Interleukin 12 gene polymorphisms enhance gastric cancer risk in H pylori infected individuals

ABSTRACTA known virulence factor ofHelicobacter pylorithat augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhydmutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhydstrain showed a decreased frequency of DNA transformation, suggesting thatH. pylorihydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhydstrain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhydstrain. By examining the hydrogenase activities from well-defined clinicalH. pyloriisolates, we observed that strains isolated from cancer patients (n= 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n= 6), further supporting an association betweenH. pylorihydrogenase activity and gastric carcinogenesis in humans.IMPORTANCEHydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen’s (H. pylori) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H2-utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H2oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.

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Antioxidant-Rich Diet, GSTP1 rs1871042 Polymorphism, and Gastric Cancer Risk in a Hospital-Based Case-Control Study

Frontiers in Oncology ◽

10.3389/fonc.2020.596355 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jimi Kim ◽

Hyejin Kim ◽

Jeonghee Lee ◽

Il Ju Choi ◽

Young-Il Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Risk ◽

Genetic Variants ◽

Total Phenolics ◽

Nucleotide Polymorphisms ◽

Gastric Cancer Risk ◽

Glutathione S Transferase ◽

Dietary Antioxidant ◽

H Pylori ◽

Gastric Cancer Patients

BackgroundChronic gastritis along with Helicobacter pylori (H. pylori) infection has been implicated in inflammatory response-related genes linked to the causation of gastric cancer. Glutathione S-transferase Pi (GSTP1) plays a role in regulating oxidative stress and detoxification against carcinogenesis. In this study, we aimed to determine whether an antioxidant-rich diet is associated with gastric cancer risk and identify how this association could be altered by GSTP1 genetic variants.MethodsThis study included 1,245 participants (415 cases and 830 controls) matched for age and sex. The dietary antioxidant capacity was estimated based on the oxygen radical absorbance capacity (ORAC) incorporated with a semiquantitative food frequency questionnaire. Five single nucleotide polymorphisms (SNPs) of GSTP1 (rs1695, rs749174, rs1871042, rs4891, and rs947895) were selected among the exome array genotype data.ResultsHigh dietary ORAC was inversely associated with gastric cancer (hydrophilic ORAC OR T3vs. T1, 95% CI = 0.57, 0.39–0.82, P = 0.004; lipophilic ORAC = 0.66, 0.45–0.95, P = 0.021; total phenolics = 0.57, 0.39–0.83, P = 0.005). The polymorphism rs1871042 increased the risk of gastric cancer (OR, 95% CI = 1.55, 1.10–2.16, P = 0.01, CT+TT vs. CC). A remarkably reduced risk of gastric cancer was observed among those who had a high dietary ORAC according to rs1871042 polymorphism (hydrophilic ORAC OR T3vs. T1, 95% CI = 0.36, 0.17–0.78, P for trend = 0.013; lipophilic ORAC = 0.58, 0.37–0.93, P for trend = 0.021; total phenolics = 0.38, 0.17–0.83, P for trend = 0.019).ConclusionsOur findings indicate that dietary ORAC intake may be inversely associated with the risk of gastric cancer altered by genetic variants of GSTP1, providing new intervention strategies for gastric cancer patients.

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P08: Effects of inflammation-related cytokine gene polymorphisms on gastric cancer risk among atomic bomb survivors

Experimental and Toxicologic Pathology ◽

10.1016/j.etp.2009.02.045 ◽

2009 ◽

Vol 61 (3) ◽

pp. 285

Author(s):

Hiroko Nagamura ◽

Tomonori Hayashi ◽

Yukari Morishita ◽

Mayumi Maki ◽

Kazue Imai ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Risk ◽

Gene Polymorphisms ◽

Atomic Bomb ◽

Cytokine Gene ◽

Gastric Cancer Risk ◽

Atomic Bomb Survivors ◽

Cytokine Gene Polymorphisms

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Association ofE-cadherin(CDH1) gene polymorphisms and gastric cancer risk

World Journal of Gastroenterology ◽

10.3748/wjg.v16.i27.3432 ◽

2010 ◽

Vol 16 (27) ◽

pp. 3432 ◽

Cited By ~ 16

Author(s):

Mansour S Al-Moundhri

Keyword(s):

Gastric Cancer ◽

Cancer Risk ◽

Gene Polymorphisms ◽

Gastric Cancer Risk ◽

Cdh1 Gene

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Su1906 Serum Levels of Eotaxin, Mip-1a Mip-1β, MCP-1, IL-8 and RANTES Support Regional Differences in Helminth Modulation of H. pylori-Associated Gastric Cancer Risk in Colombian Adults

Gastroenterology ◽

10.1016/s0016-5085(12)62045-9 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-532-S-533

Author(s):

Mark T. Whary ◽

Jennifer L. Lofgren ◽

Kvin Lertpiriyapong ◽

Arkadiusz R. Racynski ◽

Luis E. Bravo ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Risk ◽

Regional Differences ◽

Serum Levels ◽

Gastric Cancer Risk ◽

H Pylori

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Vascular Endothelial Growth Factor (Vegf) +936 C/T Gene Polymorphisms and Gastric Cancer Risk: A Meta-Analysis Involving 4,138 Subjects

The International Journal of Biological Markers ◽

10.5301/jbm.2010.6110 ◽

2010 ◽

Vol 25 (4) ◽

pp. 213-218 ◽

Cited By ~ 8

Author(s):

Yong Zhou ◽

Wen Hu ◽

Wen Zhuang ◽

Guan-Jian Liu ◽

Tai-Xiang Wu ◽

...

Keyword(s):

Gastric Cancer ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cancer Risk ◽

Gene Polymorphisms ◽

Meta Analysis ◽

Vascular Endothelial ◽

Gastric Cancer Risk ◽

Case Control Studies ◽

Endothelial Growth Factor

The association between vascular endothelial growth factor (VEGF) +936 C/T gene polymorphisms and gastric cancer risk is still controversial and ambiguous. The objective of our study was to investigate this association. The Medline and Embase databases were searched by two investigators. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to test the association between VEGF +936 C/T polymorphisms and gastric cancer risk. Our meta-analysis comprised seven case-control studies, which included 1,893 gastric cancer cases and 2,245 controls. The combined results showed that there was no relationship between VEGF +936 C/T gene polymorphisms and gastric cancer risk (cc: OR 0.97, 95% CI 0.85, 1.11; CT: OR 1.01, 95% CI 0.88, 1.16; TT: OR 1.10, 95% CI 0.79, 1.55). Subgroup analysis by ethnicity and stage, location, and Lauren classification of gastric cancer did not change the results. This meta-analysis suggests that there is no association between VEGF +936 C/T polymorphisms and gastric cancer risk. Further studies should pay attention to other potentially functional SNPs.

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