea: experience at a single institution based on Siewert's classification. Dis Esophagus 2009; 22:676-81. [PMID: 19222529 DOI: 10.1111/j.1442-2050.2009.00946.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been increasing in Western countries. It is unclear, however, whether similar changes are occurring in Asia. We therefore investigated the incidence of AEG in Korea, and assessed the clinical characteristics of three types of AEG based on Siewert's classification. We retrospectively reviewed the medical records of 16 811 patients diagnosed with esophageal squamous cell carcinoma (ESC, n= 1450) or gastric noncardiac adenocarcinoma (GNCA, n= 14 751) between 1992 and 2006. The patients were divided into three 5-year cohorts (cohort A [1992-1996], n= 2734, cohort B [1997-2001], n= 5727, and cohort C [2002-2006], n= 8350), and the ratios of AEG (n= 610) to non-AEG (ESC and GNCA) in each cohort were compared. Using Siewert's classification, the tumors were categorized into one of three types, and patient demographic features and 5-year survival rates were compared. The ratio of AEG to non-AEG cases did not change over time (0.037, 0.034, and 0.039 for cohorts A, B, and C, respectively; P= 0.40). Of the 610 patients with AEG, 23 (3.7%) had type 1 tumors, 47 (7.7%) had type 2, and 540 (88.5%) had type 3. The 5-year survival rate of patients with type 1 AEG was much lower (4.8 +/- 4.7%) than that of those with type 2 (47.9 +/- 7.8%) and type 3 (47.4 +/- 2.5%) tumors. Unlike in Western countries, the ratio of AEG to non-AEG cases has not increased over time in Korea. Type 1 AEG was rarer and associated with a more unfavorable prognosis in Korea than in Western countries.
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Affiliation(s)
- J-W Chung
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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