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Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates.

ABSTRACT: Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as Helicobacter pylori, which causes gastric cancer. We conducted a small-sample GWAS (125 gastric cancer cases and 115 controls) followed by prediction of gastric cancer and control (duodenal ulcer) H. pylori strains. We identified 11 single nucleotide polymorphisms (eight amino acid changes) and three DNA motifs that, combined, allowed effective disease discrimination. They were often informative of the underlying molecular mechanisms, such as electric charge alteration at the ligand-binding pocket, alteration in subunit interaction, and mode-switching of DNA methylation. We also identified three novel virulence factors/oncoprotein candidates. These results provide both defined targets for further informatic and experimental analyses to gain insights into gastric cancer pathogenesis and a basis for identifying a set of biomarkers for distinguishing these H. pylori-related diseases.

SUBMITTER: Tuan VP

PROVIDER: S-EPMC8743543 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Genome-wide association study of gastric cancer- and duodenal ulcer-derived <i>Helicobacter pylori</i> strains reveals discriminatory genetic variations and novel oncoprotein candidates.

Tuan Vo Phuoc VP Yahara Koji K Dung Ho Dang Quy HDQ Binh Tran Thanh TT Huu Tung Pham P Tri Tran Dinh TD Thuan Ngo Phuong Minh NPM Khien Vu Van VV Trang Tran Thi Huyen TTH Phuc Bui Hoang BH Tshibangu-Kabamba Evariste E Matsumoto Takashi T Akada Junko J Suzuki Rumiko R Okimoto Tadayoshi T Kodama Masaaki M Murakami Kazunari K Yano Hirokazu H Fukuyo Masaki M Takahashi Noriko N Kato Mototsugu M Nishiumi Shin S Azuma Takashi T Ogura Yoshitoshi Y Hayashi Tetsuya T Toyoda Atsushi A Kobayashi Ichizo I Yamaoka Yoshio Y

Microbial genomics 20211101 11

Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as <i>Helicobacter pylori</i>, which causes gastric cancer. We conducted a small-sample GWAS (125 gastric cancer cases and 115 controls) followed by prediction of gastric cancer and control (duodenal ul ...[more]

PMID: 34846284

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Project description:BackgroundHelicobacter pylori (H. pylori) represents a key factor in the etiology of autoimmune atrophic gastritis (AAG), duodenal ulcer (DU) and gastric cancer (GC). The aim of this study was to characterize the differential protein expression of H. pylori isolated from gastric biopsies of patients affected by either AAG, DU or GC.MethodsThe H. pylori strains were isolated from endoscopic biopsies from the stomach of patients with gastric disease. Protein profiles of H. pylori were compared by two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) for the identification of significantly different spots (Student t-test, p < 0.05).ResultsA total of 47 differentially expressed spots were found between H. pylori isolated from patients with either DU or AAG diseases and those isolated from patients with GC (Anova < 0.05, log fold change >1.5). These spots corresponded to 35 unique proteins. The identity of 7 protein spots was validated after one-dimensional electrophoresis and MS/MS analyses of excised gel portions. In H. pylori isolated from DU-patients a significant increase in proteins with antioxidant activity emerged (AroQ, AspA, FldA, Icd, OorA and ScoB), together with a higher content of proteins counteracting the high acid environment (KatA and NapA). In H. pylori isolated from AAG-patients proteins neutralizing hydrogen concentrations through organic substance metabolic processes decreased (GroL, TrxB and Tuf). In addition, a reduction of bacterial motility (FlhA) was found to be associated with AAG-H. pylori isolates. In GC-H. pylori strains it was found an increase in nucleic acid-binding proteins (e.g. DnaG, Tuf, RpoA, RplU) which may be involved in a higher demand of DNA- and protein-related processes.ConclusionOur data suggest the presence of specific protein signatures discriminating among H. pylori isolated from either AAG, DU or GC. Changes in protein expression profiles evaluated by DIGE succeeded in deciphering part of the molecular scenarios associated with the different H. pylori-related gastric diseases.

Project description:BackgroundHelicobacter pylori (H. pylori) infection is the main cause of chronic gastritis and duodenal ulcer in children. Little is known about the effect of H. pylori on gastric microbiota in children with duodenal ulcer. This study is aimed at the characteristics of gastric microbiota in children with duodenal ulcer on H. pylori infection.MethodsWe studied 23 children diagnosed with duodenal ulcer by gastric endoscopy because of the gastrointestinal symptoms, 15 children were diagnosed with H. pylori infection, while 8 children were without H. pylori infection. Endoscopic mucosal biopsy samples were obtained for DNA extraction. Microbiomes were analyzed by 16S rRNA profiling and microbial functions were predicted using the software Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt).ResultsBacterial richness and diversity of gastric microbiota in duodenal ulcer with H. pylori-positive were lower than those negative. The gastric microbiota in H. pylori-positive group significantly reduced proportions of six phyla and fifteen genera; only Helicobacter taxa were more abundant in H. pylori-positive group. Co-expression network analysis showed a more complex network of interactions in the H. pylori-positive group than that in the H. pylori-negative group. For the predicted functions, lower abundance in the pathways of carbohydrate metabolism, signal transduction, amino acid metabolism, and lipid metabolism were found in H. pylori-positive group than the H. pylori-negative group. H. pylori colonization reduces a microbial community with genotoxic potential in the gastric mucosa of children with duodenal ulcer.ConclusionsThe presence of H. pylori significantly influences gastric microbiota and results in a lower abundance of multiple taxonomic levels in children with duodenal ulcer. Children with duodenal ulcer exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of children with H. pylori infection.Clinical trial registration[http://www.chictr.org.cn], identifier [ChiCTR1800015190].

Dataset Information

Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates.

Publications

Genome-wide association study of gastric cancer- and duodenal ulcer-derived <i>Helicobacter pylori</i> strains reveals discriminatory genetic variations and novel oncoprotein candidates.

Similar Datasets

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