Helicobacter pylori vacA c1 Genotype Is a Benefit Biomarker for Prediction of Gastric Cancer Risk in Ardabil

BACKGROUND: Gastric cancer (GC) is the fifth common malignant disease and the third leading cause of cancer-related mortality in the world. Ardabil, a Northwestern province of Iran, includes the highest rate of GC within the country. Helicobacter pylori (H. pylori) vacA gene plays a major role in generating and maintaining the gastric inflammatory response, which alters the enteric nervous system in various combinations and may contribute to the development of GC. The aim of the current study was to investigate the relationship of the vacA c-region genotypes of H. pylori with GC among Ardabil population.METHODS: A total of 197 from 259 patients with non-atrophic gastritis (NAG) and GC, who were H. pylori positive, were selected and genotyped.RESULTS: The frequency of vacA c1 was 53.7% and c2 42.3%. There was a significant difference between the frequencies of vacA c1 in isolates from GC than those from NAG (p<0.05). Though the GC was considered as a dependent factor by the multiple logistic regression analysis, the vacA c1 genotype was significantly associated with age- and sex-adjusted risk for GC (p=0.003, odds ratio [OR] = 5.48; 95% confidence interval [CI] =1.80–16.63).CONCLUSION: It was proposed that the H. pylori vacA c1 genotype could be considered as an important determinant for prediction of risk of GC in Ardabil. It is suggested that interaction between H. pylori vacA c-region genotypes and gastric nervous system may contribute to the development of GC

Repeated out-of-Africa expansions of Helicobacter pylori driven by replacement of deleterious mutations

Erratum in: Nat Commun. 2023 Mar 20;14(1):1539. doi: 10.1038/s41467-023-37302-5.Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori fromEurope and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying selection to remove them during admixture. Simulations show that population fitness can be restored after bottlenecks bymigration and subsequent admixture of small numbers of bacteria from non-bottlenecked populations. We conclude that recent spread of African DNA has been driven by deleterious mutations accumulated during the original out-of-Africa bottleneck.This work was supported by Sequencing Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (221S0002, 18KK0266, 19H03473, 21H00346 and 22H02871) to Y.Y. F.F.V. is financed by FCT through Assistant Researcher grant CEECIND/03023/2017 and a project grant PTDC/BTM-TEC/3238/ 2020. I.K. studentship was funded by the National Strategic Reference Framework Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020, project No. MIS5002486) and sequencing of strains was supported by the InfeNeutra Project (NSRF 2007-2013, project no. MIS450598) of the Ministry of Culture and Edu- cation, Greece. K.T. and the sequencing of KI isolates was supported by Erik Philip-Sörensen Foundation grant G2016-08, and Swedish Society for Medical research (SSMF). All primary bioinformatics and parts of the comparative genomics were performed on resources provided by Swedish National Infrastructure for Computing (SNIC) through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under projects snic2018-8-24 and uppstore2017270. Work by S.S. was supported by the German Research Foundation (DFG, project number 158 989 968–SFB 900/A1) and by the Bavarian Ministry of Sci- ence and the Arts in the framework of the Bavarian Research Network “New Strategies Against Multi-Resistant Pathogens by Means of Digital Networking—bayresq.net”. D.F. was supported by Shanghai Municipal Science and Technology Major Project No. 2019SHZDZX02.info:eu-repo/semantics/publishedVersio

Bacterial and tissue biomarkers of gastric cancer: new findings and future perspectives: review article

Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. It has been proposed that the specific genotypes of Helicobacter pylori (H. pylori) are the causative agents in the development of gastroduodenal diseases, such as chronic atrophic gastritis, peptic ulcerations, and GC. However, disease progression to GC occurs in only a small proportion of infected patients. Recently, we identified a novel polymorphic site in the 3ʹ-end region of H. pylori vacA gene. The vacA c1 genotype increased the risk of GC. This association was independent of and larger than the associations of the m-, i-, and d-type of vacA or cagA status with GC. Therefore, treatment of H. pylori infection may be an effective way to prevent GC. Expression of cytokines and their associations with inflammatory responses has been shown. Several cytokine polymorphisms, such as IL-1B, IL-8, IL-10, and TNF-α have been considered as risk factors for GC. It has been shown that the interaction of bacterial genotypes and host factors plays an essential role in developing GC. Several altered molecular pathways are involved in the pathogenesis of GC. Micro-RNAs are small, non-coding RNAs of 18-25 nucleotides in length that regulate the expression of target mRNAs. Expression pattern of cancer cells is different compared with the normal cells. Micro-RNAs plays a critical role in apoptosis and classified in two groups: pro- and anti-apoptotic agents. Recent studies have confirmed the oncogenic or tumor suppression role of micro-RNAs in cancer cells. They play a significant role in the GC cell physiology and tumor progression, by translational suppression of target genes. These small RNAs have therefore emerged as a new type of GC biomarker with immeasurable clinical potential. Generally, a variety of micro-RNAs involved in different stages of cancer, including tumorigenesis, angiogenesis, and metastasis. Considering to this issue more than 50% of cancers can be cured, if they were diagnosed in the early stages. Hence, identifying the biomarkers of GC could play an important role in prevention, early diagnosis and rapid treatment of patients. In this review article, we have reviewed the latest findings about bacterial and tissue biomarkers of G

Relationship between s alleles of vacA gene of Helicobacter pylori and gastroduodenal diseases in Iran: a brief report

Background: Helicobacter pylori has been classified as the class I carcinogenic agent by world health organization. Colonization of the human stomach with H. pylori is a risk factor for gastroduodenal diseases. The secreted vacA toxin is an important H. pylori virulence factor that causes multiple alterations in gastric epithelial cells and T cells. Several families of vacA alleles have been described, and H. pylori strains containing certain vacA types (s1 and m1) are associated with an increased risk of gastric disease, compared to strains containing other vacA types (s2 and m2). We examined the association between H. pylori vacA s alleles and gastroduodenal diseases in Iran. Methods: A total of 149 H. pylori strains were obtained from patients with gastritis, peptic ulcer, and gastric cancer referring to endoscopy units of several cities in Iran. Biopsy culture and DNA extraction were performed and the frequency of vacA s alleles was investigated by using PCR amplification. Linear regression and binary logistic regression models were used to analyze the association between vacA (vacuolating cytotoxin A) s alleles and gastroduodenal diseases. Results: There was no significant association between the frequency of vacA s alleles and gastroduodenal diseases (gastritis or peptic ulcer disease and gastric adenocarcinoma (P> 0.05)). Conclusion: It is proposed that the H. pylori vacA s1 genotype could not be considered as an important determinant of gastroduodenal diseases in Iranian population and probably if s1 allele is associated with other virulence alleles of this gene, it will cause diseases

Helicobacter pylori virulence genes and microevolution in host and the clinical outcome: review article

Helicobacter pylori (H. pylori) is the causative agent in development of gastroduode-nal diseases, such as chronic atrophic gastritis, peptic ulcers, mucosa associated lym-phoid tissue (MALT) lymphoma, and gastric cancer. H. pylori has been associated with inflammation in cardia, showing the fact that infection with this bacterium could also be a risk factor for gastric cardia cancer. Gastric cancer is the fourth most common cancer worldwide. This is the second leading cause of cancer-related deaths, and ap-proximately 700,000 people succumb each year to gastric adenocarcinoma. It has been estimated that 69% of the Iranian population currently harbor H. pylori infection. The prevalence of duodenal ulcer and gastric cancer is high in Iranian populations. However, this has been largely influenced by geographic and/or ethnic origin. Epidemi-ology studies have shown that host, environmental, and bacterial factors determine the outcome of H. pylori infection. The bacterium contains allelic diversity and high genet-ic variability into core- and virulence-genes and that this diversity is geographically and ethnically structured. The genetic diversity within H. pylori is greater than within most other bacteria, and its diversity is more than 50-fold higher than that of human DNA. The maintenance of high diversification makes this bacterium to cope with particular challenges in individual hosts. It has been reported that the recombination contributed to the creation of new genes and gene family. Furthermore, the microevolution in cagA and vacA genes is a common event, leading to a change in the virulence phenotype. These factors contribute to the bacterial survival in acidic conditions in stomach and protect it from host immune system, causing tissue damage and clinical disease. In this review article, we discussed the correlation between H. pylori virulence factors and clin-ical outcomes, microevolution of H. pylori virulence genes in a single host, microevolu-tion of H. pylori during primary infection and progression of atrophic gastritis to ade-nocarcinoma, and H. pylori infection status in Iran. Finally, we put forward the hy-pothesis that if the pattern of nucleotide sequence evolution shifts from recombination (r) to mutation (m) and the r/m ratio is reduced, bacterial pathogenicity may be re-duced while maintaining the bacterial life. However, this hypothesis should be further studied with future experiments

Inverse association of Helicobacter pylori cagPAI genotypes with risk of cardia and non‐cardia gastric adenocarcinoma

Abstract Iran is a high‐risk country for cardia gastric adenocarcinoma (CGA) in Central Asia, with an incidence rate five times the average global rate, and shows a high infection rate for Helicobacter pylori (69%). The aim was to examine the associations of multiple H. pylori cagPAI genotypes (ie cagH, cagL, cagG, and orf17) with the risk of CGA, non‐CGA, and different histological types of GA in Iran. A large number of H. pylori strains (N = 336) were successfully cultured and genotyped. Histopathological evaluations were performed. The analysis showed an inverse association between the cagH+ genotype and the risk of CGA and intestinal‐type gastric adenocarcinoma (IGA) (adjusted ORs; 0.312 and 0.283, respectively), where the controls were nontumors. The orf17+ genotype decreased the risk of non‐CGA and diffuse‐type gastric adenocarcinoma (DGA)(adjusted ORs; 0.310 and 0.356, respectively). When the controls were those with nonatrophic gastritis, the cagG+ genotype was negatively associated with the risk of CGA, non‐CGA, IGA, and DGA (adjusted ORs; 0.324, 0.366, 0.306, and 0.303, respectively). We did not find such a significant association for the cagL+ genotype in multiple logistic regression analysis. Combination of the vacA c2 and cagPAI genotypes further decreased the risk estimates for GAs. This study showed the reverse association of H. pylori cagPAI genotypes—cagH+ and cagG+—with the risk of CGA in male patients aged ≥ 55 in Iran. Presence of the vacA c2 genotype in combination with cagPAI genotypes showed strong inverse associations with the risk of CGA and non‐CGA. These findings may reveal a coordinated relationship between the vacA c2 and cagPAI genotypes

Helicobacter pylori vacA i region polymorphism but not babA2 status associated to gastric cancer risk in northwestern Iran

Abstract Helicobacter pylori-specific genotypes have been strongly associated with an increased risk of gastric cancer (GC). The aim of the present work was to study the associations of H. pylori virulence factors, vacA i region polymorphisms and babA2 status with GC risk in Azerbaijan patients. The DNA extracted from gastric biopsy specimens was used to access the babA2 and vacA genotypes. Overall, babA2 was present in 85.39 % (76/89) of H. pylori strains: 19 out of 24 (79.16 %) strains from GC, 16 out of 17 (94.14 %) strains from peptic ulcer disease (PUD) and 41 out of 48 (85.14 %) strains from chronic gastritis. No significant association was found between babA2 genotype and clinical outcomes (P [ 0.05). i1 vacA polymorphism was detected in 46/89 (51.68 %) strains: in 21/24 (87.5 %), 6/17 (35.29 %) and 19/48 (39.58 %) patients with GC, PUD and chronic gastritis, respectively. i2 allele was detected in 43 (48.31 %) out of all 89 strains examined: 3 (14.28 %) of 24 strains from GC, 11 (64.71 %) of 17 from PUD, and 29 (60.42 %) of 48 strains from chronic gastritis. In this study, multiple linear regression analysis confirmed the strong association of i1 allele with GC (partial regression correlation 0.455 ± 0.101; P = 0). Results of multiple logistic regression analysis showed that vacA i1 genotype was significantly associated with GC compared with a control group (gastritis) (odds ratio 13.142, 95 % CI 3.116-55.430; P = 0). Findings from the measurement of H. pylori babA2 and vacA genotypes indicate a strong correlation between the vacA i1 allele and GC risk in the Azerbaijan area of Iran

Diagnostic value of long noncoding RNA SNHG15 in gastric cancer: <i>in vitro</i> and <i>in silico</i> studies

LncRNA SNHG15 has been recognized as the main factor in the progression of various cancer types. However, the underlying mechanisms are not well clarified. This research aimed to explore the diagnostic potential of SNHG15 in gastric cancer (GC) patients and also the effects of SNHG15-miRNA-mRNA network in GC pathobiology. The expression level of SNHG15 in GC tissues and adjacent normal tissues (ANTs) was evaluated by qRT-PCR and also considered in relation to clinicopathologic factors. The ROC curve was explored to consider the specificity and sensitivity of SNHG15. Gene ontology functional annotation and KEGG pathway analysis were performed in order to predict the effects of SNHG15-miRNA-mRNA network in GC pathobiology. SNHG15 was overexpressed in GC tissues compared to ANTs (fold change= 3.87 and P-value = 0.0022). The SNHG15 expression level was not significantly associated with clinicopathologic factors. ROC curve indicated the specificity of 63.51 and sensitivity of 79.73 and the AUC of 0.744 (P-value < 0.0001). Further gene network analysis revealed that SNHG15 interacts with has-miR-613, has-miR-542-3p, and has-miR-1236-3p, and may be involved in the GC pathobiology by affecting the EGFR tyrosine kinase inhibitor resistance, HIF-1 signaling pathway, and VEGF signaling pathway. It can be concluded that SNHG15 may be a diagnostic factor in GC and may contribute in a variety of cancer-related signaling pathways.</p

Relationship of Helicobacter pylori vacA i1 and i2 alleles with gastric cancer risk, Iran: brief report

Background: Helicobacter pylori vacA (vacuolating toxin A) gene is comprised of mid- (m), intermediate- (i) and signal-regions. Recently, the vacA-i region genotype has been suggested to be a better predictor of disease severity than either the s- or m-region. The main aim of the present study was to determine the associations of i region poly-morphisms of vacA gene with gastric cancer (GC) and peptic ulcer disease (PUD) in Azerbaijan Province patients. Methods: A number of 89 patients were enrolled. The biopsy samples were taken from patients referring to the endoscopy units of Imam Reza and Shahid Madani Hospitals, Tabriz, Iran from August 2012 to May 2013. The genotype frequencies of vacA-i1 and i2 in were studied using polymerase chain reaction (PCR). Results: The frequency of vacA-i1 and i2 was 51.68% and 48.31%, respectively. The genotypic frequency of vacA-i1 in patients with GC (21/24, 87.5%) was significantly higher than in those with non-atrophic gastritis, NAG (19/48, 39.58%). In contrast, the genotypic frequency of vacA-i2 in patients with NAG, PUD, and GC was 60.42%, 64.70%, and 14.28%, respectively. The results of multiple linear and logistic regression analyses confirmed the intensity of correlation of vacA-i1 allele with GC compared with control group (NAG). No significant correlation was found between the vacA-i-region alleles and PUD risk. Conclusion: We have proposed that the H. pylori vacA-i1 genotype could be an im-portant biomarker for predicting the gastric cancer risk in Azerbaijan Province in Iran. However, due to the difference in the allelic frequency of this gene in H. pylori strains from different parts of the world, the vacA-i1 genotype usefulness in predicting the gas-trointestinal diseases is dependent to the geographic origin of the strains